Di-n-butyl Phosphate Research Articles

Effects of Urinary Organophosphate Flame Retardants in Susceptibility to Attention-Deficit/Hyperactivity Disorder in School-age Children

Our previous studies have revealed a correlation between urinary phthalates (PAE) metabolites and parabens and PM2.5 exposure and susceptibility to attention-deficit/hyperactivity disorder (ADHD) in school-age children. Our goal was to examine the relationships between urinary organophosphate flame retardants (OPFRs) and their metabolites and the susceptibility to ADHD in the same cohort of children. We recruited 186 school children, including 132 with ADHD and 54 normal controls, living in southern Taiwan to investigate five OPFRs (1,3-dichloro-2-propyl phosphate (TDCPP), tri-n-butyl phosphate (TnBP), tris (2-chloroethyl) phosphate (TCEP), tris(2-butoxyethyl) phosphate (TBEP), and triphenyl phosphate (TPHP)) and five OPFR metabolites (bis(1,3-dichloro-2-propyl) phosphate (BDCPP), di-n-butyl phosphate (DNBP), bis(2-chloroethyl) hydrogen phosphate (BCEP), di-(2-butoxyethyl) phosphate (DBEP), and diphenyl phosphate (DPHP)) in urine. ADHD patients’ behavioral symptoms and neuropsychological function were assessed using the Swanson, Nolan, and Pelham Version IV Scale (SNAP-IV) and the Conners’ Continuous Performance Test 3rd Edition (Conners CPT3), respectively. BCEP was predominant among urinary OPFRs and the metabolites in both the ADHD and control groups. ADHD children had significantly higher levels of urinary BDCPP, BCEP, DBEP, DPHP, TCEP, TBEP, TNBP, TPHP, and Σ10OPFR compared to the controls. After controlling for age, gender, body mass index, PM2.5 exposure scenarios, and urinary phthalate metabolites, parabens, bisphenol-A and creatinine, levels of urinary BDCPP, TDCPP, and TBEP in ADHD children showed significant and dose-dependent effects on core behavioral symptoms of inattention. DNBP levels were positively correlated with neuropsychological deficits (CPT detectability, omission, and commission), while urinary DPHP in ADHD children were negatively related to CPT detectability and commission. Hyperactivity and impulsivity were not correlated with urinary OPFRs and their metabolites in ADHD children. In conclusion, the ADHD symptom of inattention and CPT performance may be closely associated with certain urinary OPFRs and their metabolites, independent of urinary PAE metabolites, parabens, and bisphenol-A in school-age-ADHD children.

Gestational organophosphate esters (OPEs) and executive function in adolescence: The HOME Study

BackgroundEvidence from toxicological studies indicate organophosphate esters (OPEs) are neurotoxic, but few epidemiological studies investigated associations between gestational OPEs and executive function. ObjectiveTo examine the associations between gestational concentrations of OPE urinary metabolites and executive function at 12 years MethodsWe used data from 223 mother-adolescent dyads from the Health Outcomes of Measures of the Environment (HOME) Study. Women provided spot urine samples at 16 weeks gestation, 26 weeks gestation, and at delivery for quantification of bis(1,3-dichloro-2-propyl) phosphate, bis-2-chloroethyl phosphate (BCEP), diphenyl phosphate (DPHP), and di-n-butyl phosphate (DNBP). Executive function was assessed at age 12 years using the parent- and self-report Behavior Rating Inventory of Executive Function (BRIEF2). Covariate-adjusted associations between specific gravity-corrected OPEs and BRIEF2 scores were estimated using multiple informant models. Bayesian Kernel Machine Regression (BKMR) was used to assess the impact of all OPEs simultaneously. ResultsParent- and self-report BRIEF2 indices and composite scores were weakly to moderately correlated (rs=0.32-0.41). A natural-log unit increase in BCEP at 26 weeks was associated with approximately a 1-point increase on the self-report Cognitive Regulation Index [CRI] (95% CI 0.4, 2.3), the Emotion Regulation Index [ERI] (95% CI 0.3, 2.2), and the Global Executive Composite [GEC] (95% CI 0.4, 2.2), indicating poorer performance. Higher DPHP at 16 weeks was associated with lower parent-report GEC score (β=-1.1, 95% CI -2.3, -0.003). BKMR identified BCEP and DNBP at 26 weeks as important contributors to CRI and ERI, respectively. ConclusionOPE metabolites during gestational development, particularly BCEP, may influence adolescent executive function. However, since the FDR p-values failed to reach statistical significance, additional studies would benefit from using larger cohorts.

Construction of Dopamine Hydrochloride Liquid Selective Electrodes

Three liquid selective electrodes were synthesized based on particle pair to selective dopamine chloride. The construction electrodes consist of phosphomolybdicacid (dopamine), di-n-butyl phosphate, Di-n-butyl phthalate, and di-octylphenyl phosphonate as plasticizers materials. The construction of preparing probes was examined potentially with successes Nernstain response around 52.50 and 50. 50 mV/decade for electrodes on both DBPH and DOPH were as plasticizers, respectively. The most direct ranges concentrations of dopamine in drug form were found to be around 2.5×10-5-1.0×10-2 for DBPH and 4.30×10-5 -1.0×10-1 M for DOPH. The detection limits were reached to 2.31×10-6 in DBPH and 5. 63×10-6 M in DOPH electrode type. While third electrode relied on di-n-butyl phosphate (DPH), a non-Nernstain equivalent of around 19.10 mV/decade with a range of concentration about 2.2×10-5 -1.0×10-1 with a detection limit equivalent to 6.35×10-6. The pH values in the experimental application were asses to obtain the best determination of dopamine concentration at 10-3M. The optimisation of both electrodes DBPH and DOPH achieved good agreements to lifetime, selectivity, potentiometric techniques and accuracy of measurements. At the same time the standard expansion, various standard expansions and potentiometric titration result in an immediate strategy for the assurance of dopamine in drug form.

B-189 Evaluate the suitability of urinary reference intervals for organophosphate flame retardants in healthy adult population from Southern Taiwan

Abstract Background Organophosphorus flame retardants (OPFRs) are chemical additives used to prevent fires and are widely used in furniture, electronics, plastics, and building materials. Its chemical structure is similar to human hormones, which are often misidentified and used in the human body, thereby interfering with the operation of normal physiological functions and causing endocrine system disorders, so it is also known as environmental hormones. Recently, it has been confirmed that exposure to OPFRs can cause health hazards such as neurotoxicity, endocrine disruption, hepatotoxicity, and reproductive dysfunction. In view of the increasing concern about the exposure of human OPFRs, but there is no laboratory in Taiwan to detect the content of human OPFRs. This study aims to develop a biomonitoring method for OPFRs, which is used to provide reliable information on the exposure status of individual OPFRs, and to establish a reference interval for OPFRs in the urine of different diseases and reference groups and confirm the potential of OPFRs as biomarkers in environmental medicine. Methods The Waters ACQUITY UPLC I-Class and Xevo TQ-XS IVD systems were developed to detect 10 OPFRs in urine: Tri-(n-butyl) phosphate (TNBP), Tris-(2-butoxyethyl) phosphate (TBEP), Tris-(1,3- dichloro-2-propyl) phosphate (TDCPP), Triphenyl phosphate (TPHP), Tris-(2-chloroethyl) phosphate (TCEP), Di-n-butylphosphate (DNBP), Bis-(butoxyethyl)-Phosphate (DBEP), Bis-(1,3-dichloro-2-propyl) phosphate (BDCPP), Diphenyl phosphate (DPHP), Bis (2-chloroethyl) phosphate (BCEP), and analytical methods. According to the CLSI C62A specifications, the methodology verification and confirmation passed the evaluation. A total of 538 patients (78 infertility, 167 hemodialysis, 96 esophageal cancer, 99 lung cancer and 98 endometrial cancer) and 175 reference groups were tested for urine samples. The ANOVA analysis was used to compare the differences in the content of 10 OPFRs compounds in the urine of subjects of different ethnic groups. ROC curve analysis was used to determine the best decision value of whether the disease was present, and Chi-square verification was used to conduct disease risk assessment and verify the feasibility of the set reference value. Results The BCEP (6.23 ± 2.19 ng/mL) of most patients with hemodialysis, lung cancer and esophageal cancer was significantly higher than the reference group (0.89 ± 0.38 ng/mL). Patients with gynecological diseases had a higher BDCPP (4.29 ± 1.97 ng/mL) than the reference population (0.76 ± 0.32 ng/mL), which was consistent with the conclusions of previous animal experiments. Since it is not easy to explain the direct correlation between OPFRs and the disease. We decided to sum the detection values of 10 OPFRs. We found that their sum was greater than 2.05 ng/mL. The risk of infertility was 37.8 (95% CI: 11.07–129.14), the risk value of esophageal cancer was 83.3 (95% CI: 25.25–274.85) and the risk value of severe chronic kidney disease was 56.7 (95% CI: 17.49–183.97). Conclusion Due to the different types of OPFRs used in different countries, it is impossible to directly apply the reference values of other countries to their own people. So we develop the OPFRs detect method and verify the reference values through a series of analysis and discussion. Which will help us further understand the association between these environmental hormones and diseases.

Organophosphate diesters (DAPs) and hydroxylated organophosphate flame retardants (HO-OPFRs) as biomarkers of OPFR contamination in a typical freshwater food chain

Organophosphate flame retardants (OPFRs) can rapidly biotransform into two types of metabolites in biota: (1) organophosphate diesters (DAPs) and (2) hydroxylated OPFRs (HO-OPFRs). Therefore, the levels of parent OPFRs alone are not sufficient to indicate OPFR pollution in biological organisms. This study analyzed 12 OPFR metabolites, including 6 DAPs and 6 HO-OPFRs, in a typical freshwater food chain consisted of crucian carp, catfish, mud carp, snakehead, and oriental river prawn. The total concentrations of OPFR metabolites were comparable to those of parent OPFRs, and ranged from 0.65 to 17 ng/g ww. Bis(2-butoxyethyl) 3′-hydroxy-2-butoxyethyl phosphate (14%–77%), di-n-butyl phosphate (DNBP) (6.7%–24%), bis(1-chloro-2-propyl) phosphate (BCIPP) (0.7%–35%), and 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP) (6.0%–24%) were the major OPFR metabolites. Various aquatic species exhibited significant differences in their OPFR metabolite/parent ratios (MPR) (p < 0.05), indicating varying biotransformation potentials of different organisms for various OPFRs. The growth-independent accumulation of tri-n-butyl phosphate (TNBP), tris(chloro-2-propyl) phosphate (TCIPP), triphenyl phosphate, and 2-ethylhexyl diphenyl phosphate in mud carps could be explained by their biotransformation potential. A significant negative correlation was found between the concentration of bis(2-butoxyethyl) phosphate and δ15N values (p < 0.05), with a calculated trophic magnification factor (TMF) of 0.66. Significant positive correlations were observed between BCIPP and TCIPP (R2 = 0.25, p < 0.05), as well as between DNBP and TNBP (R2 = 0.30, p < 0.01), implying that these two DAPs could be used as biomarkers to quantitatively assess TCIPP and TNBP contamination in wild aquatic organisms.

Prenatal organophosphate ester exposure and executive function in Norwegian preschoolers.

We selected 340 preschoolers from the Norwegian Mother, Father, and Child Cohort Study. Diphenyl-phosphate (DPhP), di-n-butyl-phosphate (DnBP), bis(2-butoxyethyl) phosphate (BBOEP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) were measured in maternal urine. EF was measured using the Behavior Rating Inventory of Executive Functioning-Preschool (BRIEF-P) and the Stanford-Binet fifth edition (SB-5). EF scores were scaled so a higher score indicated worse performance. We estimated exposure-outcome associations and evaluated modification by child sex using linear regression. Higher DnBP was associated with lower EF scores across multiple rater-based domains. Higher DPhP and BDCIPP were associated with lower SB-5 verbal working memory (β = 0.49, 95% CI = 0.12, 0.87; β = 0.53, 95% CI = 0.08, 1.02), and higher BBOEP was associated with lower teacher-rated inhibition (β = 0.34, 95% CI = 0.01, 0.63). DPhP was associated with lower parent-reported BRIEF-P measures in boys but not girls [inhibition: boys: 0.37 (95% CI = 0.03, 0.93); girls: -0.48 (95% CI = -1.27, 0.19); emotional control: boys: 0.44 (95% CI = -0.13, 1.26); girls: -0.83 (95% CI = -1.73, -0.00); working memory: boys: 0.49 (95% CI = 0.03, 1.08); girls: -0.40 (95% CI = -1.11, 0.36)]. Fewer sex interactions were observed for DnBP, BBOEP, and BDCIPP, with irregular patterns observed across EF domains. We found some evidence prenatal OPE exposure may impact EF in preschoolers and variation in associations by sex.

Exposures to Organophosphate Esters and Respiratory Morbidity among School-Aged Children with Asthma.

Organophosphate esters (OPEs) are an emerging class of chemicals used in a variety of consumer products as flame retardants, plasticizers, and additives. While prior epidemiologic studies suggest that OPEs may impact respiratory health, results remain inconclusive. We examined associations between urinary biomarkers of OPEs and symptoms of respiratory morbidity in a panel study of 147 predominantly Black school-aged children with asthma living in Baltimore City, Maryland. The study consisted of up to four seasonal, week-long, in-home visits where urine samples and self-reported asthma symptoms were collected on days 4 and 7 (nsamples = 438). We quantified concentrations of nine urinary OPE biomarkers: bis(2-chloroethyl) phosphate (BCEtp), bis(1-chloro-2-propyl) phosphate (BCPP), bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), di-n-butyl phosphate (DBuP), di-benzyl phosphate (DBzP), di-o-cresylphosphate (DOCP), di-p-cresylphosphate (DPCP), di-(2-propylheptyl) phthalate (DPHP), and 2,3,4,5-tetrabromo benzoic acid (TBBA). We estimated prevalence odds ratios (POR) of respiratory morbidity symptoms using logistic regression with generalized estimating equations to account for our repeated measure design. We assessed BDCIPP and DPHP as continuous (log2) concentrations and dichotomized exposure of BCEtP, DBuP, and DPCP (detect vs non-detect) based on their lower detection frequencies. We adjusted models for season, visit day, age, gender, caregiver education, health insurance type, exposure to household smoking, atopy, and PM2.5. Higher DPHP concentrations were significantly associated with odds of daytime symptoms (POR: 1.26; 95% CI: 1.04-1.53; p = 0.02) where daytime symptoms consisted of trouble breathing due to asthma, reporting bother caused by asthma, and/or limitation in activities due to asthma. DBuP detection was associated with use of rescue medication on the day of sample collection (POR: 2.36; 95% CI: 1.05-5.29; p = 0.04). We also observed several consistent, albeit non-significant (p > 0.05), positive associations for BCEtP and DPCP and respiratory morbidity measures. This is the first study to evaluate the relationship between OPE biomarkers and respiratory morbidity symptoms in children with asthma, and findings suggest that further studies are warranted to confirm whether these associations are causal.

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

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. 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<limit of detection (LOD) (BBOEP N=386, BDCIPP N=632), ≥LOD but<limit of quantification (LOQ) (BBOEP N=413; BDCIPP N=75), or above LOQ (BBOEP N=70; BDCIPP N=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. 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≥LOD but<LOQ had 1.39 times the odds of having a child with ADHD compared to those with BDCIPP<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=0.01]. We found modest increased odds of preschool ADHD with higher DnBP and BDCIPP exposure.

Bioaccumulation and Trophic Transfer of Organophosphate Flame Retardants and Their Metabolites in the Estuarine Food Web of the Pearl River, China.

The accumulation and trophodynamics of organophosphate flame retardants (OPFRs) and their metabolites were investigated in the estuarine food web of the Pearl River, China. The mean ∑OPFR concentration among the investigated species increased in the following order: fish [431 ± 346 ng/g lipid weight (lw)] < snail (1310 ± 621 ng/g lw) < shrimp (1581 ± 1134 ng/g lw) < crab (1744 ± 1397 ng/g lw). The di-alkyl phosphates (DAPs) of di-(n-butyl) phosphate (DNBP), bis(2-butoxyethyl) phosphate (BBOEP), and diphenyl phosphate (DPHP) were the most abundant metabolites, with concentrations same as or even higher than their corresponding parent compounds. The log bioaccumulation factors for most OPFRs were lower than 3.70, and significant biomagnification was only found for trisphenyl phosphate [TPHP, with the trophic magnification factors (TMFs) > 1]. The TMFs of OPFRs, except for TPHP and tributyl phosphate had a positive correlation with lipophilicity (log KOW, p ≤ 0.05) and a negative correlation with the biotransformation rate (log KM, p ≤ 0.05). The mean TMF > 1 was observed for all of the OPFR metabolites based on the bootstrap regression method. The "pseudo-biomagnification" of OPFR metabolites might be attributed to the biotransformation of OPFRs in organisms at high trophic levels.

Determination of organophosphate diesters in facility vegetable soils using ultra-high performance liquid chromatography-electrostatic field orbitrap high resolution mass spectrometry

Organophosphate diesters (Di-OPEs) are biotic or abiotic degradation products of organophosphate esters (OPEs). Current analytical methods focus on detecting Di-OPEs in human urine. Human exposure to Di-OPEs in environmental matrices has not been systematically studied. Soil plays an important role in the environmental migration and transformation of organic pollutants. Previous studies found that OPEs are ubiquitous in soil. However, few studies reported OPEs metabolite pollution in soil, especially in facility vegetable soil. In this study, an ultra-high performance liquid chromatography-electrostatic field orbitrap high resolution mass spectrometry (UPHLC-Orbitrap HRMS) method was developed for the determination of five Di-OPEs (bis(2-chloroethyl) phosphate (BCEP), bis(1,3-dichloro-2-propyl) phosphate (BDCP), di-n-butyl phosphate (DnBP), diphenyl phosphate (DPhP), and bis(2-ethylhexyl) phosphate (DEHP)) in the facility vegetable soil. The pretreatment process and chromatographic and mass spectrometric conditions were optimized in the present study. Comparative study of the purification effects of different solid-phase extraction columns showed that Oasis WAX cartridge had best purification efficiency for the five Di-OPEs. The cartridge was first activated using 3 mL methanol, 3 mL methanol containing 5% (v/v) ammonia, and 3 mL 0.1 mol/L sodium acetate-acetic acid buffer solution. Then, the cartridge was rinsed with 3 mL of 30% (v/v) methanol aqueous solution, and finally eluted using 8 mL methanol containing 5% (v/v) ammonia. The effects of mobile phase (with respect to solvent composition and flow rate) and column temperature on the shape and intensity of chromatographic peaks were studied. The optimized UHPLC conditions were as follows: chromatographic column, Thermo Accucore RP-MS; column temperature, 30 ℃; mobile phase, 0.2 mmol/L ammonium acetate aqueous solution and methanol; flow rate, 0.2 mL/min. In the UHPLC-Orbitrap HRMS experiment, the five Di-OPEs were analyzed in full MS mode with negative ionization. Instrumental parameters, such as sheath gas and auxiliary gas, were optimized to determine the MS conditions. The optimized Orbitrap HRMS conditions were as follows: heating electrospray ionization source (HESI), full MS mode with negative ionization; scan range, m/z 100-500; ion transfer tube temperature, 320 ℃; automatic gain control of target particle count, 1×106; sheath gas flow rate, 8.58 L/min; auxiliary gas flow rate, 17.40 L/min; spray voltage, 3.2 kV; and S-lens voltage, 50 V. The limits of detection and quantification were 0.001-0.047 ng/g and 0.004-0.156 ng/g, respectively. The correlation coefficients of the calibration curve were 0.9985-0.9999. At three spiked levels, 5.0, 25.0, and 50.0 ng/g, the recoveries of the five Di-OPEs ranged from 56.9% to 133.0% with relative standard deviations of 4.4%-18.9%. The established method was applied to the analysis of the five Di-OPEs in 16 facility vegetable soils. The detection frequencies of the five Di-OPEs exceeded 60% in all soil samples, indicating that the Di-OPEs were ubiquitous in the facility vegetable soil. The contents of the five Di-OPEs in the facility vegetable soil samples ranged from 2.53-6.94 ng/g. DnBP (1.37-3.20 ng/g) and DPhP (0.47-2.44 ng/g) were the predominant congeners in the facility vegetable soil samples, accounting for 23.4%-68.8% and 16.3%-35.9% of the five Di-OPEs, respectively. The developed method is simple, sensitive, and reproducible and can be used effectively for the determination of Di-OPEs in soil. The results of this study will be helpful for understanding the environmental behavior of Di-OPEs and their human exposure in facility vegetable soils.

Gestational exposure to organophosphate esters and infant anthropometric measures in the first 4 weeks after birth.

Few studies have examined whether gestational exposure to organophosphate esters (OPEs), widely used chemicals with potential endocrine-disrupting potency and developmental toxicity, is associated with impaired infant growth. We analyzed data from 329 mother-infant pairs in the Health Outcomes and Measures of the Environment (HOME) Study (2003-2006, Cincinnati, Ohio, USA). We quantified concentrations of four OPE metabolites in maternal urine collected at 16 and 26 weeks of gestation, and at delivery. We calculated z-scores using 2006 World Health Organization (WHO) child growth standards for the 4-week anthropometric measures (weight, length, and head circumference), the ponderal index, and weekly growth rates. We used multiple informant models to examine window-specific associations between individual OPE metabolites and anthropometric outcomes. We further modeled OPEs as a mixture for window-specific associations with 4-week anthropometric outcomes using mean field variational Bayesian inference procedure for lagged kernel machine regression (MFVB-LKMR). We stratified the models by infant sex. Diphenyl phosphate (DPHP) in mothers at 16 weeks, and bis(2-chloroethyl) phosphate (BCEP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) at delivery were positively associated with z-scores of weight, length, and head circumference in all infants at 4 weeks of age. After stratifying by infant sex, positive associations were only observed in males for DPHP at 16 weeks and BCEP at delivery and in females for BDCIPP at delivery. Negative associations not present in all infants were observed in males for di-n-butyl phosphate (DNBP) at 26 weeks of gestation with weight z-score and DPHP at delivery with head circumference z-score. Results were generally similar using MFVB-LKMR models with more conservative 95 % credible intervals. We did not identify consistent associations of gestational OPE metabolite concentrations with the ponderal index and weekly growth rates. In this cohort, exposure to OPEs during gestation was associated with altered infant anthropometry at 4 weeks after birth.

Exploratory analysis of the association between organophosphate ester mixtures with high blood pressure of children and adolescents aged 8-17years: cross-sectional findings from the National Health and Nutrition Examination Survey.

Epidemiological studies on the effect of organophosphate esters (OPEs) on high blood pressure (BP) among children and adolescents are scant. Therefore, the main objective of the present study was to explore the effect of exposure to OPEs on high BP among children and adolescents. A total of 1340 participants were included in the current analyses. Multivariable logistic regression models were implemented to calculate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) to examine the association between OPE metabolites and high BP. We also assessed the modified effect of sex, age, and overweight/obesity on this association. Furthermore, quantile g-computation (Qgcomp) and Bayesian kernel machine regression (BKMR) were exhibited to analyze the association between multiple OPE metabolite mixtures and high BP. After adjusting for covariates, the highest (vs. lowest) tertiles of bis (1-choloro-2-propyl) phosphate (BCPP), bis-2-chloroethyl phosphate (BCEP), and di-n-butyl phosphate (DBUP) were associated with 1.23 (95% CI: 0.83, 1.83), 1.27 (95% CI: 0.85, 1.92), and 1.01 (95% CI: 0.67, 1.53) odds ratios for high BP, respectively. In the Qgcomp, a quartile increase in OPE metabolite mixtures was weakly associated with an elevated risk of high BP (adjusted OR: 1.06, 95CI%: 0.81, 1.37). The results from BKMR showed a positive trend of association between OPE metabolite mixture on the risk of high BP. In conclusion, our study demonstrated that higher levels of BCPP, BCEP, and DBUP were weakly associated with high BP among US children and adolescents. Moderate evidence suggested OPE metabolite mixtures had positive joint effects on high BP. Consequently, longitudinal studies with repeated measurements are warranted to examine the relationships between multiple OPE metabolites and high blood pressure among children and adolescents.

Early life organophosphate ester exposures and bone health at age 12 years: The Health Outcomes and Measures of the Environment (HOME) Study

BackgroundNo human studies have evaluated early life organophosphate ester (OPE) exposures with bone health outcomes, despite evidence of osteotoxicity. ObjectivesWe assessed associations of urinary OPE metabolites measured across early life with areal bone mineral density (aBMD) and bone mineral content (BMC) at age 12 years. MethodsAmong 223 mother-child dyads enrolled in the Health Outcomes and Measures of the Environment (HOME) Study, we quantified concentrations of bis-2-chloroethyl phosphate (BCEP), bis-(1,3-dichloro-2-propyl) (BDCIPP), di-n-butyl phosphate (DnBP), and diphenyl phosphate (DPHP) in urine collected from mothers during pregnancy and children at ages 1, 2, 3, 5, and 8 years. At age 12 years, we performed dual energy x-ray absorptiometry and calculated aBMD and BMC z-scores at six skeletal sites. We estimated overall and sex-stratified BMD/BMC z-score differences per interquartile range (IQR) increase in OPE concentrations at multiple exposure timepoints: gestation (average) and 1–3 (average), 5, and 8 years. ResultsIn adjusted models, overall associations of BCEP and BDCIPP with total hip and 1/3rd distal radius aBMD and BMC varied significantly by exposure timepoint, as did BDCIPP with whole body aBMD. For example, differences (95 % CI) in total hip aBMD z-score per IQR increase in BDCIPP were 0.33 (0.01, 0.64), −0.10 (−0.34, 0.14), −0.18 (−0.40, 0.05), and 0.14 (−0.09, 0.38) for concentrations during gestation and at 1–3, 5, and 8 years, respectively. Overall DnBP and DPHP associations were generally null at all timepoints. We observed sex-specific associations for some timepoints and skeletal sites. For example, an IQR increase in 8-year DPHP was associated with a 0.21 (0.05, 0.38) greater total hip aBMD z-score among females but −0.19 (−0.43, 0.05) lower z-score among males. DiscussionEarly life OPE exposures may be associated with sex- and exposure period-dependent alterations in early adolescent bone mineral accrual and strength.

Human Exposure to Chlorinated Organophosphate Ester Flame Retardants and Plasticizers in an Industrial Area of Shenzhen, China.

Human exposure to organophosphate esters (OPEs) is more pervasive in industrial areas manufacturing OPE-related products. OPE exposure is of great concern due to its associations with adverse health effects, while studies on OPE exposure in industrial districts are scarce. This study aimed to assess human exposure to OPEs in a typical industrial area producing large amounts of OPE-related products in Shenzhen, China. Tris (2-chloroethyl)-phosphate (TCEP), tris (2-chloroisopropyl) phosphate (TCPP) and other common OPEs were analyzed in urine (n = 30) and plasma (n = 21) samples. Moreover, we measured five OPE metabolites (mOPEs) in plasma samples (n = 21). The results show that TCPP and TCEP are dominant compounds, with moderate to high levels compared with those reported in urine and plasma samples from other regions. In addition, di-n-butyl phosphate (DnBP) and diethyl phosphite (DEP) were frequently detected in plasma samples and could be considered as biomarkers. Risk assessment revealed a moderate to high potential health risk from TCEP exposure. Our results provide basic data for human exposure to OPEs in industrial areas and call for the prevention and mitigation of industrial chlorinated OPE pollution.

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.

Prenatal exposure to a mixture of organophosphate esters and intelligence among 8-year-old children of the HOME Study

Many environmental chemicals are being identified as suspected neurotoxicants based on the findings of both experimental and epidemiological studies. Organophosphate esters (OPEs), which are among the chemicals that have replaced neurotoxic polybrominated diphenyl ethers (PBDEs) after 2004, have also become an important public health topic as evidence regarding their potential for early-life neurotoxicity is growing. In 233 mother child pairs from Cincinnati, OH, we measured concentrations of the OPE metabolites bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), bis-2-chloroethyl phosphate (BCEP), diphenyl phosphate (DPHP), and di-n-butyl phosphate (DNBP) in the urine of pregnant women at 16 and 26 weeks gestation and at delivery. At age 8 years, we assessed children’s cognition using the Wechsler Intelligence Scale for Children-IV. In models adjusted for maternal race, income, body mass index, and IQ, maternal urinary BCEP was associated with a modest increase in child full-scale IQ (ß: 0.81 per a ln-unit BCEP increase; 95 % CI: 0.00, 1.61) while other OPEs were not associated with changes in full-scale IQ or any IQ subscales. Maternal serum PBDE concentrations did not confound the relationships between urinary OPE metabolites and child IQ. Using Bayesian kernel machine regression, we did not find that concentrations of a mixture of OPE metabolites during gestation was associated with any child cognition measures. The results of this study are not consistent with other published work, and a larger sample size would be beneficial to explore potential associations more fully. Therefore, additional studies are necessary to continue studying prenatal OPE exposure and child neurodevelopment and behavior.

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

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

BackgroundOrganophosphate 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. ObjectiveTo 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). MethodsWe 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. ResultsDPHP 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]. ConclusionPrenatal 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.

Pregnancy exposure to common-detect organophosphate esters and phthalates and maternal thyroid function

BackgroundContemporary human populations are exposed to elevated concentrations of organophosphate esters (OPEs) and phthalates. Some metabolites have been linked with altered thyroid function, however, inconsistencies exist across thyroid function biomarkers. Research on OPEs is sparse, particularly during pregnancy, when maintaining normal thyroid function is critical to maternal and fetal health.In this paper, we aimed to characterize relationships between OPEs and phthalates exposure and maternal thyroid function during pregnancy, using a cross-sectional investigation of pregnant women nested within the Norwegian Mother, Father, and Child Cohort (MoBa). MethodsWe included 473 pregnant women, who were euthyroid and provided bio-samples at 17 weeks' gestation (2004–2008). Four OPE and six phthalate metabolites were measured from urine; six thyroid function biomarkers were estimated from blood. Relationships between thyroid function biomarkers and log-transformed concentrations of OPE and phthalate metabolites were characterized using two approaches that both accounted for confounding by co-exposures: co-pollutant adjusted general linear model (GLM) and Bayesian Kernal Machine Regression (BKMR). ResultsWe restricted our analysis to common-detect OPE and phthalate metabolites (>94%): diphenyl phosphate (DPHP), di-n-butyl phosphate (DNBP), and all phthalate metabolites. In GLM, pregnant women with summed di-isononyl phthalate metabolites (∑DiNP) concentrations in the 75th percentile had a 0.37 ng/μg lower total triiodothyronine (TT3): total thyroxine (TT4) ratio (95% credible interval: [−0.59, −0.15]) as compared to those in the 25th percentile, possibly due to small but diverging influences on TT3 (−1.99 ng/dL [−4.52, 0.53]) and TT4 (0.13 μg/dL [−0.01, 0.26]). Similar trends were observed for DNBP and inverse associations were observed for DPHP, monoethyl phthalate, mono-isobutyl phthalate, and mono-n-butyl phthalate. Most associations observed in co-pollutants adjusted GLMs were attenuated towards the null in BKMR, except for the case of ∑DiNP and TT3:TT4 ratio (−0.48 [−0.96, 0.003]). ConclusionsMaternal thyroid function varied modestly with ∑DiNP, whereas results for DPHP varied by the type of statistical models.

Organophosphate Esters and Their Metabolites in Breast Milk from the United States: Breastfeeding Is an Important Exposure Pathway for Infants

Organophosphate esters (OPEs) are among the synthetic chemicals found in the highest concentrations in the indoor environment due to their use as flame retardants and plasticizers. In fish and wildlife, metabolites of OPEs have been found to build up in tissues. In this study, 28 triester OPEs (tri-OPEs) and their seven corresponding diester (di-OPE) and three hydroxyl metabolites were measured in breast milk collected from 50 U.S. mothers. Tris(1-chloro-2-propyl) phosphate, used in foam for insulation and furniture and the target compound with the largest U.S. production volume, was the most abundant tri-OPE (median level of 1.47 ng/mL). Di-n-butyl phosphate (DNBP), the metabolite of tri-n-butyl phosphate (TNBP), which has broad uses in adhesives, plastics, and hydraulic fluids, was the most abundant OPE metabolite (median level of 7.44 ng/mL) detected in these samples. Overall, the Σdi-OPE concentrations (median level of 8.32 ng/mL) were twice as high as the Σtri-OPE concentrations (median of 3.85 ng/mL). The estimated daily intakes of tri- and di-OPEs through lactation were up to 50 times higher than those through diet and dust ingestion. This is the first study to simultaneously determine OPEs and their metabolites in breast milk, and our findings indicate that breastfeeding is a significant source of OPE exposure for infants.