Bis ( 2-butoxyethyl ) Phosphate Research Articles

Association between organophosphate esters individual and mixed exposure with the risk of hyperlipidemia and serum lipid levels among adults in Wuhan, China.

Toxicologic studies reported that organophosphate esters (OPEs) may disrupt lipid metabolism, thus affecting serum lipid levels. However, epidemiological evidence regarding the association between OPEs and the risk of hyperlipidemia (HPL) as well as serum lipid levels is scarce. In the present study, our aim was to investigate the impact of individual and mixed OPE exposure on HPL. A total of 1981 Chinese adults were involved based on a cross-sectional design. Overall, we found a positive association between bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and the risk of HPL. Bis(1-chloro-2-propyl) phosphate (BCIPHIPP) showed a positive association with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). BDCIPP, diphenyl phosphate (DPHP), di-ocresyl phosphate and di-p-cresyl phosphate (Docp&Dpcp), and 4-hydroxyphenyl-diphenyl phosphate (4-OH-DPHP) exhibited a negative association with high-density lipoprotein cholesterol (HDL-C). In stratified analyses, BDCIPP and BCIPHIPP were significantly correlated with the increased risk of HPL in the age ≤ 45 group. Bis(2-butoxyethyl) phosphate (BBOEP) was in relationship with an elevated risk of HPL in the subgroup of BMI < 24kg/m2. BDCIPP was also positively associated with HPL in men. Quantile-based g computation (qgcomp) and generalized weighted quantile sum regression (gWQS) models demonstrated a negative association between OPEs mixed exposure and HDL-c in the total population, as well as a positive effect of them on HPL in the subgroup of age ≤ 45years, which is consistent with the individual analyses. Furthermore, joint effect analyses revealed that participants with detected BDCIPP urinary levels and unhealthy lifestyles had the highest risk of HPL. Our findings offer evidence supporting the correlation between exposure to OPE and the risk of HPL, necessitating further prospective studies for validation.

Estimated daily intake and cumulative risk assessment of organophosphate esters and associations with DNA damage among e-waste workers in Hong Kong

Organophosphate esters (OPEs) are extensively used as additives in various products, including electronic equipment, which becomes e-waste when obsolete. Nevertheless, no study has evaluated OPEs exposure levels and the related health risks among e-waste workers in Hong Kong. Therefore, 201 first-spot morning urine samples were collected from 101 e-waste workers and 100 office workers to compare eight urinary OPE metabolites (mOPEs) levels in these groups. The concentrations of six mOPEs were similar in e-waste workers and office workers, except for significantly higher levels of diphenyl phosphate (DPHP) in e-waste workers and bis(1-chloro-2propyl) phosphate (BCIPP) in office workers. Spearman correlation analysis showed that most non-chlorinated mOPEs were correlated with each other in e-waste workers (i.e., nine out of ten pairs, including di-p-cresyl phosphate (DpCP) and di-o-cresyl phosphate (DoCP), DpCP and bis(2-butoxyethyl) phosphate (BBOEP), DpCP and DPHP, DpCP and dibutyl phosphate (DBP), DoCP and BBOEP, DoCP and DPHP, DoCP and DBP, BBOEP and DPHP, DPHP and DBP), indicating that handling e-waste could be the exposure source of specific OPEs. The median values of estimated daily intake (EDI) and hazard quotient (HQ) suggested that the health risks from OPEs exposures were under the recommended thresholds. However, linear regression models, Quantile g-computation, and Bayesian kernel machine regression found that urinary mOPEs elevated 8-hydroxy-2-deoxyguanosine (8-OhdG) levels individually or as a mixture, in which DPHP contributed prominently. In conclusion, although e-waste might not elevate the internal OPEs levels among the participating Hong Kong e-waste workers, attention should be paid to the potential DNA damage stimulated by OPEs under the currently recommended thresholds.

Trimester-specific effect of maternal co-exposure to organophosphate esters and phthalates on preschooler cognitive development: The moderating role of gestational vitamin D status

Organophosphate esters (OPEs) and phthalate acid esters (PAEs) are prevalent endocrine-disrupting chemicals (EDCs). Humans are often exposed to OPEs and PAEs simultaneously through multiple routes. Given that fetal stage is a critical period for neurodevelopment, it is necessary to know whether gestational co-exposure to OPEs and PAEs affects fetal neurodevelopment. However, accessible epidemiological studies are limited. The present study included 2, 120 pregnant women from the Ma'anshan Birth Cohort (MABC) study. The concentrations of tris (2-chloroethyl) phosphate (TCEP), 6 OPE metabolites and 7 PAE metabolites were measured in the first, second and third trimester using ultra-performance liquid chromatography-tandem mass spectrometry (LC-MS). Cognitive development of preschooler was assessed based on the Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition (WPPSI-IV) of the Chinese version. Generalized estimating equations (GEEs), restricted cubic spline (RCS) and generalized additive models (GAMs) were employed to explore the associations between individual OPE exposure and preschooler cognitive development. The quantile-based g-computation (QGC) method was used to estimate the joint effect of PAEs and OPEs exposure on cognitive development. GEEs revealed significant adverse associations between diphenyl phosphate (DPHP) (β: −0.58, 95% CI: −1.14, −0.01), bis (2-butoxyethyl) phosphate(BBOEP) (β: −0.44, 95% CI: −0.85, −0.02), bis(1-chloro-2-propyl) phosphate (BCIPP) (β: −0.81, 95%CI: −1.43, −0.20) and full-scale intelligence quotient (FSIQ) in the first trimester; additionally, TCEP and bis(2-ethylhexyl) phosphate (BEHP) in the second trimester, as well as DPHP in the third trimester, were negatively associated with cognitive development. Through the QGC analyses, mixture exposure in the first trimester was negatively associated with FSIQ scores (β: −1.70, 95% CI: −3.06, −0.34), mono-butyl phthalate (MBP), BCIPP, and DPHP might be the dominant contributors after controlling for other OPEs and PAEs congeners. Additionally, the effect of OPEs and PAEs mixture on cognitive development might be driven by vitamin D deficiency.

Determinants of organophosphate esters exposure in pregnant women from East China

Organophosphate esters (OPEs) have been broadly used in various industrial and consumer products, resulting in global distribution and human exposure. Gestational exposure to OPEs may adversely affect the health of both pregnant women and their offspring. To better understand OPE exposure in pregnant women, our study determined eight urinary metabolites of major OPEs in pregnant women (n = 733) recruited at 12–16 weeks of gestation from Shanghai, China, and explored the determinants of OPE exposure among various sociodemographic characteristics, lifestyles, and dietary factors. Urinary metabolites of OPEs, including bis (1,3-dichloro-2-propyl) phosphate (BDCPP), bis (2-chloroethyl) phosphate (BCEP), bis (1-chloro-2-propyl) phosphate (BCIPP), dicresyl phosphate (DCP), diphenyl phosphate (DPP), dibutyl phosphate (DBP), bis (2-ethylhexyl) phosphate (BEHP), and bis (2-butoxyethyl) phosphate (BBOEP), exhibited a detection rate ranging from 69.30% to 99.32%. Multivariate linear regression models indicated that pregnant women who were multiparous, had a higher family income per capita, worked in white-collar jobs, and took nutritional supplements such as milk powder and fish oil tended to have higher urinary OPE metabolite concentrations. Besides, independent of sociodemographic characteristics and lifestyle factors, consumption of more aquatic products, soy products, pork, and puffed food, as well as drinking of purified tap water versus tap water, were associated with increased urinary OPEs metabolite concentrations. Our study demonstrated that OPE exposure was ubiquitous in pregnant women from Shanghai, and provided new insights into the potential factors influencing OPE exposure during pregnancy.

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.

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.

Urinary concentrations of organophosphate esters in relation to semen quality: A cross-sectional study

Organophosphate esters (OPEs) are widely used as flame retardants and plasticizers in consumer products. Toxicological studies have indicated that OPEs may affect male reproductive health, but human evidence is inconclusive. In this study, we explored associations of individual and mixtures of OPE exposure with semen quality among 1015 Chinese men from an infertility clinic. After adjusting for potential confounders, we observed that higher diphenyl phosphate (DPHP) and [Bis(2-methylphenyl) phosphate (BMPP)] exposure was associated with increased odds ratios (ORs) of having below-reference total sperm count. Higher bis (2-butoxyethyl) phosphate (BBOEP) exposure was associated with increased ORs of having below-reference progressive motility and total motility. For semen quality parameters modeled as continuous outcomes, inverse associations with individual OPE were still observed. In addition, urinary 1-hydroxy-2-propyl bis (1-chloro-2-propyl) phosphate (BCIPHIPP) concentrations were inversely associated with the percentage of normal morphology while positively associated with the percentage of abnormal heads. Quantile g-computation regression analyses showed that exposure to higher OPE mixtures was associated with lower total sperm motility and normal morphology. Our results indicated that both individual and mixtures of OPE exposure were associated with reduced semen quality.

The associations between renal disease severity and exposure to organophosphate flame retardants in patients with chronic kidney disease

Organophosphate flame retardants (OPFRs) are emerging and widespread environmental pollutants with potential health hazards, including nephrotoxicity. However, the exposure patterns and nephrotoxic potential of OPFRs are yet to be investigated in patients with chronic kidney disease (CKD). We conducted a cross-sectional study involving 166 patients with CKD stratified by estimated glomerular filtration rate (eGFR) and severity of proteinuria. The urinary concentrations of 10 OPFR compounds were measured to evaluate the exposure patterns. Clinical and urinary OPFR profiles were compared among subgroups to identify whether the OPFR compounds were independently correlated with eGFR and proteinuria. Additionally, lifestyle factors were compared among subgroups stratified by median concentrations of urinary OPFR compounds associated with renal disease severity. This study revealed universal exposure to OPFRs in the CKD population, with an overall urinary detection rate of 98.80 %. Furthermore, after adjusting for covariates, the urinary concentration of bis(2-chloroethyl) phosphate (BCEP) was identified as an independent predictor of lower eGFR (low vs high eGFR, odds ratio (OR) (95 % confidence interval (CI)), 1.761 (1.032–3.005) per log μg/g creatinine, p = 0.038), and the urinary concentration of bis(2-butoxyethyl) phosphate (BBOEP) was independently correlated with overt proteinuria in CKD patients (with vs without overt proteinuria, OR (95 % CI), 1.813 (1.065–3.086) per log μg/g creatinine, p = 0.028). Moreover, frequent seafood consumption was negatively correlated with urinary BCEP concentration (high vs low BCEP, OR (95 % CI), 0.455 (0.228–0.908), p = 0.025), and age was inversely associated with urinary BBOEP concentration (high vs low BBOEP, OR (95 % CI), 0.968 (0.937–0.999) per year, p = 0.048). In conclusion, our investigation highlights the extensive exposure to OPFRs and the independent association between renal disease severity and urinary BCEP/BBOEP concentrations in the CKD population, indicating the nephrotoxic potential of these pollutants.

Prenatal exposure to organophosphate esters is associated with decreased anogenital distance in offspring

BackgroundEvidence from in vitro and rodent studies suggests that organophosphate esters (OPEs) may disrupt sex steroid hormone homeostasis, but no human studies, to date, have examined the effects of in utero exposure to OPEs on offspring reproductive development. ObjectiveAnogenital distance (AGD) is a sensitive biomarker of fetal hormonal milieu and has been used to assess reproductive toxicity. We evaluated the longitudinal effects of prenatal exposure to OPEs on the AGD of offspring from birth to 4 years. MethodsBased on Shanghai-Minhang Birth Cohort Study, pregnant women provided urine samples at a gestational age of 12–16 weeks, which were analyzed for eight OPE metabolites. AGD was measured in offspring at birth and 0.5, 1, and 4 years of age. We used generalized estimating equations (GEE) and Bayesian kernel machine regression (BKMR) models to estimate the associations of prenatal exposure to individual OPE metabolites and OPE mixtures with AGD stratified by sex. ResultsA total of 733 mother-infant pairs were analyzed. Prenatal exposure to diphenyl phosphate and bis-(2-ethylhexyl) phosphate was associated with decreased AGD in boys in GEE models. Bis-(1-chloro-2-propyl) phosphate (BCIPP) showed a similar but marginally significant effect. Prenatal exposure to most OPE metabolites was associated with decreased AGD in girls, with the most profound association observed for bis (2-butoxyethyl) phosphate (BBOEP) and alkyl-OPEs. The OPE mixture was also inversely associated with AGD in both sexes. The single-exposure effects of BKMR models were largely consistent with those observed in the GEE models. In addition, alkyl-OPEs, particularly BBOEP, contributed the most to the decreased AGD in girls, while BCIPP contributed the most to the decreased AGD in boys. ConclusionsThis study provides the first human evidence that prenatal exposure to OPEs is associated with decreased AGD in offspring. The magnitude of these effects may vary depending on the structure of OPEs.

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.

Association between organophosphorus flame retardants exposure and cognitive impairment among elderly population in southern China

The wide application of organophosphorus flame retardants (OPFRs) in consumer products leads to their ubiquitous occurrence. The neurotoxicity of OPFRs has been raised, whereas evidence from the elderly population were rather scarce. Hence, a case-control study was conducted based on the Shenzhen Aging-related Disorder Cohort. A total of 184 cases [Mini-mental State Examination (MMSE) < 24] and 795 participants as controls (MMSE ≥24) were recruited. Eight metabolites of OPFRs (m-OPFRs) in urine samples were measured, including bis(2-butoxyethyl) phosphate (BBOEP), bis(2-chloroethyl) phosphate (BCEP), bis(1-chloro-2-propyl) phosphate (BCIPP), bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), dibutyl phosphate (DBP), di-o-cresyl phosphate (DOCP), di-p-cresyl phosphate (DPCP) and diphenyl phosphate (DPHP). The detection frequencies of m-OPFRs ranged from 88.8 % to 95.4 %. BCEP had the highest median concentration (0.93 μg/L), followed by BCIPP (0.32 μg/L), DPHP (0.27 μg/L) and DBP (0.20 μg/L). Significant correlations were found between all pairs of urinary m-OPFRs with correlation coefficients ranging from 0.22 to 0.71 (p< 0.05). Logistic regression models showed that urinary concentrations of BDCIPP (adjusted odds ratio [OR]: 1.25, 95 % confidential interval [CI]: 1.04–1.50) and DBP (adjusted OR: 1.10, 95 % CI: 1.01–1.20) were positively associated with lower cognitive functions. Furthermore, a nonlinear dose-response relationship was found between urinary BDCIPP concentration and cognitive decline. To our knowledge, this is the first report on OPFR exposure and cognitive impairment among elderly population. Further toxicological tests of BDCIPP and DBP are needed to illustrate these results.

Prenatal exposure to organophosphate esters and neonatal thyroid-stimulating hormone levels: A birth cohort study in Wuhan, China.

Increasing animal studies have indicated that organophosphate esters (OPEs) have endocrine-disruptive potential. However, human epidemiological evidence is limited, especially in susceptible populations, such as pregnant women and neonates. The purpose of this present study was to examine the trimester-specific relationships of prenatal exposure to OPEs with neonatal thyroid-stimulating hormone (TSH). A total of 102 mother-newborn pairs were recruited from a birth cohort study between April 2015 and September 2016 in Wuhan, China. Eight OPE metabolites were detectable in urine samples from pregnant women across the different three trimesters. Neonatal TSH levels were measured using time-resolved immunofluorescence assay. The associations between maternal urinary OPE metabolites and neonatal TSH and the critical exposure windows of fetal vulnerability were estimated using multiple informant models. Seven OPE metabolites with detection frequency>50% (52.9%-98.0%) were detected in repeated urine samples from different three trimesters, and the urinary OPE metabolites across pregnancy was of high variability (ICCs: 0.09-0.26). After adjusted for confounders (e.g., maternal age, prepregnancy BMI, passive smoking during pregnancy), some suggestive associations were observed between maternal urinary OPE metabolites and neonatal TSH in different trimesters. A doubling of second trimester di-o-cresyl phosphate & di-p-cresyl phosphate (DoCP & DpCP) was associated with a 7.82% increase in neonatal TSH level (95% CI: -0.70%, 17.06%, p-value=0.07), a doubling of third trimester diphenyl phosphate (DPHP) was associated with a 4.71% decrease in neonatal TSH level (95% CI: -9.80%, 0.67%, p-value=0.09), and a doubling of third trimester bis(2-butoxyethyl) phosphate (BBOEP) was associated with a 6.38% increase in neonatal TSH level (95% CI: -0.12%, 13.31%, p=0.05). However, such associations did not differ materially across trimesters. When performing stratified analysis by infant sex, the associations were statistically significant and were sex-dependent.In females, maternal urinary DoCP & DpCP concentrations in each trimester were associated with increased neonatal TSH levels, and urinary DPHP concentration in the third trimester was associated with decreased neonatal TSH level. In males, maternal urinary BBOEP concentration in the first trimester was positively related to neonatal TSH level. This prospective study demonstrated that prenatal exposure to OPEs can lead to a sex-dependent change in neonatal TSH levels. Although the sex-selective effect was differed among various urinary OPE metabolites, more evidence was supported that OPE exposure was related to increased TSH levels for both males and females.

Trimester-specific effects of maternal exposure to organophosphate flame retardants on offspring size at birth: A prospective cohort study in China

Organophosphate flame retardants (OPFRs) are substantially applied as flame retardants and plasticizers in consumer products. Although the embryonic developmental toxicity of OPFRs has been reported, human data are limited and the critical windows of susceptibility to OPFRs exposure urgently need to be identified. Here, we investigated the trimester-specific associations between prenatal OPFR exposure and birth size for the first time. The concentrations of 15 OPFR metabolites and tris(2-chloroethyl) phosphate were repeatedly determined in urine samples of 213 pregnant women collected in the first, second, and third trimesters in Wuhan, China, and anthropometric data were retrieved from medical records. In multiple informant models, urinary concentrations of bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and bis(2-butoxyethyl) phosphate (BBOEP) in the third trimester, 4-hydroxyphenyl-diphenyl phosphate (4-HO-DPHP) in the second trimester, and diphenyl phosphate (DPHP) in the first trimester were negatively associated with birth weight, among which a significant difference in exposure-effect relationships across the three trimesters was observed for BDCIPP. BBOEP concentrations in the third trimester were negatively correlated to birth length with significant varying exposure effects. Our results suggest that prenatal exposure to certain OPFRs may impair fetal growth, and the fetus is vulnerable to the developmental toxicity of BDCIPP and BBOEP in the third trimester.

Association between urinary organophosphate flame retardant diesters and steroid hormones: A metabolomic study on type 2 diabetes mellitus cases and controls

Metabolomic analysis was conducted by collecting urine samples from 128 participants in diagnose of type 2 diabetes mellitus (T2DM) and 105 volunteers in healthy condition, in order to identify biomarkers of experimental populations. The urinary concentrations of organophosphate flame retardant (OPFR) diesters were determined and linear regression model was used to find associations between OPFR diesters and the identified biomarkers. The urinary concentrations of OPFR diesters ranged from 0.17–779 μg/g creatinine. Diphenyl phosphate (DPHP) was detected with the highest frequency of 97% at a median level of 1.21 μg/g, and bis(1-chloro-2-propyl) phosphate (BCIPP) dominated the highest median level at 4.24 μg/g with a detection frequency of 94.4%. As compared with the control, the urinary median concentrations of bis(2-butoxyethyl) phosphate (BBOEP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP) and DPHP were 2.76, 2.48, and 1.46 times higher in people with T2DM, respectively. Urinary metabolomic data revealed that steroid synthesis was the most significantly altered metabolic pathway between the case and control population. Two biomarkers of cortisol and cortisone that play an important role in steroid hormone regulation were quantified. The linear regression model indicated that per-quartile range increase in the concentrations of each OPFR diester was associated 18%–41% increase in the concentrations of cortisol and cortisone, which may impact energy metabolism linked with T2DM. To our knowledge, this study for the first time reported the altered levels of steroid hormones associated with urinary OPFR diesters.

Multiple exposures to organophosphate flame retardants alter urinary oxidative stress biomarkers among children: The Hokkaido Study

Organophosphate flame retardants (PFRs) are used as additives in plastics and other applications such as curtains and carpets as a replacement for brominated flame retardants. As such, exposure to PFR mixtures is widespread, with children being more vulnerable than adults to associated health risks such as allergies and inflammation. Oxidative stress is thought to be able to modulate the development of childhood airway inflammation and atopic dermatitis. To evaluate these associations, the present study investigated the relationship between urinary PFR metabolites, their mixtures and urinary oxidative stress biomarkers in children as part of the Hokkaido Study on Environment and Children's Health. The levels of the oxidative stress biomarkers, such as 8-hydroxy-2′-deoxyguanosine (8-OHdG), hexanoyl-lysine (HEL), and 4-hydroxynonenal (HNE), and of 14 PFR metabolites were measured in morning spot urine samples of 7-year-old children (n = 400). Associations between PFR metabolites or PFR metabolite mixtures and oxidative stress biomarkers were examined by multiple regression analysis and weighted quantile sum regression analysis, respectively. We found that the non-chlorinated PFR metabolites, 2-ethylhexyl phenyl phosphate (EHPHP), bis(2-butoxyethyl) phosphate (BBOEP), and diphenyl phosphate (DPHP) were associated with increased levels of oxidative stress biomarkers. Furthermore, the PFR metabolite mixture was associated with increased levels of HEL and HNE, but not 8-OHdG. The combination of elevated top 2 PFR metabolites was not associated with higher urinary oxidative stress marker levels. This is the first study to report associations between urinary PFR metabolites and oxidative stress biomarkers among children.

Co-Existence of Organophosphate Di- and Tri-Esters in House Dust from South China and Midwestern United States: Implications for Human Exposure.

Despite numerous studies on the contamination of organophosphate triesters (tri-OPEs) in indoor environments, organophosphate diesters (di-OPEs) have rarely been investigated. The present study aimed to investigate whether di-OPEs coexist with tri-OPEs in house dust collected from Guangzhou ( n = 30), South China and the city of Carbondale ( n = 17) located in the Midwestern United States (U.S.). Median concentrations of bis(2-butoxyethyl) phosphate (BBOEP), bis(1-chloro-2-propyl) phosphate (BCIPP), bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), bis(2-ethylhexyl) phosphate (BEHP), bis(2-methylphenyl phosphate) (BMPP), and diphenyl phosphate (DPHP) were determined to be 15.9, < LOQ, 33.6, 654, 9.5, and 605 ng/g in South China house dust, and 1580, 90.6, 234, 867, 4.0, and 6500 ng/g in Midwestern U.S. dust, respectively. The total concentrations of di-OPEs (referred to ΣdiOPEs) constituted an average of 22.9% and 21.3% of the total concentrations of tri-OPEs in dust from these two locations, respectively. Median concentration ratios of DPHP and BEHP to their respective tri-OPEs (i.e., TPHP and TEHP) were determined to be 1.1 and 1.0 in South China dust and 3.7 and 1.4 in Midwestern U.S. dust, respectively, indicating possible commercial applications for these two di-OPEs. Correlative analyses reveal chemical- and region-specific relationships between di-OPEs and their respective tri-OPEs, suggesting that the relative importance of different sources (e.g., direct commercial use, impurity in tri-OPE formulas, and tri-OPE degradation) could vary for different di-OPEs. Our findings demonstrate wide occurrences of di-OPEs in an indoor environment from the studied locations and raise concerns on human exposure to dust associated di-OPEs. Future studies are needed to explore more possible di-OPEs in indoor environments and elucidate their sources, human exposure pathways, and toxicokinetics.

Toxicokinetic patterns, metabolites formation and distribution in various tissues of the Chinese rare minnow (Gobiocypris rarus) exposed to tri(2‑butoxyethyl) phosphate (TBOEP) and tri-n-butyl phosphate (TNBP)

Alkylated organophosphate esters (alkyl-OPEs) are widely used and extensively detected in aquatic organisms. This work investigated the tissue-specific toxicokinetics of two common alkyl-OPEs, tri(2‑butoxyethyl) phosphate (TBOEP) and tri‑n‑butyl phosphate (TNBP) in Chinese rare minnow (Gobiocypris rarus) through a 50 day uptake and depuration experiment. The tissue-specific bioconcentration factor (BCF) values for the two alkyl-OPEs ranged from 1 to 30 L/kg wet weight (ww), with the kidney and ovary as the tissues with the highest accumulation. The tissue BCFs only exhibited a significant correlation with lipid contents only in storage tissues (i.e., muscle, brain, ovary and testis), indicating that lipids might not be the major contributor to tissue distribution of TBOEP and TNBP. However, the contribution of blood perfusion and active transport to tissue-specific OPE accumulation needs to be further investigated. Lower accumulation of metabolites than parent chemicals was observed, with metabolite parent concentration factors (MPCFs) <1. Di-alkyl phosphate (DAP), bis(2‑butoxyethyl) phosphate (BBOEP) and di(n-butyl) phosphate (DNBP) were the most abundantly formed metabolites of TBOEP and TNBP in various tissues, followed by the monohydroxylated OPEs (OH-OPEs). However, bis(2‑butoxyethyl) hydroxyethyl phosphate (BBOEHEP), was detected at much lower levels in the tissues. All the investigated metabolites showed high production rates (kprod,metabolites) in the fish liver, followed by the GI tract and the kidney, indicating the importance of the hepatobiliary and urinary systems in eliminating the metabolites. Our study suggested that metabolism plays an important role in eliminating these two alkyl-OPEs in rare minnow and results in different tissue distribution mechanisms for metabolites and their compounds.

Metabolites of organophosphate ester flame retardants in urine from Shanghai, China

The metabolites of nine organophosphate ester (OPE) flame retardants were measured in 180 urine samples collected from a population (including adults and children) in western Shanghai, China, using liquid chromatography-tandem spectrometry (LC-MS/MS). The total urinary concentrations of nine OPE metabolites ranged 100–23800 pg/mL, with a geometric mean (GM) value of 1450 pg/mL. The concentrations of alkyl-OPE metabolites (879 pg/mL) were approximately an order of magnitude higher than those of aryl-OPE (53.7 pg/mL) and chlorinated-OPE metabolites (52.7 pg/mL). Diphenyl phosphate (DPHP), diethyl phosphate (DEP), di-n-butyl phosphate (DNBP), bis(2-ethylhexyl) phosphate (BEHP), and bis(2-butoxyethyl) phosphate (BBOEP) were the dominant OPE metabolites found in urine. The results showed that an increase in age was associated with a significant decrease in urinary DPHP (r = −0.278, p < 0.01) and DNBP (r = −0.314, p < 0.01) concentrations. The highest concentrations of DPHP (GM = 80.7 pg/mL) and DNBP (GM = 16.9 pg/mL) were found in urine from people living in homes that were less than 10 years old. The urinary DNBP concentration was significantly associated with self-reported symptoms of allergy. Our result establishes baseline value for OPE exposure in a population in China for comparison in future studies.

Concentrations of organophosphate flame retardants and plasticizers in urine from young children in Queensland, Australia and associations with environmental and behavioural factors

In recent years, the production and usage volumes of organophosphate flame retardants (OPFRs) has increased substantially. Certain OPFRs are suspected reproductive toxins, carcinogenic, and neurotoxic. Insufficient information is available on human exposure pathways to these chemicals, particularly in Australia. We aim to assess the association between OPFR concentrations in the urine of children to environmental and behavioural risk factors. Concentrations of eight OPFRs and eleven metabolites were measured in the urine of 51 children, aged 3–29 months, in Southeast Queensland, Australia and compared to their behavioural and environmental risk factor data obtained by an online questionnaire. Of the 11 OPFR metabolites analysed, 55% were frequently detected in the majority (> 80%) of samples. The most frequently detected metabolite was bis(1,3-dichloroisopropyl) phosphate (BDCIPP) (detected in 100% of samples), followed by 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP) (96%), diphenyl phosphate (DPHP) (94%) and bis(1-chloroisopropyl) phosphate (BCIPP) (86%). In multivariable modelling, age was positively associated with concentrations of bis(2-butoxyethyl) phosphate (BBOEP) and negatively associated with concentrations of BCIPP and BCIPHIPP. Other non-age related factors, including vacuuming frequency, hand-washing frequency and presence and number of some electrical appliances in the home were also associated with concentrations of OPFR metabolites.