Urinary Organophosphate Esters Metabolites Research Articles

Exposure to organophosphate esters and early menopause: A population-based cross-sectional study

Organophosphate esters (OPEs), increasingly used as new flame retardants and plasticizers in various products, have been found to have reproductive toxicity with overt endocrine disruption potential, yet the relationship between OPEs and early menopause remains unexplored. In the present study, we included 2429 women who participated in the U.S. National Health and Nutrition Examination Survey data (2011–2020) and had data of five urinary OPE metabolite levels and information of menopause characteristics, to investigate the associations of OPEs exposure with premature ovarian insufficiency (POI) and age of menopause. Multivariable adjusted linear and logistic regression were used to assess the associations of urinary OPE metabolites with age of menopause and POI, respectively. Quantile g computation (QGC) models were used to assess the relative contribution of individual metabolites to associations of OPE metabolites mixture. After adjusting for covariates, urinary bis(2-chloroethyl) phosphate (BCEP) concentration was inversely associated with menopause age (β = - 0.21; 95% confidence interval (CI): 0.41, - 0.002). Higher urinary BCEP level (>median) was associated with earlier age at menopause (β = −1.14, 95% CI: 1.83, - 0.46), and elevated odds of having POI (OR = 1.93; 95% CI: 1.02, 3.66). These associations were robust to the further adjustment of cardiometabolic diseases and related traits (e.g., body mass index). Further QGC analyses confirmed that BCEP was the dominant metabolite contributing most to the associations of OPEs mixture with age of menopause (weight = 49.5%) and POI (weight = 75.1%). No significant associations were found for the other four OPE metabolites. In this cross-sectional study, urinary BCEP level was associated with earlier menopause and increased odds of POI, highlighting the potential negative impacts of this chemical and its parent compound tris(2-chloroethyl) phosphate on ovarian function. Further studies are required to validate our findings and reveal potential underlying mechanisms.

Association between organophosphate esters exposure and all-cause and cause-specific mortality: a national population-based cohort study

ABSTRACT Exposure to organophosphate esters (OPEs) is associated with several chronic diseases, but the relationship with mortality risk is unclear. Therefore, we used the National Health and Nutrition Examination Survey 2011–2018 data to evaluate these relationships. 6,869 participants aged 18 years or older were included. Survival status information was obtained through the National Death Index through 31 December 2019. Multivariable COX regression model was adopted to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the relationships of urinary OPEs metabolites with mortality risk. During an average of 5.0 years of follow-up, 406 deaths were documented. After adjusting for confounders, bis(2-chloroethyl) phosphate was associated with an increased risk of all-cause mortality [HR (95%CI) = 1.12(1.05–1.20)] and cardiovascular mortality [HR (95%CI) = 1.15(1.04–1.26)]. Our study found that exposure to OPEs was significantly associated with increased risks of all-cause and cardiovascular mortality. Consequently, controlling OPEs exposure is needed to alleviate the health-related burden.

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.

Investigation of Urinary Metabolites of Organophosphate Esters in Hanoi, Vietnam: Assessment Exposure and Estimated Daily Intake.

In recent years, organophosphate esters (OPEs) have become one of the most common additives in various consumer products worldwide, therefore the exposure and impact of OPEs on human health are drawing a lot of attention. In this study, three metabolites of OPEs including bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPhP) and diethyl phosphate (DEP) were investigated in first-morning void urine samples taken from a population (age range: 3-76years old) in Hanoi, Vietnam. The most dominant urinary OPE metabolite was DEP with the geometric mean of specific gravity adjust (SG-adjusted) concentration were 1960ngmL-1 and detected frequency (DF) of 98%. Followed by DPhP (8.01ngmL-1, DF: 100%) and BDCIPP (2.18ngmL-1, DF: 51%). The results indicated that gender and age might have associations with the OPE metabolites variation in urine samples. The levels of OPE metabolites in urine samples from females were slightly higher than in males. An increase in age seems to have an association with a decrease in DPhP levels in urine. Exposure doses of parent OPEs were evaluated from the unadjusted urinary concentration of corresponding OPE metabolite. The estimated exposure doses of triethyl phosphate (TEP) (mean: 534,000ngkg-1d-1) were significantly higher than its corresponding reference dose, suggesting the high potential risk from the current exposure doses of TEP to human health. The results of this work provided the initial information on the occurrence of three OPE metabolites in urine from Hanoi, Vietnam and estimated exposure dose of corresponding parent OPEs.

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.

Reproductive hormones, organophosphate esters and semen quality: Exploring associations and mediation effects among men from an infertility clinic

Accumulating evidence indicates that organophosphate esters (OPEs) exposure may affect semen quality. As a crucial factor in male reproduction, reproductive hormones might be linked organophosphate esters (OPEs) exposure and semen quality. This study aimed to explore the mediating role of reproductive hormones on the association between OPEs exposure and semen quality. Five serum reproductive hormones, semen quality, and 16 urinary OPE metabolites were measured among 491 reproductive-aged men from a reproductive center. The associations of urinary OPE metabolites with reproductive hormones and semen quality were assessed using multivariable linear regression models, and the mediating role of reproductive hormones was evaluated by mediation analyses. We found that follicle stimulating hormone (FSH) was positively associated with diphenyl phosphate (DPHP) that in turn was negatively associated with sperm total count. In addition, inverse associations were exhibited between serum FSH and sperm concentration, sperm total count, total motility, and progressive motility (all Ptrend <0.05). Mediation analysis further showed that FSH mediated 13.7% of the inverse association of DPHP and sperm total count. Although further investigations are required, our results suggest that FSH was an intermediate mechanism in the associations between OPEs exposure and impaired semen quality.

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.

Patterns of urinary organophosphate ester metabolite trajectories in children: the HOME Study.

Organophosphate esters (OPEs) have replaced flame retardant polybrominated diphenyl ethers as flame retardants in consumer products, but few longitudinal studies have characterized childhood OPE exposure. We aimed to examine the exposure pattern of urinary OPE metabolites in children. We quantified three urinary OPE metabolites five times in children (1, 2, 3, 5, 8 years) from 312 mother-child pairs in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort in Cincinnati, Ohio, USA. We examined the associations of average maternal OPE metabolite concentrations with OPE metabolite concentrations in childhood, characterized childhood OPE trajectories with latent class growth analysis (LCGA), and examined factors related to trajectory membership. Bis(2-chloroethyl) phosphate (BCEP) had the lowest median concentrations over time (0.66-0.97 mg/L) while the median concentrations of bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) increased with age (1.44-3.80 mg/L). The median concentrations of diphenyl phosphate (DPHP) fluctuated between 1.96 and 2.69 mg/L. Intraclass correlation coefficients for urinary metabolites measured at five time points indicated high variability within individuals (0.13-0.24). Average maternal urinary BCEP and BDCIPP were associated with concentrations in early childhood. Maternal education, the birth year of the child, and having a carpet in the main activity room were associated with BCEP and BDCIPP trajectory while none of the factors were associated with DPHP trajectory. The trajectory analysis showed different patterns of urinary OPE metabolite concentrations, suggesting the need to collect multiple samples to adequately reflect OPE exposure. In this well-established cohort, we evaluated the patterns of urinary OPE metabolites in children ages 1-8 years. The number of repeated measures over childhood has not been achieved in prior studies. Our results suggested the high variability of urinary OPE metabolites within individuals. Maternal metabolite concentrations during pregnancy were related to child concentrations at ages 1-3 years. BCEP, BDCIPP, and DPHP demonstrated different trajectories in children, which suggests that multiple samples may be required to capture OPE exposure patterns in childhood.

Urinary concentrations of organophosphate esters and associated health outcomes in Korean firefighters

Although firefighters are at an increased risk of occupational exposure to chemicals, such as flame retardants, research on the exposure of Korean firefighters to organophosphate esters (OPEs)—a group of emerging flame retardants—remains limited. Therefore, in the present study, OPE metabolite concentrations in the urine samples of 149 former and current Korean firefighters were measured. Based on the data obtained, the estimated daily intakes (EDIs) of OPEs were calculated. Subsequently, the association between the urinary concentrations of OPE metabolites and the potential determinants of OPE exposure and health outcomes (e.g., obesity and serum lipids) was investigated. We found that bis(1-chloro-2-propyl) phosphate (BCIPP) and bis(2-chloroethyl) phosphate (BCEP) were the most prevalent urinary OPE metabolites, with median concentrations of 2.33 and 1.80 ng/mL, respectively; these concentrations were higher than those reported previously in other countries, such as the USA and China. Moreover, their parent compounds—tris(1-chloro-2-propyl) phosphate (TCIPP) and tris(2-chloroethyl) phosphate (TCEP)—exhibited EDIs of 126 and 94.8 ng/kg bw/day, respectively. Unlike the high detection rate of bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) in other populations, its detection rate in this study was low (6.7%), suggesting regional differences in the exposure pattern of OPEs among countries. Furthermore, occupational characteristics, such as recent participation in firefighting activity, were identified as determinants of the urinary concentrations of OPE metabolites. Total OPE metabolites were inversely associated with body mass index and positively associated with high-density lipoprotein cholesterol. Overall, our findings demonstrate that Korean firefighters are highly exposed to several occupation-related OPEs. Further prospective studies will help elucidate the potential health implications of occupational exposure to OPEs among firefighters.

Associations of urinary organophosphate esters metabolites with asthma and lung function in adolescents.

Organophosphate esters (OPEs) are ubiquitously detected in environments and their exposure may affect respiratory health. However, epidemiological evidence, particularly among adolescents, is very limited. We aimed to investigate the associations of urinary OPEs metabolites with asthma and lung function among adolescents and to identify potential effect modifiers. Included were 715 adolescents aged 12-19 years old participating in the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Multivariable binary logistic regression and linear regression were used to assess associations with asthma and lung function, respectively. Stratified analyses were conducted to assess the effect modifications of serum sex hormones, vitamin D levels, and body mass index (BMI). After multivariable adjustment, we found that bis(2-chloroethyl) phosphate (BCEP) (3rd tertile [T3] vs 1st tertile [T1], OR = 1.87, 95% CI: 1.08, 3.25; P-trend=0.029) and diphenyl phosphate (DPHP) (T3 vs T1, OR = 2.52, 95%CI: 1.25, 5.04; P-trend=0.013) were associated with elevated odds of asthma in all adolescents. Sex-stratified analyses revealed that associations of these two OPEs metabolites tended to be stronger in males. Meanwhile, BCEP and the molecular sum of OPEs metabolites (∑OPEs) were significantly associated with declined lung function, either in all adolescents or by sex. Furthermore, stratified analyses revealed that positive associations of OPEs metabolites with asthma tended to be stronger among adolescents with insufficient levels of Vitamin D (VD < 50 nmol/L), relatively high levels of total testosterone (≥356 ng/dL and ≥22.5 ng/dL for males and females, respectively), or low levels of estradiol (<19.1 pg/mL and <47.3 pg/mL for males and females, respectively). Certain urinary OPEs metabolites, especially DPHP and BCEP, were associated with elevated odds of asthma and declined lung function in adolescents. Such associations might be partly modified by levels of VD and sex steroid hormones. The observed associations of urinary OPEs metabolites with increased risk of asthma and declined lung function highlight the potential hazard of OPEs exposure to respiratory health among adolescents.

Associations of urinary organophosphate esters metabolites and diet quality with nonalcoholic/metabolic dysfunction-associated fatty liver diseases in adults

Whether exposure to organophosphate esters (OPEs) is associated with metabolic dysfunction-associated fatty liver disease (MAFLD) and nonalcoholic fatty liver disease (NAFLD) remains unclear. A healthy diet is crucial to metabolic health and dietary intake is also an important route for OPEs exposure. However, the joint associations of OPEs, diet quality, and the effect modification by diet quality remain unknown. This study comprised 2618 adults with complete data on 6 urinary OPEs metabolites, 24 h dietary recalls, and definitions of NAFLD and MAFLD from the 2011–2018 National Health and Nutrition Examination Survey cycles. Multivariable binary logistic regression was applied to assess the associations of OPEs metabolites with NAFLD, MAFLD, and components of MAFLD. We also adopted the quantile g-Computation method to examine the associations of OPEs metabolites mixture. Our results revealed that OPEs metabolites mixture and three individual metabolites [i.e., bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), bis(2-chloroethyl) phosphate, and diphenyl phosphate] were significantly and positively associated with NAFLD and MAFLD (P-trend<0.001), with BDCIPP being identified as the dominant metabolite, whereas the 4 diet quality scores were monotonically and inversely associated with both MAFLD and NAFLD (P-trend<0.001). Of note, 4 diet quality scores were by and large negatively associated with BDCIPP, but not with other OPEs metabolites. Joint association analyses revealed that individuals with higher diet quality and lower BDCIPP concentration tend to have lower odds of having MAFLD and NAFLD in comparison with people in the low diet quality and high BDCIPP group, but the associations of BDCIPP were not modified by diet quality. Our findings suggest that certain OPEs metabolites and diet quality exhibited opposing associations with both MAFLD and NAFLD. Individuals adherent to a healthier diet may have a lower level of certain OPEs metabolites, and thus could have lower odds of having NAFLD and MAFLD.

Independent and combined effects of exposure to organophosphate esters on thyroid hormones in children and adolescents.

Toxicological studies suggest that organophosphate esters (OPEs) may impair thyroid function. Epidemiological evidence, related to children and adolescents, has not been reported, and little is known about the combined effects of exposure to OPE mixtures. In this study, we collected information of 1156 children and adolescents (aged 6-18years, 48.4% males) from a cross-sectional study in Liuzhou, China, and measured the levels of 15 urinary OPE metabolites and 5 serum thyroid hormones. Multivariate linear regression and quantile g-computation (QGC) approach were used to examine the associations which adjusted for demographic and lifestyle characteristics. Few participants had levels of triiodothyronine (T3) and free thyroxine (FT4) outside age-specific pediatric ranges. QGC analyses showed that individuals in the second, third, and fourth quartiles (Q2-Q4) of exposure had 3.93% (2.14%, 5.75%), 8.01% (4.32%, 11.8%), and 12.3% (6.54%, 18.3%) higher T3 than those in the first quartile (Q1), with similar pattern for free triiodothyronine (FT3). Individuals in Q2 and Q3 had higher thyroid-stimulating hormone (TSH) than those in Q1, but no differences were observed in TSH between Q1-Q4. In contrast, compared to the lowest quartile, FT4 was lower for those in Q2 (- 1.54%; 95% CI: - 3.02%, -0.04%), Q3 (-3.07%; 95% CI: -5.95%, -0.09%), and Q4 (-4.56%; 95% CI: - 8.80%, - 0.13%). These associations were consistent with the results from multivariate linear regression. When stratified by sex, OPE exposure (individual or mixtures) was associated with increased T3 and FT3 in males and decreased FT4 in females. This study provides the first evidence to characterize the thyroid-disrupting effects of OPE exposure in children and adolescents.

Associations between organophosphate esters concentrations and markers of liver function in US adolescents aged 12–19 years: A mixture analysis

Liver disease has become a growing health burden, and little is known about the impairment of liver function caused by exposure to organophosphate esters (OPEs) in adolescents aged 12–19 years in the United States. To investigate the relationship between urinary metabolites of OPEs including diphenyl phosphate (DPHP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP), bis(1-chloroethyl) phosphate (BCPP), bis(2-chloroethyl) phosphate (BCEP), and dibutyl phosphate (DBUP) and liver function in US adolescents aged 12–19 years. Liver function tests (LFTs) include aspartate aminotransferase (AST), albumin (ALB), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), total bilirubin (TBIL), total protein (TP), and AST/ALT. Meanwhile, potential confounding and interaction effects were assessed. The study sample included 592 adolescents aged 12–19 from two consecutive NHANES cycles (2011–2012, 2013–2014). A composite statistical strategy combining traditional linear regression with advanced multi-pollutant models quantile based g-computation (QGC) and eXtreme Gradient Boosting (XGBoost) regression was used to analyze the joint effects of multiple OPEs on liver function indicators, and to describe the interaction between different OPEs in detail. 592 adolescent participants were 15 (14–17) years old, with similar numbers of males and females (304 vs. 288). The analysis results showed that (1) in the linear regression model, individual DPHP, BCEP exposure and ALP changes, BCEP and AST/ALT changes were positively associated. DPHP, BDCPP were negatively associated with TP changes. (2) The combined effects of various OPEs on ALB, ALT, ALP, GGT, TBIL, TP, and AST/ALT were statistically significant. (3) There is no potential interaction between different OPEs. Several OPEs and their combinations are closely related to the 8 LFT indicators. In addition, data suggest that exposure to OPEs in adolescents may be associated with liver damage. Due to limited evidence in the literature and potential limitations of the current study, our findings require more studies to confirm.

Maternal urinary organophosphate ester metabolite concentrations and glucose tolerance during pregnancy: The HOME Study.

Endocrine-disrupting chemicals may alter glucose homeostasis, especially during pregnancy. Biomonitoring studies suggest ubiquitous human exposure to organophosphate esters (OPEs), chemicals with endocrine-disrupting capabilities. Few studies have examined the association between maternal exposure to OPEs and blood glucose during pregnancy. With data from 301 pregnant women in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort in Cincinnati, Ohio, USA, we examined whether OPE concentrations were associated with changes in blood glucose. We quantified four OPE metabolites in maternal spot urine samples collected at 16- and 26-weeks pregnancy. We extracted results from the glucose challenge test (GCT) and oral glucose tolerance test (OGTT) via medical chart review. Women with GCT ≥ 140mg/dL or any abnormal values in OGTT (≥ 95mg/dL fasting glucose, ≥ 180mg/dL 1-h glucose, ≥ 155mg/dL 2-h glucose, ≥ 140mg/dL 3-h glucose) were defined as having elevated glucose levels. We used linear regression and Bayesian Kernel Machine Regression (BKMR) to estimate the associations of individual OPE metabolites and OPE mixtures with blood glucose levels during pregnancy. We used modified Poisson regression to estimate the associations of OPE metabolite concentrations with elevated glucose levels. We further examined effect measure modification by maternal characteristics (age, pre-pregnancy body mass index [BMI], and race/ethnicity). Diphenyl phosphate (DPHP) had the highest geometric mean concentration of the urinary OPE metabolites (1.83μg/L at 16 weeks, 1.24μg/L at 26 weeks). Thirty women (10.0%) had elevated glucose levels. Individual OPE metabolites or their mixtures were not significantly associated with continuous GCT results. We did not observe effect measure modification by maternal age, pre-pregnancy BMI categories, or race/ethnicity. Compared with women in the 1st tertile of average DPHP of 16- and 26 weeks of pregnancy, women in the 3rd tertile tended to have a reduced risk of elevated glucose levels (RR=0.41, 95% CI=0.16-1.06, p for trend=0.06). In this cohort, maternal urinary OPE metabolite concentrations were weakly associated with blood glucose levels during pregnancy.

Development of magnetic molecularly imprinted solid-phase extraction and ultra-high performance liquid chromatography tandem mass spectrometry for rapid and selective determination of urinary diphenyl phosphate of college students

Organophosphate esters (OPEs), known as novel alternative flame retardants, are a class of environmental endocrine disruptors. Long-term exposure to OPEs may bring a non-negligible health risk to human. Urinary OPE metabolites (mOPEs) are generally used as biomarkers to evaluate the internal exposure to OPEs. Diphenyl phosphate (DPHP), the main metabolite of aryl-OPEs, exhibited high detection rates and concentrations in urine samples. To establish a selective and simple analytical method for biomonitoring urinary DPHP, a specific magnetic molecular imprinted polymer (MMIP) was fabricated via a sol-gel method. Under optimum magnetic solid-phase extraction (MSPE) conditions, the resultant MMIP exhibited selective recognition ability, ideal adsorption capacity and good reusability on urinary DPHP enrichment. The developed MSPE method coupled with ultra-high performance liquid chromatography tandem mass spectrometry (U-HPLC-MS/MS) exhibited good precision and accuracy (spiked recoveries of 85.8%-109% with relative standard deviations (RSDs) ranged from 5.1%-13%), low detection limit of 0.035 ng/mL, and negligible matrix inhibition. Then we used this proposed method to detect urinary DPHP levels of recruited 30 college students and investigate the time variability and potential determinants. All urine samples revealed the presence of DPHP at a median concentration of 0.56 μg/g Creatinine (Cr). Moderate reproducibility of DPHP level was observed in first morning urine samples (ICC>0.40). Significant correlations were found between urinary DPHP levels and gender (β=0.72; 95% CI: 0.48∼0.96), sampling time (β=0.36; 95% CI: 0.08∼0.65) as well as the frequency for take-out food (β=0.45; 95% CI: 0.07∼0.74) (p< 0.05). Hence, a fast and sensitive MSPE-U-HPLC-MS/MS method was successfully built to quantify urinary DPHP.

Organophosphate esters exposure in relation to glucose homeostasis and type 2 diabetes in adults: A national cross-sectional study from the national health and nutrition survey

BackgroundExposure to organophosphate esters (OPEs) may be associated with impaired glucose homeostasis and increased risk of type 2 diabetes (T2D) in adolescent. However, the evidence in general population is scarce, especially for glucose homeostasis. We used data from the National Health and Nutrition Examination Survey (NHANES) 1999–2008 and 2011–2012 to investigate the relationship of urinary OPEs with glucose homeostasis and T2D in adults. MethodsA total of 5347 participants aged ≥20 years were included. The exposures were the concentrations of urinary OPEs metabolites [dimethyl phosphate (DMP), dimethyl thiophosphate (DMTP), dimethyl dithiophosphate (DMDTP), diethyl phosphate (DEP), diethyl thiophosphate (DETP), and diethyl dithiophosphate (DEDTP)]. The health outcomes were prevalence of T2D and glucose homeostasis [i.e., fasting glucose, 2-h plasma glucose during a 75-g oral glucose tolerance test (2 h-OGTT), serum insulin, HemoglobinA1c (HbA1c), HOMA-IR, and HOMA-β]. The multivariable linear regression model was used to evaluate the relationship between OPEs and glucose homeostasis. The multivariable binary logistic regression analysis was used to investigate the relationship between OPEs and prevalence of T2D. ResultsThe OPEs compound DMTP was significantly associated with higher levels of serum insulin [β (95%confidence interval, CI) = 0.21 (0.06,0.36), for one unit increase in log2-transformed exposure] and HOMA IR [β (95%CI) = 0.08 (0.02,0.14)], and increased odds of T2D [odds ratio (95% CI) = 1.05 (1.01–1.08)]. Other OPEs were not statistically associated with the serum markers for glucose homeostasis or T2D prevalence. ConclusionOur study found that the OPEs compound DMTP might be associated with impaired glucose homeostasis and may increase the prevalence of T2D in U.S. adults. Further longitudinal or experimental studies are warranted to verify our findings in different populations and different OPEs concentrations.

Organophosphate esters in children and adolescents in Liuzhou city, China: concentrations, exposure assessment, and predictors.

Dermal contact with dust is commonly considered an important pathway of exposure to organophosphate esters (OPEs), but the importance of OPE uptake from diet is unclear. Herein, we used hand wipes to estimate OPE exposure from indoor dust and examined whether urinary OPE metabolite concentrations were influenced by sociodemographic characteristics, OPE amount in hand wipes, and dietary factors. OPEs were measured in urine and hand wipes from 6 to 18-year-old children and adolescents (n=929) in Liuzhou, China. Sociodemographic and dietary factors were obtained from questionnaire. Six OPE metabolites were detected in >70% of the urine samples, and seven OPEs were detected in >50% of the hand wipes. Estimated daily intakes (EDIs) were calculated using urinary OPE metabolites to investigate the total daily intake of OPEs, in which 0.36-10.1% of the total intake was attributed to the exposure from dermal absorption. In multivariate linear regression models, sex, age, and maternal education were significant predictors of urinary OPE metabolite concentrations. Urinary diphenyl phosphate (DPHP) is positively associated with its parent compounds 2-ethylhexyl-diphenyl phosphate (EHDPP) and triphenyl phosphate (TPHP) in hand wipes. High versus low vegetable intake was associated with a 23.7% higher DPHP (95% confidence interval (CI): 0.51%, 52.1%). Barreled water drinking was associated with a 30.4% (95% CI: 11.8%, 52.0%) increase in bis(1-chloro-2-propyl) 1-hydroxy-2-propyl phosphate (BCIPHIPP) compared to tap water drinking. Our results suggested the widespread exposure to OPEs in children and adolescents. In addition to dermal absorption, dietary intake may be an important exposure source of certain OPEs.

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.

Maternal urinary organophosphate ester concentrations and blood pressure during pregnancy: The HOME Study

BACKGROUND AND AIM: Organophosphate esters (OPEs) flame retardants found in various consumer products, may be a risk factor of adverse reproductive health outcomes. No study has examined whether gestational exposure to OPEs alters maternal blood pressure (BP) during pregnancy. METHODS: We analyzed data from 346 women who had liveborn singletons without congenital abnormalities in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective birth cohort (Cincinnati, OH, USA). The exposure variables were maternal urinary OPE metabolite concentrations at 16 weeks of gestation, standardized by specific gravity. We extracted the first two recorded maternal BP measures (20 weeks) to assess for chronic hypertension. We also extracted the two highest BP measures (≥20 weeks), and any diagnosis of hypertensive disorders of pregnancy (HDP: gestational hypertension, preeclampsia, and eclampsia) from medical charts. We defined HDP for this analysis as two BP140/90 or HDP noted in the chart at or after 20 weeks gestation. We used linear mixed models and modified Poisson regression with covariate adjustment to estimate associations between OPE concentrations with maternal BP and the risk of HDP. RESULTS:Diphenyl phosphate (DPHP) had the highest urinary geometric mean concentration (1.81 µg/L), followed by bis(1,3-dichloro-2-propyl) phosphate (BDCIPP; 0.80 µg/L), bis(2-chloroethyl) phosphate (BCEP; 0.61 µg/L), and di-n-butyl phosphate (DNBP; 0.26 µg/L). Thirty women (8.7%) were diagnosed with HDP. Every 10-fold increase of maternal BCEP concentrations was associated with 1.87 mmHg (95%CI 0.05-3.70) increase in the highest diastolic BP≥20 weeks. No urinary metabolites were associated with an increased risk of HDP (RR=1.17, 95%CI: 0.55-2.50 for DPHP; RR=1.68, 95%CI: 0.62-4.58 for BDCIPP; RR= 0.75, 95%CI 0.37-1.53 for BCEP; RR=2.34, 95% CI:0.88-6.24 for DNBP). CONCLUSIONS:Maternal urinary BCEP concentrations may be associated with increased diastolic BP. However, no associations were found between maternal urinary OPE metabolites and an increased risk of HDP. KEYWORDS: Endocrine disrupting chemicals, Pregnancy outcomes, Environmental epidemiology

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.