Bis(2-chloroethyl) Phosphate Research Articles

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.

Urinary Concentrations of Organophosphate Flame-Retardant Metabolites in the US Population

Organophosphate flame retardants (OPFRs) are an important group of pollutants associated with endocrine disorders, cancer, and nephrotoxicity. However, temporal trends in OPFR metabolite concentrations remain understudied. To examine changes in urinary concentrations of OPFR metabolites among US children, youths, and adults from 2011 to 2020, and to evaluate whether sociodemographic factors were associated with variations in temporal trends. This population-based cross-sectional study used data from 4 US National Health and Nutrition Examination Survey (NHANES) cycles (2011-2012, 2013-2014, 2015-2016, and 2017-2020 [to March 2020 before the COVID-19 pandemic]). The study included children and youths (aged 6-19 years) and adults (aged ≥20 years) with valid urinary concentrations of the following OPFR metabolites: bis(2-chloroethyl) phosphate (BCEtP), bis(1-chloro-2-propyl) phosphate (BCPP), diphenyl phosphate (DPhP), and dibutyl phosphate (DBuP). Data analysis was performed between February and May 2024. Calendar year and key sociodemographic subgroups (age, race and ethnicity, sex, educational attainment, and poverty-to-income ratio). The main outcome was urinary concentrations of OPFR metabolites among children, youths, and adults. Survey-weighted linear regression models were applied to estimate trends. The study population of 10 549 NHANES participants included 3154 children and youths (mean [SE] age, 12.5 [0.1] years; 51.2% were male) and 7395 adults (mean [SE] age, 47.8 [0.4] years; 52.0% were women). Among children and youths, mean (95% CI) BCEtP concentrations decreased from 0.68 (0.60-0.77) μg/L in 2011-2012 to 0.41 (0.37-0.45) μg/L in 2017-2020 (P for trend < .001). Among adults, mean (95% CI) BCEtP concentrations decreased from 0.43 (0.37-0.50) μg/L in 2011-2012 to 0.29 (0.27-0.33) μg/L in 2017-2020 (P for trend < .001), and mean BCPP concentrations decreased from 0.15 (0.14-0.17) μg/L to 0.13 (0.12-0.14) μg/L (P for trend = .002). Parent level of educational attainment was associated with concentrations of BCPP and BCEtP among children and youths; however, no significant differences among adults were observed. This study identified variations in temporal trends in urinary concentrations of OPFR metabolites among the US population from 2011 to 2020. In addition, substantial disparities in exposure levels persisted among children with different levels of parent educational attainment. These findings suggest that policy makers should consider socioeconomic factors to further reduce OPFR exposure and promote equity, ensuring a safe living environment for all individuals.

Metagenomic analyses of aerobic bacterial enrichment cultures that degraded Tris(2-chloroethyl) phosphate (TCEP) and its transformation products

Tris(2-chloroethyl) phosphate (TCEP) is of growing public concern worldwide because of its ubiquitous contamination, toxicity, and persistence. In this study, we investigated bacterial communities in aerobic enrichment cultures with TCEP and its two major transformation products bis(2-chloroethyl) phosphate (BCEP) and 2-chloroethanol (2-CE) as the sole carbon source. Burkholderiales and Rhizobiales were likely two main bacterial guilds involved in the hydrolysis of TCEP, while Rhizobiales and Sphingomonadales may play an important role in the hydrolysis of BCEP, given the increase of Rhizobiales and Sphingomonadales-related phosphoesterase genes when the carbon source was switched from TCEP to BCEP. All Burkholderiales, Rhizobiales, Sphingomonadales were probably efficient in 2-CE metabolism, because their dehydrogenase genes and dehalogenase genes increased after 2-CE enrichment. The different substrate preference of different bacterial guilds highlighted the importance to understand the diversity and collaboration among functional bacteria. Meanwhile, two TCEP-degrading strains affiliated with Xanthobacter and Ancylobacter were isolated. Xanthobacter sp. strain T2-1 was able to degrade both TCEP and BCEP following the pseudo-first-order kinetics with reaction rates of 1.66 h−1 for TCEP and 1.02 h−1 for BCEP, respectively. Ancylobacter sp. strain T3-4 could degrade TCEP following the pseudo-first-order kinetics with a reaction rate of 2.54 h−1, but is unable to degrade BCEP. Additionally, strains that were phylogenetically closely related were found to have different degradation capabilities toward TCEP and/or BCEP, indicating the importance to investigate functional genes such as phosphoesterase genes.

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 flame retardant exposure and lipid metabolism: data from the 2013-2014 National Health and Nutrition Examination Survey.

Organophosphate flame retardants (OPFRs) are emerging environmental pollutants that can be detected in water, dust, and biological organisms. Certain OPFRs can disrupt lipid metabolism in animal models and cell lines. However, the effects of OPFRs on human lipid metabolism remain unclear. We included 1,580 participants (≥20 years) from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) to explore the relationship between OPFR exposure and lipid metabolism biomarkers. After adjusting for confounding factors, results showed that one-unit increases in the log levels of diphenyl phosphate (DPhP) (regression coefficient = -5.755; S.E. = 2.289; p = 0.023) and log bis-(1-chloro-2-propyl) phosphate (BCPP) (regression coefficient = -4.637; S.E. = 2.019; p = 0.036) were negatively associated with the levels of total cholesterol (TC) in all participants. One-unit increases in the levels of DPhP (regression coefficient = -2.292; S.E. = 0.802; p = 0.012), log bis (1,3-dichloro-2-propyl) phosphate (BDCPP) (regression coefficient = -2.046; S.E. = 0.825; p = 0.026), and log bis-2-chloroethyl phosphate (BCEP) (regression coefficient = -2.604; S.E. = 0.704; p = 0.002) were negatively associated with the levels of high-density lipoprotein cholesterol (HDL-C). With increasing quartiles of urine BDCPP levels, the mean TC levels significantly decreased in all participants (p value for trend = 0.028), and quartile increases in the levels of DPhP (p value for trend = 0.01), BDCPP (p value for trend = 0.001), and BCEP (p value for trend<0.001) were negatively corelated with HDL-C, with approximately 5.9, 9.9, and 12.5% differences between the upper and lower quartiles. In conclusion, DPhP, BDCPP, and BCEP were negatively related to HDL-C concentration, whereas DPhP and BCPP levels were negatively associated with TC level. Thus, exposure to OPFRs may interfere with lipid metabolism.

Association between urinary organophosphate ester metabolite exposure and thyroid disease risk among US adults: National Health and Nutrition Examination Survey 2011-2014.

Organophosphate esters (OPEs) may interfere with thyroid function, but the relationship between OPEs and thyroid disease remains unclear. This study aims to elucidate the relationship between OPEs exposure and thyroid disease risk in the general population in the United States. Data were obtained from the 2011-2014 National Health and Nutrition Examination Survey cycle. All participants were tested for seven OPE metabolites in their urine and answered questions about whether they had thyroid disease through questionnaires. Logistic regression was employed to analyze the association between exposure to individual OPE metabolites and thyroid disease. Weighted Quantile Sum (WQS) regression modeling was utilized to assess exposure to mixed OPE metabolites and risk of thyroid disease. Bayesian kernel machine regression(BKMR) models to analyze the overall mixed effect of OPE metabolites. A total of 2,449 participants were included in the study, 228 of whom had a history of thyroid disease. Bis(1,3-dichloro-2-propyl) phos (BDCPP), Diphenyl phosphate (DPHP) and Bis(2-chloroethyl) phosphate (BCEP) were the top three metabolites with the highest detection rates of 91.75%, 90.77% and 86.57%, respectively. In multivariate logistic regression models, after adjustment for confounding variables, individuals with the highest tertile level of BCEP were significantly and positively associated with increased risk of thyroid disease (OR=1.57, 95% CI=1.04-2.36), using the lowest tertile level as reference. In the positive WQS regression model, after correcting for confounding variables, mixed exposure to OPE metabolites was significantly positively associated with increased risk of thyroid disease (OR=1.03, 95% CI=1.01-1.06), with BCEP and DPHP having high weights. In the BKMR model, the overall effect of mixed exposure to OPE metabolites was not statistically significant, but univariate exposure response trends showed that the risk of thyroid disease decreased and then increased as BCEP exposure levels increased. The study revealed a significant association between exposure to OPE metabolites and an increased risk of thyroid disease, with BCEP emerging as the primary contributor. The risk of thyroid disease exhibits a J-shaped pattern, whereby the risk initially decreases and subsequently increases with rising levels of BCEP exposure. Additional studies are required to validate the association between OPEs and thyroid diseases.

Association of organophosphate flame retardants with all-cause and cause-specific mortality among adults aged 40 years and older

The longitudinal associations of urinary concentrations of diphenyl phosphate (DPHP), bis(2-chloroethyl) phosphate (BCEP), and bis(1,3-dichloro-2-propyl) phosphate (BDCPP) with all-cause, cardiovascular, and cancer mortality in a population of adults aged 40 years and older are still unclear. A total of 3238 participants were included in this cohort study. Urinary BCEP levels were positively associated with all-cause mortality and cardiovascular mortality. Specifically, a logarithmic increase in BCEP concentration was related to a 26 % higher risk of all-cause mortality and a 32 % higher risk of cardiovascular mortality. No significant associations were observed for DPHP and BDCPP in relation to mortality. Doseresponse analysis confirmed the linear associations of BCEP with all-cause and cardiovascular mortality and the nonlinear inverted U-shaped association between DPHP exposure and all-cause mortality. Notably, the economic burden associated with BCEP exposure was estimated, and it was shown that concentrations in the third tertile of BCEP exposure incurred approximately 507 billion dollars of financial burden for all-cause mortality and approximately 717 billion dollars for cardiovascular mortality. These results highlight the importance of addressing exposure to BCEP and its potential health impacts on the population. More research is warranted to explore the underlying mechanisms and develop strategies for reducing exposure to this harmful chemical.

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.

The relationship of organophosphate flame retardants with hyperuricemia and gout via the inflammatory response: An integrated approach

BackgroundEvidence regarding the relationships between organophosphate flame retardants (OPFRs) and hyperuricemia and gout as well as the underlying mechanisms remains scarce, but some evidence indicates that inflammation might play a key role. ObjectivesUsing an integrated approach, we aim to elucidate the associations of urinary metabolite OPFRs (m-OPFRs) with hyperuricemia and gout. MethodsCross-sectional analyses using data from the National Health and Nutrition Examination Survey were performed to reveal the associations. Adults with complete data on five m-OPFRs with high detection frequencies and outcomes were enrolled. We used multivariate logistic regression, restricted cubic spline (RCS), and Bayesian kernel machine regression (BKMR) methods to account for single, nonlinear, and joint effects. The mediating effect of the inflammatory response was also estimated. Moreover, adverse outcome pathways (AOPs) based on network analysis were further constructed to reveal the underlying mechanism. ResultsMultivariate logistic models revealed that bis(2-chloroethyl) phosphate (BCEP) significantly increased risk of hyperuricemia (OR [95 % CI]: 1.165 [1.047, 1.296]) in the fully adjusted model. Elevated levels of bis(1-chloro-2-propyl) phosphate were associated with gout (OR [95 % CI]: 1.293 [1.015, 1.647]). No nonlinear relationship was observed in RCS. There was a positive association between mixed m-OPFRs and hyperuricemia risk in BMKR, with bis(1,3-dichloro-2-propyl) phosphate and BCEP being the main contributors (PIP > 0.5). We found that the inflammatory response significantly mediated the association between BCEP and hyperuricemia (P < 0.05). Network topology analysis identified seven genes and six phenotypes related to OPFR exposure and hyperuricemia. The AOP framework suggested that the inflammatory response, especially the activation of the TNF pathway, played a core role in the above relationships. ConclusionOur results first revealed that individual and mixed OPFRs were associated with hyperuricemia, in which the inflammatory response plays an important role. Further longitudinal studies are warranted to consolidate or refute our main findings.

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.

New dechlorination products and mechanisms of tris(2-chloroethyl) phosphate by an anaerobic enrichment culture from a vehicle dismantling site

End-of-life vehicles (ELVs) dismantling sites are the notorious hotspots of chlorinated organophosphate esters (Cl-OPEs). However, the microbial-mediated dechlorination of Cl-OPEs at such sites has not yet been explored. Herein, the dechlorination products, pathways and mechanisms of tris(2-chloroethyl) phosphate (TCEP, a representative Cl-OPE) by an anaerobic enrichment culture (ZNE) from an ELVs dismantling plant were investigated. Our results showed that dechlorination of TCEP can be triggered by reductive transformation to form bis(2-chloroethyl) phosphate (BCEP), mono-chloroethyl phosphate (MCEP) and by hydrolytic dechlorination to form bis(2-chloroethyl) 2-hydroxyethyl phosphate (TCEP-OH), 2-chloroethyl bis(2-hydroxyethyl) phosphate (TCEP-2OH), 2-chloroethyl (2-hydroxyethyl) hydrogen phosphate (BCEP-OH). The combination of 16S rRNA gene amplicon sequencing, quantitative real-time PCR (qPCR) and metagenomics revealed that the Dehalococcoides played an important role in the reductive transformation of TCEP to BCEP and MCEP. A high-quality metagenome-assembled genome (completeness >99% and contamination <1%) of Dehalococcoides was obtained. The sulfate-reducing bacteria harboring haloacid dehalogenase genes (had) may be responsible for the hydrolytic dechlorination of TCEP. These findings provide insights into microbial-mediated anaerobic transformation products and mechanisms of TCEP at ELVs dismantling sites, having implications for the environmental fate and risk assessment of Cl-OPEs at those sites.

Tissue distribution and trophic transfer of organophosphate triesters and diesters in three marine mammals of the Liaodong Bay and the Northern Yellow Sea

Tissue (muscle, liver, kidney, lung, and heart) distribution and trophic transfer of organophosphate (OP) triesters and diesters in stranded 10 minke whales, 20 spotted seals and 27 East Asian finless porpoises from the Liaodong Bay and the Northern Yellow Sea were evaluated. The OP triesters and diesters were widely found in the tissues of the three marine mammals and their preys, with mean concentrations ranging from below the limits of detection (LOD) to 4342 μg/kg dry weight (dw) and from below the LOD to 1460 μg/kg dw, respectively. Tissue-specific distribution of the OP triesters or diesters were found in the investigated marine mammals with chemical-specific and species-specific. Log Kow negatively affect the accumulation of OP diesters in the marine mammals (p < 0.05), which related to their accumulation pathway in the tissues. The biological traits of the three marine mammals, body length, gender and age could affect the distribution of several OP triesters or diesters. Yet more concern is that significantly biological magnification was found for bis(2-chloroethyl) phosphate (BCEP) with trophic magnification factor (TMF) of 5.36 and for tris(2-ethylhexyl) phosphate (TEHP)(TMF:2.88) along with the finless porpoise food web. These results considerably contribute to expanding understanding of OP triesters or diesters pollution on the organisms in marine ecosystem.

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.

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.

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.

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

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

Early-life exposure to a mixture of organophosphate esters and child behavior.

Organophosphate esters (OPEs), widely used as flame retardants and plasticizers for commercial and residential purposes, are suspected of being neurotoxic. We aimed to assess exposure to an OPE mixture in early life and its relationship to parent-reported child behavior. We measured urinary concentrations of three OPE metabolites, bis-2-chloroethyl phosphate (BCEP), bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), and diphenyl phosphate (DPHP), at pregnancy (16 and 26 weeks of gestation and delivery) and postnatal time points (ages 1, 2, 3, and 5 years) in the Health Outcomes and Measures of the Environment Study, a longitudinal pregnancy and birth cohort in Cincinnati, Ohio, USA (enrolled 2003-2006, n=219). We used latent variable analysis in structural equations models and quantile g-computation to investigate associations of a mixture of the three OPE metabolites with parent-reported child behaviors at 3 and 8 years, measured using the Behavioral Assessment System for Children, Second Edition. Higher log-transformed urinary OPE latent variable values at 16 weeks were associated with fewer externalizing problem behaviors (ß=-5.74; 95% CI=-11.24, -0.24) and fewer overall behavioral problems at age 3 years (ß=-5.26; 95% CI=-10.33, -0.19), whereas having higher OPEs at delivery was associated with poorer overall behavioral problems at age 3 years (ß=2.87; 95% CI=0.13, 5.61). OPE latent variable values at 16 weeks, 26 weeks, and delivery were not associated with child behavior at 8 years. However, higher OPE latent variable values at 3 years were associated with fewer externalizing behaviors at 8 years (ß=-2.62; 95% CI=-5.13, -0.12). The quantile g-computation estimates had directions largely consistent with the latent variable analysis results. Pregnancy and postnatal urinary OPE metabolite mixtures were associated with child internalizing, externalizing, and overall negative behaviors at 3 and 8 years, but we did not identify a consistent pattern in terms of the direction of the effects or a particularly sensitive time point.

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.

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.

Gestational exposure to organophosphate esters and adiposity measures of children up to 6 years: Effect modification by breastfeeding

Organophosphate esters (OPEs) are synthetic chemicals used in various commercial products. Accumulating evidence has shown that they may act as metabolic disruptors. However, no study has investigated the long-term effects of gestational OPEs exposure on childhood adiposity. Breast milk represents the optimal nutritional form of feeding for infants and may protect against the adverse effects of gestational OPEs exposure on offspring development. Using data from the Shanghai-Minhang birth cohort study, we investigated the associations of gestational OPEs exposure with adiposity measures in children up to 6 years of age, and whether breastfeeding could modify these associations. A total of 733 mother-child pairs with available data on OPE concentrations and child anthropometry were included. Eight OPE metabolites were assessed in maternal urine samples collected at 12-16 weeks of pregnancy. Information on children's weight, height, arm circumference, and waist circumference was collected at birth and 0.5, 1, 4, and 6 years of age. Weight-for-age and body mass index-for-age z scores were calculated. The duration of children's breastfeeding was categorized as ≤4 months or >4 months. The generalized estimate equation and Bayesian Kernel Machine Regression models were used to examine the associations of OPEs exposure with children's adiposity measures. Selected OPEs exposure was associated with higher children's adiposity measures. Particularly, we found stronger associations of bis(1-chloro-2-propyl) phosphate (BCIPP), bis(2-chloroethyl) phosphate (BCEP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP), and di-o-cresyl phosphate and di-p-cresyl phosphate (DCP) with higher adiposity measures in children breastfed for ≤4 months, while little evidence of associations was found among those breastfed for >4 months. Our study suggested that gestational OPEs exposure could alter children's adiposity measures, but the potential effects were attenuated if children were breastfed for >4 months.