Organophosphate Flame Retardants Metabolites Research Articles

Global Trends and Hotspots in Research on the Health Risks of Organophosphate Flame Retardants: A Bibliometric and Visual Analysis.

Organophosphate flame retardants (OPFRs) are compounds with a wide range of industrial and commercial applications and are mainly used as flame retardants and plasticizers. The global consumption of OPFRs has risen rapidly in recent decades, and they have been widely detected in environmental media. Unfortunately, OPFRs have been associated with many adverse health outcomes. The issue of the health risks of OPFRs is attracting increasing attention. Therefore, there is a need to review the current state of research and trends in this field to help researchers and policymakers quickly understand the field, identify new research directions, and allocate appropriate resources for further development of the OPFR health risk research field. This study statistically analyzed 1162 relevant publications included in the Web of Science Core Collection from 2003-2023. The internal and external features of the literature, such as publication trends, countries, authors, journals, and keywords, were quantitatively analyzed and visually presented to identify the research hotspots, compositions, and paradigms of the field and to horizontally and vertically analyze the development trends and structural evolution of the field. The development of the field can be divided into three stages, and the field entered a period of rapid development in 2016. China (649 papers) is the most prolific country, followed by the United States (188 papers). The authors STAPLETON HM and WANG Y have the highest combined impact. International collaboration between countries and researchers still needs to be strengthened. Science of The Total Environment is the most frequently published journal (162 papers), and Environmental Science and Technology is the most frequently cited journal (5285 citations). Endocrine disruption, developmental toxicity, and neurotoxicity are the health effects of greatest interest. Future research is expected to be multidisciplinary, and research hotspots may involve a comprehensive assessment of OPFR exposure in the population, exploration of the mechanisms of endocrine-disrupting effects and in vivo metabolic processes, and examination of the health effects of OPFR metabolites.

Cognitive Performance and Exposure to Organophosphate Flame Retardants in Children: Evidence from a Cross-Sectional Analysis of Two European Mother-Child Cohorts.

The knowledge of the effects of organophosphate flame retardants on children's neurodevelopment is limited. The purpose of the present research is to evaluate the association between exposure to organophosphate flame retardants and children's neurodevelopment in two European cohorts involved in the Human Biomonitoring Initiative Aligned Studies. The participants were school-aged children belonging to the Odense Child Cohort (Denmark) and the PCB cohort (Slovakia). In each cohort, the children's neurodevelopment was assessed through the Full-Scale Intelligence Quotient score of the Wechsler Intelligence Scale for Children, using two different editions. The children's urine samples, collected at one point in time, were analyzed for several metabolites of organophosphate flame retardants. The association between neurodevelopment and each organophosphate flame retardant metabolite was explored by applying separate multiple linear regressions based on the approach of MM-estimation in each cohort. In the Danish cohort, the mean ± standard deviation for the neurodevelopment score was 98 ± 12; the geometric mean (95% confidence interval (95% CI)) of bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) standardized by creatinine (crt) was 0.52 µg/g crt (95% CI = 0.49; 0.60), while that of diphenyl phosphate (DPHP) standardized by crt was 1.44 µg/g crt (95% CI = 1.31; 1.58). The neurodevelopment score showed a small, negative, statistically imprecise trend with BDCIPP standardized by crt (β = -1.30; 95%CI = -2.72; 0.11; p-value = 0.07) and no clear association with DPHP standardized by crt (β = -0.98; 95%CI = -2.96; 0.99; p-value = 0.33). The neurodevelopment score showed a negative trend with BDCIPP (β = -1.42; 95% CI = -2.70; -0.06; p-value = 0.04) and no clear association with DPHP (β = -1.09; 95% CI = -2.87; 0.68; p-value = 0.23). In the Slovakian cohort, the mean ± standard deviation for the neurodevelopment score was 81 ± 15; the geometric mean of BDCIPP standardized by crt was 0.18 µg/g crt (95% CI = 0.16; 0.20), while that of DPHP standardized by crt was 2.24 µg/g crt (95% CI = 2.00; 3.52). The association of the neurodevelopment score with BDCIPP standardized by crt was -0.49 (95%CI = -1.85; 0.87; p-value = 0.48), and with DPHP standardized by crt it was -0.35 (95%CI = -1.90; 1.20; p-value = 0.66). No clear associations were observed between the neurodevelopment score and BDCIPP/DPHP concentrations that were not standardized by crt. No clear associations were observed with bis(1-chloro-2-propyl) phosphate (BCIPP) in either cohort, due to the low detection frequency of this compound. In conclusion, this study provides only limited evidence of an inverse association between neurodevelopment and exposure to BDCIPP and DPHP. The timing of exposure and effect modification of other organophosphate flame retardant metabolites and other substances should be the subject of further investigations that address this scientific hypothesis.

Levels of organophosphate flame retardants and their metabolites among 391 volunteers in Taiwan: difference between adults and children.

Organophosphate flame retardants (OPFRs) are ubiquitous in the environment. The compositions and concentrations of different OPFRs metabolites vary in different environments depending on different human activities. The objective of the present study was to evaluate the exposure of different age groups to OPFRs in Taiwan. Volunteers provided urine samples and responded to questionnaires including demographic factors, underlying disease, lifestyle information, and occupation from October 2021 to January 2022. OPFR measurements were performed using a Waters Acquity Ultra-Performance Liquid Chromatography system coupled with a Waters Xevo TQ-XS mass spectrometer. A total of 391 volunteers (74 children and 317 adults) were enrolled in this study. The concentrations (presented as μg/g creatinine) of bis(1,3-dichloro-2-propyl) phosphate (BDCPP, p = 0.029) and tri-n-butyl phosphate (TNBP, p = 0.008) were higher in the adult group, while the concentrations of bis-2-chloroethyl phosphate (BCEP, p = 0.024), diphenyl phosphate (DPHP, p < 0.001), tris(1,3-dichloro-2-propyl) phosphate (TDCPP, p = 0.009), and Tris(2-butoxyethyl) phosphate (TBEP, p = 0.007) were higher in the child group. Compared with school age children (>6 years), the concentration of di(2-n-butoxyethyl) phthalate (DBEP, 1.14 vs. 0.20 μg/g creatinine, p = 0.001), DPHP (1.23 vs. 0.54 μg/g creatinine, p = 0.036), TBEP (1.63 vs. 0.29 μg/g creatinine, p < 0.001), and the sum of OPFR metabolites (ΣOPFRs, 6.58 vs. 2.04 μg/g creatinine, p < 0.001) were statistically higher in preschool-aged children. After adjusting for confounding factors, pre-school age [odds ratio (OR): 4.579, 95% confidence interval (CI): 1.389-13.115] and current smoker (OR: 5.328, 95%CI: 1.858-14.955) were independently associated with the risk of ΣOPFRs higher than 90 percentile. This study revealed the distribution of different OPFRs metabolites in children and adults. DBEP, DPHP, TBEP, and ΣOPFR were higher in preschool-aged children. Pre-school age and current smoking status were independent risk factors for ΣOPFRs higher than 90 percentile.

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

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

Urinary levels of organophosphate flame retardants metabolites in a young population from Southern Taiwan and potential health effects.

Organophosphate flame retardants (OPFRs) are widely distributed in the environment and their metabolites are observed in urine, but little is known regarding OPFRs in a broad-spectrum young population from newborns to those aged 18 years. Investigate urinary levels of OPFRs and OPFR metabolites in Taiwanese infants, young children, schoolchildren, and adolescents within the general population. Different age groups of subjects (n=136) were recruited from southern Taiwan to detect 10 OPFR metabolites in urine samples. Associations between urinary OPFRs and their corresponding metabolites and potential health status were also examined. The mean level of urinary Σ10 OPFR in this broad-spectrum young population is 2.25 μg/L (standard deviation (SD) of 1.91 μg/L). Σ10 OPFR metabolites in urine are 3.25 ± 2.84, 3.06 ± 2.21, 1.75 ± 1.10, and 2.32 ± 2.29 μg/L in the age groups comprising of newborns, 1-5 year-olds, 6-10 year-olds, and 11-18 year-olds, respectively, and borderline significant differences were found in the different age groups (p=0.125). The OPFR metabolites of TCEP, BCEP, DPHP, TBEP, DBEP, and BDCPP predominate in urine and comprise more than 90% of the total. TBEP was highly correlated with DBEP in this population (r=0.845, p<0.001). The estimated daily intake (EDI) of Σ5OPFRs (TDCPP, TCEP, TBEP, TNBP, and TPHP) was 2,230, 461, 130, and 184 ng/kg bw/day for newborns, 1-5 yr children, 6-10 yr children, and 11-17 yr adolescents, respectively. The EDI of Σ5OPFRs for newborns was 4.83-17.2 times higher than the other age groups. Urinary OPFR metabolites are significantly correlated with birth length and chest circumference in newborns. To our knowledge, this is the first investigation of urinary OPFR metabolite levels in a broad-spectrum young population. There tended to be higher exposure rates in both newborns and pre-schoolers, though little is known about their exposure levels or factors leading to exposure in the young population. Further studies should clarify the exposure levels and factor relationships.

Organophosphate Flame Retardants in Pregnant Women: Sources, Occurrence, and Potential Risks to Pregnancy Outcomes

Organophosphate flame retardants (OPFRs) are found in various environmental matrixes and human samples. Exposure to OPFRs during gestation may interfere with pregnancy, for example, inducing maternal oxidative stress and maternal hypertension during pregnancy, interfering maternal and fetal thyroid hormone secretion and fetal neurodevelopment, and causing fetal metabolic abnormalities. However, the consequences of OPFR exposure on pregnant women, impact on mother-to-child transmission of OPFRs, and harmful effects on fetal and pregnancy outcomes have not been evaluated. This review describes the exposure to OPFRs in pregnant women worldwide, based on metabolites of OPFRs (mOPs) in urine for prenatal exposure and OPFRs in breast milk for postnatal exposure. Predictors of maternal exposure to OPFRs and variability of mOPs in urine have been discussed. Mother-to-child transmission pathways of OPFRs have been scrutinized, considering the levels of OPFRs and their metabolites in amniotic fluid, placenta, deciduae, chorionic villi, and cord blood. The results showed that bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and diphenyl phosphate (DPHP) were the two predominant mOPs in urine, with detection frequencies of >90%. The estimated daily intake (EDIM) indicates low risk when infants are exposed to OPFRs from breast milk. Furthermore, higher exposure levels of OPFRs in pregnant women may increase the risk of adverse pregnancy outcomes and influence the developmental behavior of infants. This review summarizes the knowledge gaps of OPFRs in pregnant women and highlights the crucial steps for assessing health risks in susceptible populations, such as pregnant women and fetuses.

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.

Exposure to flame retardants in European children - Results from the HBM4EU aligned studies.

Many legacy and emerging flame retardants (FRs) have adverse human and environmental health effects. This study reports legacy and emerging FRs in children from nine European countries from the HBM4EU aligned studies. Studies from Belgium, Czech Republic, Germany, Denmark, France, Greece, Slovenia, Slovakia, and Norway conducted between 2014 and 2021 provided data on FRs in blood and urine from 2136 children. All samples were collected and analyzed in alignment with the HBM4EU protocols. Ten halogenated FRs were quantified in blood, and four organophosphate flame retardants (OPFR) metabolites quantified in urine. Hexabromocyclododecane (HBCDD) and decabromodiphenyl ethane (DBDPE) were infrequently detected (<16% of samples). BDE-47 was quantified in blood from Greece, France, and Norway, with France (0.36ng/g lipid) having the highest concentrations. BDE-153 and -209 were detected in <40% of samples. Dechlorane Plus (DP) was quantified in blood from four countries, with notably high median concentrations of 16ng/g lipid in Slovenian children. OPFR metabolites had a higher detection frequency than other halogenated FRs. Diphenyl phosphate (DPHP) was quantified in 99% of samples across 8 countries at levels ∼5 times higher than other OPFR metabolites (highest median in Slovenia of 2.43ng/g lipid). FR concentrations were associated with lifestyle factors such as cleaning frequency, employment status of the father of the household, and renovation status of the house, among others. The concentrations of BDE-47 in children from this study were similar to or lower than FRs found in adult matrices in previous studies, suggesting lower recent exposure and effectiveness of PBDE restrictions.

Chlorinated Organophosphate Flame Retardants Impair the Lung Function via the IL-6/JAK/STAT Signaling Pathway.

Toxicological studies have revealed the adverse impacts of organophosphate flame retardants (OPFRs) on the respiratory system, while there is a lack of epidemiological evidence, and information for risk assessment remains insufficient. Herein, we investigated the associations of urinary metabolites of OPFRs with the lung function in 987 adults participating in the U.S. National Health and Nutrition Examination Survey 2011-2012. The elevation of three primary metabolites of chlorinated OPFRs [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), bis(2-chloroethyl) phosphate (BCEP), and bis(1-chloro-2-propyl) phosphate (BCIPP)] was related to pulmonary dysfunction in a sample-weighted regression model. Each one-unit increase in the log-transformed levels of BDCIPP and BCEP was related to 91.52 and 79.34 mL reductions in the forced vital capacity (FVC). Each one-unit elevation in BCIPP was correlated with 130.86, 153.56, 302.26, and 148.24 mL reductions in forced expiratory volume 1st second (FEV1), FVC, peak expiratory flow rate (PEF), and forced expiratory flow at 25-75% of FVC (FEF25-75%), respectively. Then, an adverse outcome pathway (AOP) framework was constructed using the Comparative Toxicogenomics Database, the Toxicity Forecaster, and the GeneCards database. Based on the weight of the evidence, BDCIPP, BCEP, BCIPP, and their parent compounds (TDCIPP, TCEP, and TCIPP) may affect the IL-6/Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, induce airway remodeling, and impair the lung function. Additionally, tobacco smoke exposure may modify the effects of BDCIPP on the lung function (Pint < 0.05) and affect the IL-6-mediated AOP. These results suggested that chlorinated OPFRs were associated with pulmonary dysfunction via the IL-6/JAK/STAT pathway.

Simultaneous determination of 16 urinary metabolites of organophosphate flame retardants and organophosphate pesticides by solid phase extraction and ultra performance liquid chromatography coupled to tandem mass spectrometry

Organophosphate flame retardants (OPFRs) and organophosphate pesticides (OPPs), pertaining to organophosphate esters, are ubiquitous in environment and have been verified to pose noticeable risks to human health. To evaluate human exposures to OPFRs and OPPs, a fast and sensitive approach based on a solid phase extraction (SPE) followed by the ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) detection has been developed for the simultaneous analysis of multiple organophosphorus metabolites in urine. The method allows the identification and quantification of ten metabolites of the most common OPFRs and all six dialkylphosphates (DAPs) of OPPs concerning the population exposure characteristics. The method provided good linearities (R2 = 0.998–0.999), satisfactory method detection limits (MDLs) (0.030–1.129 ng/mL) and only needed a small volume (200 μL) of urine. Recovery rates ranged 73.4–127.1% at three spiking levels (2, 10 and 25 ng/mL urine), with both intra- and inter-day precision less than 14%. The good correlations for DAPs in a cross-validation test with a previous gas chromatography-mass spectrometry (GC-MS) method and a good inter-laboratory agreement for several OPFR metabolites in a standard reference material (SRM 3673) re-enforced the precision and validity of our method. Finally, the established method was successfully applied to analyze 16 organophosphorus metabolites in 35 Chinese children's urine samples. Overall, by validating the method's sensitivity, accuracy, precision, reproducibility, etc., data reliability and robustness were ensured; and the satisfactory pilot application on real urine samples demonstrated feasibility and acceptability of this method for being implemented in large population-based studies.

Associations between polyfluoroalkyl substance and organophosphate flame retardant exposures and telomere length in a cohort of women firefighters and office workers in San Francisco

BackgroundEnvironmental chemical exposures can affect telomere length, which in turn has been associated with adverse health outcomes including cancer. Firefighters are occupationally exposed to many hazardous chemicals and have higher rates of certain cancers. As a potential biomarker of effect, we assessed associations between chemical exposures and telomere length in women firefighters and office workers from San Francisco, CA.MethodsWe measured serum concentrations of polyfluoroalkyl substances (PFAS), urinary metabolites of flame retardants, including organophosphate flame retardants (OPFRs), and telomere length in peripheral blood leukocytes in women firefighters (N = 84) and office workers (N = 79) who participated in the 2014–15 Women Workers Biomonitoring Collaborative. Multiple linear regression models were used to assess associations between chemical exposures and telomere length.ResultsRegression results revealed significant positive associations between perfluorooctanoic acid (PFOA) and telomere length and perfluorooctanesulfonic acid (PFOS) and telomere length among the whole cohort. Models stratified by occupation showed stronger and more significant associations among firefighters as compared to office workers. Among firefighters in models adjusted for age, we found positive associations between telomere length and log-transformed PFOA (β (95%CI) = 0.57(0.12, 1.02)), PFOS (0.44 (0.05, 0.83)), and perfluorodecanoic acid (PFDA) (0.43 (0.02, 0.84)). Modeling PFAS as categories of exposure showed significant associations between perfluorononanoic acid (PFNA) and telomere length among firefighters. Significant associations between OPFR metabolites and telomere length were seen for bis (1,3-dichloro-2-propyl) phosphate (BDCPP) and telomere length among office workers (0.21(0.03, 0.40)) and bis (2-chloroethyl) phosphate (BCEP) and telomere length among firefighters (− 0.14(− 0.28, − 0.01)). For OPFRs, the difference in the direction of effect by occupational group may be due to the disparate detection frequencies and concentrations of exposure between the two groups and/or potential unmeasured confounding.ConclusionOur findings suggest positive associations between PFAS and telomere length in women workers, with larger effects seen among firefighters as compared to office workers. The OPFR metabolites BDCPP and BCEP are also associated with telomere length in firefighters and office workers. Associations between chemical exposures and telomere length reported here and by others suggest mechanisms by which these chemicals may affect carcinogenesis and other adverse health outcomes.

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

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

High-throughput biomonitoring of organophosphate flame-retardant metabolites in urine via 96-blade solid-phase microextraction coupled with ultra-performance liquid chromatography-tandem mass spectrometry

Organophosphate flame retardants (OPFRs) are widely used in consumer products and building materials, but their propensity for migration poses a problem with respect to polluting indoor environments, water, soil, and dust. OPFR metabolites in urine samples are appropriate biomarkers for assessing exposure risk levels. In this paper, a high-throughput method that couples 96-blade solid-phase microextraction with ultra-performance liquid chromatography-tandem mass spectrometry (SPME-UPLC-MS/MS) is applied for the simultaneous detection of four OPFR metabolites in urine samples. The results indicated that the best extraction was achieved using 96 blades coated with hydrophilic-lipophilic balance weak anion exchange (HLB-WAX). The proposed SPME method's extraction efficiency was maximized by optimizing extraction time, pH value, desorption solution, desorption volume, and desorption time, and it was validated in accordance with the Food and Drug Administration's guidelines. The findings indicated that the proposed method has a wide linearity range (0.5–100 ng mL−1) and low detection limits (0.09–0.14 ng mL−1). The method's accuracy ranged from 98% to 118%, with intra-day precision ranging from 1% to 10%. In contrast, inter-day precision ranged from 3% to 16%. Accuracy was also evaluated using independent urine samples, which ranged from 78% to 124% with corresponding relative standard deviations (1%–16%). Ultimately, DoCP was detected in two real samples at a concentration of 0.5–1.1 ng mL−1, and BEHP was detected at a concentration of 0.2–1.2 ng mL−1. Overall, the proposed SPME-UPLC-MS/MS method is reliable, accurate, and capable of simultaneously determining four OPFR metabolites in urine samples and screening them to assess exposure risk for humans.

Organophosphate Flame Retardants, Highly Fluorinated Chemicals, and Biomarkers of Placental Development and Disease During Mid-Gestation.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) and organophosphate flame retardants (OPFRs) are chemicals that may contribute to placenta-mediated complications and adverse maternal-fetal health risks. Few studies have investigated these chemicals in relation to biomarkers of effect during pregnancy. We measured 12 PFASs and four urinary OPFR metabolites in 132 healthy pregnant women during mid-gestation and examined a subset with biomarkers of placental development and disease (n = 62). Molecular biomarkers included integrin alpha-1 (ITGA1), vascular endothelial-cadherin (CDH5), and matrix metalloproteinase-1 (MMP1). Morphological endpoints included potential indicators of placental stress and the extent of cytotrophoblast (CTB)-mediated uterine artery remodeling. Serum PFASs and urinary OPFR metabolites were detected in ∼50%-100% of samples. The most prevalent PFASs were perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), and perfluorooctane sulfonic acid (PFOS), with geometric mean (GM) levels of ∼1.3-2.8 (95% confidence limits from 1.2-3.1) ng/ml compared to ≤0.5 ng/ml for other PFASs. Diphenyl phosphate (DPhP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) were the most prevalent OPFR metabolites, with GMs of 2.9 (95% CI: 2.5-3.4) and 3.6 (95% CI: 2.2-3.1) ng/ml, respectively, compared to <1 ng/ml for bis(2-chloroethyl) phosphate (BCEP) and bis(1-chloro-2-propyl) phosphate (BCIPP). We found inverse associations of PFASs or OPFRs with ITGA1 or CDH5 immunoreactivity and positive associations with indicators of placental stress in multiple basal plate regions, indicating these chemicals may contribute to abnormal placentation and future health risks. Associations with blood pressure and lipid concentrations warrant further examination. This is the first study of these chemicals with placental biomarkers measured directly in human tissues and suggests specific biomarkers are sensitive indicators of exposure during a vulnerable developmental period.

Exposure to organophosphate flame esters during early pregnancy and risk of spontaneous abortion: A case-control study

Prenatal exposure to organophosphate flame retardants (OPFRs) has been associated with adverse pregnancy outcomes including low birth weight and preterm birth. However, no study has addressed the impacts of OPFRs exposure on spontaneous abortion (SAB) and fetal chromosome abnormalities. We examined whether prenatal exposure to OPFRs was associated with increased risk of SAB and fetal chromosome abnormalities. A total of 272 pregnant women, including 136 SAB cases and 136 healthy controls, were enrolled in this case-control study. Urinary concentrations of 3 OPFRs metabolites (diphenyl phosphate (DPHP), bis (1,3-dichloro-2-propyl) phosphate (BDCIPP) and bis (1-chloro-2-propyl) phosphate (BCIPP)) were measured using ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). More than 70% of the urine samples detected quantifiable levels of 3 OPFRs metabolites. Concentrations of BCIPP were significantly higher in SAB cases than in healthy controls. Higher urinary BCIPP levels were associated with increased risk of SAB. Per unit increase in ln-transformed BCIPP concentrations was associated with 103% (OR = 2.03, 95% CI, 1.57, 2.63) increase in the odds of SAB. While higher BDCIPP levels were associated with increased risk of fetal chromosome abnormalities and the corresponding OR associated with a unit increase in ln-transformed BDCIPP concentrations were 2.34 (95% CI, 1.14, 4.81). Our results suggested the potential developmental toxicity and teratogenicity of some OPFRs.

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.

Moving toward understanding specific pathways of inflammation in pregnancy: prenatal exposure to consumer product chemicals and changes in plasma eicosanoids

Background. Exposure to consumer product chemicals during pregnancy can influence maternal inflammation, making mothers and infants more susceptible to pregnancy-related disorders. These chemicals can differentially affect inflammatory pathways, but specific pathways during pregnancy are not well characterized. Eicosanoids, an important class of lipid mediators that influence key pathways of inflammation, can now be measured in comprehensive lipid panels. We aimed to determine the association between plasma eicosanoids and urinary biomarkers of three classes of consumer product chemicals among pregnant women.Methods. Our data come from a pilot study of 90 pregnant women nested within the LIFECODES birth cohort study. Maternal plasma and urine were collected at up to three prenatal visits. Plasma was analyzed for 61 eicosanoids, which were grouped into biosynthetic pathways defined by the upstream: 1) fatty acid precursor, including linoleic, arachidonic, docosahexaenoic, or eicosapentaenoic acid; and 2) enzyme pathway, including cyclooxygenase, lipoxygenase, or cytochrome P450. Urine was analyzed for three chemical classes, including 12 phthalate metabolites, 12 phenols, and 9 organophosphate flame retardant metabolites (OPFRs). Each eicosanoid-chemical association was examined using repeated measures from generalized additive mixed effects models. Quantile g-computation was used to examine the association between eicosanoids and a simultaneous increase in all chemicals within each class mixture.Results. Both single-pollutant and mixture analyses showed positive associations between phthalates and phenols with specific eicosanoid pathways. The most consistent associations were between phthalate metabolites and eicosanoids produced from arachidonic acid by lipoxygenase or cyclooxygenase enzymes. In the mixture analyses, a quartile increase in all di-2(ethylhexyl)-phthalate metabolites were most strongly associated with prostaglandin E2 (β = 1.61, 95% confidence interval: 0.98, 2.24).Conclusions. We estimate that higher exposure to phthalates and phenols, but not OPFRs, is associated with elevated inflammation-related eicosanoids, which can provide insight into specific exposure-related pathways of maternal inflammation during pregnancy.

Temporal variability of organophosphate flame retardant metabolites in spot, first morning, and 24-h urine samples among healthy adults

A single measurement of organophosphate flame retardant (OPFR) metabolites in a spot sample is often used in epidemiological studies to estimate individual exposures. Over seven consecutive days, we collected 661 spot samples, including 127 first morning voids (FMVs) and 123 simulated 24-h collections, from 20 healthy adults and analyzed for eight OPFR metabolites. Intraclass correlation coefficients (ICCs) were calculated to evaluate the variability of the analyzed metabolites. In spot samples group, serial measurements of OPFR metabolites showed poor reproducibility (0.0422 ≤ ICC ≤ 0.349), and the within-day variability was the main contributor of the total variability. The estimated ICCs based on different correction methods for urine dilution (i.e., specific gravity-adjusted, creatinine-adjusted, and creatinine as a covariate) were similar, but varied according to gender and body mass index. Uniformly low sensitivities (0.417–0.633) were observed when using a single FMV or spot sample to predict the 1-week highly (top 33.0%) exposed volunteers. Therefore, using a single urinary measurement to predict chronic exposure to OPFRs can lead to a high degree of classification errors. When multiple urine samples are collected, considering the sampling type, the time of collection, and demographic characteristics may provide a more complete approach to assess exposure to diverse OPFRs.

New Insights in the Endocrine Disrupting Effects of Three Primary Metabolites of Organophosphate Flame Retardants

Despite the ubiquity of organophosphate flame retardants (OPFRs) metabolites in the biota, the endocrine disrupting potency has not been well examined. Herein, we chose three primary metabolites of OPFRs (BCIPP, BDCIPP, and DPHP) to investigate their potential endocrine disrupting effects by in vitro, in vivo, and in silico assays. Three metabolites were agonistic to rat estrogenic receptor alpha (ERα) and antagonists to human mineralocorticoid receptor (MR). BCIPP exerted endocrine disrupting effect contrasting to the negative response of its parental compound. It also poses the strongest binding capacity to ERα among the tested compounds. Both BCIPP and BDCIPP upregulated the genes encoded for estrogenic synthesis enzymes in H295R cells, including 17βHSD and CYP19. All three compounds stimulated the transcription of CYP11B1, whereas BCIPP and DPHP also triggered CYP11B2, encoding for corticoid production. BDCIPP inhibits genes for progesterone synthesis including CYP11A1, STAR, and 3-βHSD. The induction of mortality and low hatchability of zebrafish embryo were ranked as BCIPP ≥ BDCIPP > DPHP. All compounds lead to malformation of zebrafish larvae. Both of the hypothalamic-pituitary-adrenocortical and hypothalamic-pituitary-gonadal axes were disrupted, with the highest impact by BCIPP. Altogether, the data clarified OPFRs metabolites may produce comparable or even higher endocrine disrupting effects than OPFRs.

Association of urinary metabolites of organophosphate flame retardants with chronic kidney function markers in the US general population

Association of urinary metabolites of organophosphate flame retardants with chronic kidney function markers in the US general population