PFR Metabolites Research Articles

Exposure to organophosphate flame retardants and plasticizers is positively associated with wheeze and FeNO and eosinophil levels among school-aged children: The Hokkaido study

Exposure to organophosphate flame retardants and plasticizers (PFRs) increases the risk of asthma and allergies. However, little is known about its association with type 2 inflammation (T2) biomarkers used in the management of allergies. The study investigated associations among urinary PFR metabolite concentrations, allergic symptoms, and T2 biomarkers. The data and samples were collected between 2017 and 2020, including school children (n = 427) aged 9–12 years living in Sapporo City, Japan, among the participants of “The Hokkaido Study on Environment and Children’s Health.” Thirteen urinary PFR metabolites were measured by LC-MS/MS. Allergic symptoms were assessed using the International Study of Asthma and Allergies in Childhood questionnaire. For T2 biomarkers, the peripheral blood eosinophil counts, fraction of exhaled nitric oxide level (FeNO), and serum total immunoglobulin E level were measured. Multiple logistic regression analysis, quantile-based g-computation (qg-computation), and Bayesian kernel machine regression (BKMR) were used to examine the associations between the health outcomes of the individual PFRs and the PFR mixtures. The highest concentration of PFR was Σtris(1-chloro-isopropyl) phosphates (ΣTCIPP) (Median:1.20 nmol/L). Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) was significantly associated with a high odds ratio (OR, 95%CI:1.36, 1.07–1.72) for wheeze. TDCIPP (OR, 95%CI:1.19, 1.02–1.38), Σtriphenyl phosphate (ΣTPHP) (OR, 95%CI:1.81, 1.40–2.37), and Σtris(2-butoxyethyl) phosphate (ΣTBOEP) (OR, 95%:1.40, 1.13–1.74) were significantly associated with increased odds of FeNO (≥35 ppb). ΣTPHP (OR, 95%CI:1.44, 1.15–1.83) was significantly associated with high eosinophil counts (≥300/μL). For the PFR mixtures, a one-quartile increase in all PFRs (OR, 95%CI:1.48, 1.18–1.86) was significantly associated with high FeNO (≥35 ppb) in the qg-computation model. The PFR mixture was positively associated with high FeNO (≥35 ppb) and eosinophil counts (≥300/μL) in the BKMR models. These results may suggest that exposure to PFRs increases the probability of asthma, allergies, and T2 inflammation.

Exposure levels, determinants and risk assessment of organophosphate flame retardants and plasticizers in adolescents (14–15 years) from the Flemish Environment and Health Study

The ubiquitous use of organophosphate flame retardants and plasticizers (PFRs) in a variety of consumer products has led to widespread human exposure. Since certain PFRs are developmental and carcinogenic toxicants, detailed exposure assessments are essential to investigate the risk associated with environmental exposure levels. However, such data are still lacking for European countries. In this study, concentrations of thirteen PFR metabolites were measured in urine samples from 600 adolescents from Flanders, Belgium. 1-Hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP), diphenyl phosphate (DPHP), bis(1,3-dichloro-isopropyl) phosphate (BDCIPP), 2-hydroxyethyl bis(2-butoxyethyl) phosphate (BBOEHEP), 2-ethylhexyl phenyl phosphate (EHPHP) and 2-ethyl-5-hydroxyhexyl diphenyl phosphate (5-HO-EHDPHP) were frequently detected (>83%) in all participants. Comparisons with study populations from outside the EU showed that urinary levels of DPHP, BDCIPP and BCIPHIPP were generally within the same range. Only exposure to 2-ethylhexyl diphenyl phosphate (EHDPHP) was presumably higher in Flemish adolescents. However, determinants analysis through multivariate regression analyses did not reveal significant predictors that may explain this finding. Significantly higher levels of BDCIPP were observed in participants with new decorations at home, while adolescents with highly educated parents had higher levels of BBOEHEP and BDCIPP. Furthermore, multiple PFR metabolite concentrations followed a seasonal pattern. Estimated daily intakes (EDIs) were calculated from the internal dose by including fractions of urinary excretion (FUE) estimated in in vitro metabolism studies. EDIs ranged from 6.3 ng/kg bw/day for TBOEP to 567.7 ng/kg bw/day for EHDPHP, which were well below the available oral reference doses for all investigated PFRs. This suggests that the associated risk is low at present. This is the first report on internal exposure to seven commonly used PFRs in a European population.

Short-term temporal variability of urinary biomarkers of organophosphate flame retardants and plasticizers

BackgroundExposure to organophosphate flame retardants and plasticizers (PFRs) is commonly estimated by measuring biomarker concentrations in spot urine samples. However, their concentrations in urine can vary greatly over time due to short biological half-lives and variable exposure, potentially leading to exposure misclassification. In this study, we examined the within- and between-individual and within- and between-day variability of PFR metabolites in spot and 24-hour pooled urine samples during five consecutive days. MethodsWe collected all spot urine samples from 10 healthy adults for 5 days. On one additional day, we collected 24-hour pooled urine samples. Samples were analyzed by solid-phase extraction coupled to high-performance liquid chromatography tandem mass spectrometry. We calculated intraclass correlation coefficients (ICCs) to assess the reproducibility of metabolite concentrations in morning void and spot samples. ResultsFair-to-good reproducibility was observed for serial measurements of bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP), 2-hydroxyethyl bis(2-butoxyethyl) phosphate (BBOEHEP) and 2-ethyl-5-hydroxyhexyl diphenyl phosphate (5-HO-EHDPHP) (ICC: 0.396 – 0.599), whereas concentrations of diphenyl phosphate (DPHP) and 2-ethylhexyl phenyl phosphate (EHPHP) were more variable in time (ICC: 0.303 and 0.234). Reproducibility improved significantly when only morning void samples were considered and when concentrations were adjusted for urinary dilution. Collecting 24-hour pooled urine could be a reliable alternative for PFR biomarkers with poor short-term temporal variability. ConclusionsThe between-day variability was minor compared to variability observed within the same day, which suggests that collecting multiple samples could reduce exposure missclassification. Differences in the observed between- and within-individual variance were compound specific and related to both the nature of the exposure (e.g., diet vs other exposure routes, multiple sources) and the individual toxicokinetic properties of the investigated PFRs.

Occurrence, biomagnification and maternal transfer of legacy and emerging organophosphorus flame retardants and plasticizers in water snake from an e-waste site

Water snake and small common carp samples collected from a Chinese pond polluted with electronic waste (e-waste) were analyzed for organophosphorus flame retardants (PFRs), PFR metabolites, and plasticizers to investigate their occurrence, biomagnification, and maternal transfer in ovoviviparous species. Mean concentrations of total PFRs, PFR metabolites, and plasticizers were 2.2–16, 1.3–2.8 and 151–1320 ng/g wet weight (ww), respectively in analyzed organisms. Metabolites of PFRs were found in the same order of magnitude as or even higher than their parent compounds, indicating the importance of monitoring metabolites to evaluate the internal exposure of PFRs in organisms. Biomagnification factors (BMFs) were below 1 for all targeted chemicals and negatively correlated with metabolite/parent ratios (MPRs), suggesting a biodilution driven by metabolism. The lipid normalized concentrations were lower in eggs than in muscle for most of targeted chemicals. The maternal transfer potential was significantly and positively correlated with log KOW (p < 0.05) when log KOW was below 6.

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

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

Human exposure pathways to organophosphate flame retardants: Associations between human biomonitoring and external exposure

Organophosphate flame retardants (PFRs) have largely replaced the market of polybrominated diphenyl ethers (PBDEs). Concerns about PFR contamination and its impact on human health have consequently increased. A comprehensive investigation on the human exposure pathways to PFRs is to be endeavoured. This study investigated the occurrence of PFR metabolites in human urine, serum and hair, correlating them with external exposure data that was presented in our previous studies. Participants from Oslo (n = 61) provided a set of samples, including dust, air, handwipes, food, urine, serum and hair. Associations between PFR metabolites analyzed in the biological samples and the PFRs in environmental samples were explored. Different sampling strategies for dosimeters (e.g. floor/surface dust, personal/stationary air) were also compared to understand which is better for predicting human exposure to PFRs. Seven out of the eleven target PFR metabolites, including diphenyl phosphate (DPHP) and bis(1-chloro-2-propyl)-1-hydroxy-2-propyl phosphate (BCIPHIPP), were frequently detected (DF > 30%) in urine. DPHP was the most frequently detected metabolite in both serum and hair. Several PFR metabolites had higher levels in morning urine than in afternoon urine. Floor dust appeared to be a better proxy for estimating PFR internal exposure than surface dust, air, and handwipes. Some PFRs in handwipes and air were also correlated with their metabolites in urine and hair. Age, beverage consumption and food consumption were negatively associated with DPHP levels in urine. Discrepancies observed between the external and internal exposure for some PFRs call for further investigation on PFR bioaccessibility and clearance.

Organophosphate flame-retardant metabolite concentrations and pregnancy loss among women conceiving with assisted reproductive technology

To evaluate whether urinary concentrations of organophosphate flame retardant (PFR) metabolites are associated with pregnancy loss among women conceiving with assisted reproductive technology (ART). Prospective preconception cohort of subfertile women. Academic hospital fertility center in Boston, Massachusetts. A total of 155 women conceiving 179 pregnancies with ART. None. Mean exposure to each of five PFR metabolites was estimated by averaging the specific-gravity adjusted natural log concentrations from two urine samples collected during the ART cycle of conception. Adjusted risk ratios (RRs) and 95% confidence intervals (CIs) for biochemical and total pregnancy loss (all losses <20weeks' gestation) by quartiles of PFR metabolite concentrations were estimated using a repeated measures log-binomial model, accounting for multiple pregnancies per woman. Of the 179 pregnancies, 31% ended in pregnancy loss (12% in biochemical loss). Among the three metabolites with high detection frequency [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), and isopropylphenyl phenyl phosphate (ip-PPP)], an increased risk of biochemical loss was observed for women with DPHP concentrations in the fourth vs. first quartile (RR 1.64; 95% CI 0.61-4.39). Also found was an elevated risk of biochemical pregnancy loss among women in the highest quartile of the molar sum of urinary PFR metabolites compared with the lowest (RR 1.89; 95% CI 0.64-5.58). Urinary concentrations of ip-PPP and BDCIPP were not associated with either outcome. Among subfertile women, urinary DPHP metabolite concentrations measured during the ART cycle of conception may be associated with early pregnancy loss. Although this study is uniquely designed to investigate early markers of pregnancy success and maintenance, the small sample size likely contributed to imprecision. Given their increasing use as replacement chemicals for traditional flame retardants, exposure to PFRs may increase, and more studies will be needed to investigate their potential to impact pregnancy and reproduction.

Simultaneous determination of 14 urinary biomarkers of exposure to organophosphate flame retardants and plasticizers by LC-MS/MS.

Organophosphate flame retardants and plasticizers (PFRs) are a group of chemicals widely added to consumer products. PFRs are quickly metabolized inthe human body into two types of metabolites, (1) dialkyl and diaryl phosphate esters (DAPs), such as diphenyl phosphate (DPHP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP); and (2) hydroxylated PFRs (HO-PFRs), such as 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP) and 2-hydroxyethyl bis(2-butoxyethyl) phosphate (BBOEHEP). Existing analytical methods usually focus on DAPs; therefore, human biomonitoring data on HO-PFRs remain scarce. In this study, an analytical procedure was developed for the simultaneous quantification of multiple PFR metabolites in human urine, covering eight DAPs and six HO-PFRs. Sample preparation was optimized to include all target compounds using Bond-Elut C18 solid-phase extraction cartridges, followed by instrumental analysis based on liquid-chromatography coupled to tandem mass spectrometry (LC-MS/MS). Method performance was validated according to established guidelines and satisfactory results were obtained for all metabolites in terms of recovery, linearity, limits of quantification, precision, and accuracy. Recoveries ranged from 87 to 112%. Method detection limits from 0.002ng/mL for 2-ethyl-5-hydroxyhexyl diphenyl phosphate (5-HO-EHDPHP) to 0.66ng/mL for 4-hydroxyphenyl phenyl phosphate (4-HO-DPHP). Seven PFR metabolites were frequently detected in a small biomonitoring study (n = 14), among them bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), di-n-butyl phosphate (DNBP), 5-HO-EHDPHP, and BBOEHEP. Highest mean concentrations were found for DPHP, 2-ethylhexyl phenyl phosphate (EHPHP), and BCIPHIPP, while 4-HO-DPHP, 5-HO-EHDPHP, and EHPHP were detected in urine for the first time. Overall, the obtained results demonstrate that the developed method can be used for the simultaneous determination of 14 urinary biomarkers of exposure to PFRs. Graphical abstract ᅟ.

Associations between allergic symptoms and phosphate flame retardants in dust and their urinary metabolites among school children

BackgroundPhosphate flame retardants (PFRs) are ubiquitously detected in indoor environments. Despite increasing health concerns pertaining to PFR exposure, few epidemiological studies have examined PFR exposure and its effect on children's allergies. ObjectivesTo investigate the association between PFRs in house dust, their metabolites in urine, and symptoms of wheeze and allergies among school-aged children. MethodsA total of 128 elementary school-aged children were enrolled. House dust samples were collected from upper-surface objects. Urine samples were collected from the first morning void. Levels of 11 PFRs in dust and 14 PFR metabolites in urine were measured. Parent-reported symptoms of wheeze, rhinoconjunctivitis, and eczema were evaluated using the International Study of Asthma and Allergies in Childhood questionnaire. The odds ratios (ORs) of the Ln transformed PFR concentrations and categorical values were calculated using a logistic regression model adjusted for sex, grade, dampness index, annual house income, and creatinine level (for PFR metabolites only). ResultsThe prevalence rates of wheeze, rhinoconjunctivitis, and eczema were 22.7%, 36.7%, and 28.1%, respectively. A significant association between tris(1,3-dichloroisopropyl) phosphate (TDCIPP) in dust and eczema was observed: OR (95% confidence interval), 1.44 (1.13–1.82) (>limit of detection (LOD) vs <LOD). The ORs for rhinoconjunctivitis (OR = 5.01 [1.53–16.5]) and for at least one symptom of allergy (OR = 3.87 [1.22–12.3]) in the 4th quartile of Σtris(2-chloro-isopropyl) phosphate (TCIPP) metabolites was significantly higher than those in the 1st quartile, with significant p-values for trend (Ptrend) (0.013 and 0.024, respectively). A high OR of 2.86 (1.04–7.85) (>LOD vs <LOD) was found for hydroxy tris(2-butoxyethyl) phosphate (TBOEP)-OH and eczema. OR of the 3rd tertile of bis (1,3-dichloro-2-propyl) phosphate (BDCIPP) was higher than the 1st tertile as a reference for at least one symptom (OR = 3.91 [1.25–12.3]), with a significant Ptrend = 0.020. ConclusionsWe found that TDCIPP in house dust, and metabolites of TDCIPP, TBOEP and TCIPP were associated with children's allergic symptoms. Despite some limitations of this study, these results indicate that children's exposure to PFR may impact their allergic symptoms.

A case-control study of exposure to organophosphate flame retardants and risk of thyroid cancer in women

BackgroundGrowing evidence demonstrates that exposure to organophosphate flame retardants (PFRs) is widespread and that these chemicals can alter thyroid hormone regulation and function. We investigated the relationship between PFR exposure and thyroid cancer and whether individual or temporal factors predict PFR exposure.MethodsWe analyzed interview data and spot urine samples collected in 2010–2013 from 100 incident female, papillary thyroid cancer cases and 100 female controls of a Connecticut-based thyroid cancer case-control study. We measured urinary concentrations of six PFR metabolites with mass spectrometry. We estimated odds ratios (OR) and 95% confidence intervals (95% CI) for continuous and categories (low, medium, high) of concentrations of individual and summed metabolites, adjusting for potential confounders. We examined relationships between concentrations of PFR metabolites and individual characteristics (age, smoking status, alcohol consumption, body mass index [BMI], income, education) and temporal factors (season, year) using multiple linear regression analysis.ResultsNo PFRs were significantly associated with papillary thyroid cancer risk. Results remained null when stratified by microcarcinomas (tumor diameter ≤ 1 cm) and larger tumor sizes (> 1 cm). We observed higher urinary PFR concentrations with increasing BMI and in the summer season.ConclusionsUrinary PFR concentrations, measured at time of diagnosis, are not linked to increased risk of thyroid cancer. Investigations in a larger population or with repeated pre-diagnosis urinary biomarker measurements would provide additional insights into the relationship between PFR exposure and thyroid cancer risk.

Paternal urinary concentrations of organophosphate flame retardant metabolites, fertility measures, and pregnancy outcomes among couples undergoing in vitro fertilization

BackgroundUse of organophosphate flame retardants (PFRs) has increased over the past decade following the phase out of some brominated flame retardants, leading to increased human exposure. We recently reported that increasing maternal PFR exposure is associated with poorer pregnancy outcomes among women from a fertility clinic. Because a small epidemiologic study previously reported an inverse association between male PFR exposures and sperm motility, we sought to examine associations of paternal urinary concentrations of PFR metabolites and their partner's pregnancy outcomes. MethodsThis analysis included 201 couples enrolled in the Environment and Reproductive Health (EARTH) prospective cohort study (2005–2015) who provided one or two urine samples per IVF cycle. In both the male and female partner, we measured five urinary PFR metabolites [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), isopropylphenyl phenyl phosphate (ip-PPP), tert-butylphenyl phenyl phosphate (tb-PPP) and bis(1-chloro-2-propyl) phosphate (BCIPP)] using negative electrospray ionization liquid chromatography tandem mass spectrometry (LC-MS/MS). The sum of the molar concentrations of the urinary PFR metabolites was calculated. We used multivariable generalized linear mixed models to evaluate the association of urinary concentrations of paternal PFR metabolites with IVF outcomes, accounting for multiple in vitro fertilization (IVF) cycles per couple. Models were adjusted for year of IVF treatment cycle, primary infertility diagnosis, and maternal urinary PFR metabolites as well as paternal and maternal age, body mass index, and race/ethnicity. ResultsDetection rates were high for paternal urinary concentrations of BDCIPP (84%), DPHP (87%) and ip-PPP (76%) but low for tb-PPP (12%) and zero for BCIPP (0%). We observed a significant 12% decline in the proportion of fertilized oocytes from the first to second quartile of male urinary ΣPFR and a 47% decline in the number of best quality embryos from the first to third quartile of male urinary BDCIPP in our adjusted models. An 8% decline in fertilization was observed for the highest compared to lowest quartile of urinary BDCIPP concentrations (95% CI: 0.01, 0.12, p-trend=0.06). ConclusionsUsing IVF as a model to investigate human reproduction and pregnancy outcomes, we found that paternal urinary concentrations of BDCIPP were associated with reduced fertilization. In contrast to previously reported findings for the female partners, the paternal urinary PFR metabolites were not associated with the proportion of cycles resulting in successful implantation, clinical pregnancy, and live birth. These results indicate that paternal preconception exposure to TDCIPP may adversely impact successful oocyte fertilization, whereas female preconception exposure to ΣPFRs may be more relevant to adverse pregnancy outcomes.

Current-use flame retardants: Maternal exposure and neurodevelopment in children of the CHAMACOS cohort

Flame retardants are commonly used in consumer products found in U.S. households. Restrictions on the use of polybrominated diphenyl ether flame retardants have resulted in increased use of replacement chemicals, including Firemaster 550® (FM 550®) and organophosphate flame retardants (PFRs): tris(1,3- dichloro-2-propyl) phosphate (TDCIPP); tris(chloropropyl) phosphate (TCIPP); tris(2-chloroethyl) phosphate (TCEP); and triphenyl phosphate (TPHP). Animal research suggests that PFRs may affect neurodevelopment through noncholinergic mechanisms similar to some organophosphate (OP) pesticides. Despite the widespread presence of these compounds in home environments, and their structural similarity to neurotoxic OP pesticides, understanding of human exposure and health effects of PFRs is limited. We measured four urinary PFR metabolites from pregnant women in the CHAMACOS birth cohort study (n = 310) and assessed neurodevelopment of their children at age 7. Metabolites of TDCIPP (BDCIPP: bis(1,3-dichloro-2-propyl) phosphate) and TPHP (DPHP: diphenyl phosphate) were detected in >75% of urine samples, and isopropylphenyl phenyl phosphate (ip-PPP), a metabolite of one component of FM 550®, was detected in 72% of urine samples. We observed decreases of 2.9 points (95% Confidence Interval (CI): −6.3, 0.5) and 3.9 points (95% CI: −7.3,-0.5) in Full-Scale intelligence quotient and Working Memory, respectively, for each ten-fold increase in DPHP in adjusted regression models (n = 248). Decreases in Full-Scale IQ and Working Memory were greater in models of the molar sum of the PFR metabolites compared to the DPHP models. This is the first study to examine PFR and FM 550® exposures and potential neurodevelopmental outcomes in pregnant women and children. Additional research is warranted.

Urinary Concentrations of Organophosphate Flame Retardant Metabolites and Pregnancy Outcomes among Women Undergoing in Vitro Fertilization.

Background:Evidence from animal studies suggests that exposure to organophosphate flame retardants (PFRs) can disrupt endocrine function and impair embryo development. However, no epidemiologic studies have been conducted to evaluate effects on fertility and pregnancy outcomes.Objectives:We evaluated associations between urinary concentrations of PFR metabolites and outcomes of in vitro fertilization (IVF) treatment among couples recruited from an academic fertility clinic.Methods:This analysis included 211 women enrolled in the Environment And Reproductive Health (EARTH) prospective cohort study (2005–2015) who provided one or two urine samples per IVF cycle. We measured five urinary PFR metabolites [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), isopropylphenyl phenyl phosphate (ip-PPP), tert-butylphenyl phenyl phosphate (tb-PPP), and bis(1-chloro-2-propyl) phosphate (BCIPP)] using negative electrospray ionization liquid chromatography tandem mass spectrometry (LC-MS/MS). Molar concentrations of the urinary PFR metabolites were summed. We used multivariable generalized linear mixed models to evaluate the association of the PFR metabolites with IVF outcomes, accounting for multiple IVF cycles per woman.Results:Detection frequencies were high for BDCIPP (87%), DPHP (94%), and ip-PPP (80%), but low for tb-PPP (14%) and BCIPP (0%). We observed decreased success for several IVF outcomes across increasing quartiles of both summed and individual PFR metabolites (DPHP and ip-PPP) in our adjusted multivariable models. Significant declines in adjusted means from the lowest to highest quartile of were observed for the proportion of cycles resulting in successful fertilization (10% decrease), implantation (31%), clinical pregnancy (41%), and live birth (38%).Conclusions:Using IVF to investigate human reproduction and pregnancy outcomes, we found that concentrations of some urinary PFR metabolites were negatively associated with proportions of successful fertilization, implantation, clinical pregnancy, and live birth. https://doi.org/10.1289/EHP1021

Influence of storage vial material on measurement of organophosphate flame retardant metabolites in urine

Use of organophosphate flame retardants (PFRs) has increased over the past decade with the phase out of polybrominated diphenyl ethers. Urinary metabolites of PFRs are used as biomarkers of exposure in epidemiologic research, which typically uses samples collected and stored in polypropylene plastic cryovials. However, a small study suggested that the storage vial material may influence reported concentrations. Therefore, we aimed to examine the influence of the storage vial material on analytical measurement of PFR urinary metabolites. Using urine samples collected from participants in the Environment and Reproductive Health (EARTH) Study, we analyzed the PFR metabolites in duplicate aliquots that were stored in glass and plastic vials (n = 31 pairs). Bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP) and isopropyl-phenyl phenyl phosphate (ip-PPP) were detected in 98%, 97% and 87% of duplicates. We observed high correlations between glass-plastic duplicates for BDCIPP (rs = 0.95), DPHP (rs = 0.79) and ip-PPP (rs = 0.82) (p < 0.0001). Urinary ip-PPP was an average of 0.04 ng/ml (p = 0.04) higher among samples stored in glass, with a mean relative difference of 14%. While this difference is statistically significant, it is small in magnitude. No differences were observed for BDCIPP or DPHP, however future research should seek to reduce the potential for type II error (false negatives). We conclude that storing urine samples in polypropylene plastic cryovials may result in slightly reduced concentrations of urinary ip-PPP relative to storage in glass vials and future research should seek to increase the sample size, reduce background variability and consider the material of the urine collection cup.

Flame retardants and their metabolites in the homes and urine of pregnant women residing in California (the CHAMACOS cohort)

Organophosphate flame retardants (PFRs), used in consumer products since the 1970s, persist in the environment. Restrictions on penta-polybrominated diphenyl ether (PBDE) flame retardants resulted in increased use of Firemaster® 550 (FM® 550), and the organophosphate triesters: tris(1,3- dichloro-2-propyl) phosphate (TDCIPP); tris(chloropropyl) phosphate (TCIPP); tris(2-chloroethyl) phosphate (TCEP); and triphenyl phosphate (TPHP). The objectives of this study were to (1) identify determinants of flame retardants (4 PFRs, PentaBDEs and FM® 550) in house dust, (2) measure urinary PFR metabolites in pregnant women, and (3) estimate health risks from PFR exposure. We measured flame retardants in house dust (n = 125) and metabolites in urine (n = 310) collected in 2000–2001 from Mexican American women participating in the CHAMACOS birth cohort study in California. We detected FM® 550 and PFRs, including two (TCEP and TDCIPP) known to the state of California to cause cancer, in most dust samples. The maximum TCEP and TDCIPP dust levels were among the highest ever reported although the median levels were generally lower compared to other U.S. cohorts. Metabolites of TDCIPP (BDCIPP: bis(1,3-dichloro-2-propyl) phosphate) and TPHP (DPHP: diphenyl phosphate) were detected in 78% and 79% of prenatal urine samples, respectively. We found a weak but positive correlation between TPHP in dust and DPHP in 124 paired prenatal urine samples (Spearman rho = 0.17; p = 0.06). These results provide information on PFR exposure and risk in pregnant women from the early 2000's and are also valuable to assess trends in exposure and risk given changing fire safety regulations and concomitant changes in chemical flame retardant use.

Method development for assessing the human exposure to organophosphate flame retardants in hair and nails

In the present study, a new extraction method based on acid digestion and SPE clean-up (Oasis Wax) was developed for measuring four PFR metabolites (i.e. dibutyl phosphate (DBP), diphenyl phosphate (DPhP), bis(1,3-dichloro-2-propyl)phosphate (BDCPP) and bis(2-butoxy ethyl) phosphate (BBEP)) in hair and nails. The method optimization was done according to a combinatorial design (Taguchi) where several parameters were efficiently optimized. Precision was lower for hair than for nails (RSD % 18 and 28%). Recoveries were >74%. High DBP levels in procedural blanks were traced back to the use of SPE cartridges. Therefore a new SPE pre-treatment was tested, reducing significantly DBP levels (<1 ng).Levels of the PFR metabolites were measured in scalp hair, finger, and toe nails collected over two months in two volunteers (female and male). DPhP levels were extremely high (in μg/g range) in both finger and toe nails in the female. BDCPP and BBEP were the minor metabolites detected in nails (average levels of 28–64 ng/g and <2.2–4.1 ng/g, respectively). DPhP was the only metabolite detected in hair (0.23–0.25 ng/g). Results showed that there is a possible contribution from both an external (via deposition) and an internal exposure, however it was not possible to fully understand their extent. Since there were no records of lifestyle and due to the small sample size, the major exposure source could not be addressed here. Nevertheless, there is evidence that hair and nails (finger and toe) might be good indicators of human exposure to PFRs, especially to TPhP.

Predictors of urinary flame retardant concentration among pregnant women

BackgroundOrganophosphate compounds are commonly used in residential furniture, electronics, and baby products as flame retardants and are also used in other consumer products as plasticizers. Although the levels of exposure biomarkers are generally higher among children and decrease with age, relatively little is known about the individual characteristics associated with higher levels of exposure. Here, we investigate urinary metabolites of several organophosphate flame retardants (PFRs) in a cohort of pregnant women to evaluate patterns of exposure. MethodsPregnant North Carolina women (n=349) provided information on their individual characteristics (e.g. age and body mass index (BMI)) as a part of the Pregnancy Infection and Nutrition Study (2002–2005). Women also provided second trimester urine samples in which six PFR metabolites were measured using mass spectrometry methods. ResultsPFR metabolites were detected in every urine sample, with BDCIPP, DHPH, ip-PPP and BCIPHIPP detected in >80% of samples. Geometric mean concentrations were higher than what has been reported previously for similarly-timed cohorts. Women with higher pre-pregnancy BMI tended to have higher levels of urinary metabolites. For example, those classified as obese at the start of pregnancy had ip-PPP levels that were 1.52 times as high as normal weight range women (95% confidence interval: 1.23, 1.89). Women without previous children also tended to have higher urinary levels of DPHP, but lower levels of ip-PPP. In addition, we saw strong evidence of seasonal trends in metabolite concentrations (e.g. higher DPHP, BDCIPP, and BCIPHIPP in summer, and evidence of increasing ip-PPP between 2002 and 2005). ConclusionsOur results indicate ubiquitous exposure to PFRs among NC women in the early 2000s. Additionally, our work suggests that individual characteristics are related to exposure and that temporal variation, both seasonal and annual, may exist.

Regional comparison of organophosphate flame retardant (PFR) urinary metabolites and tetrabromobenzoic acid (TBBA) in mother-toddler pairs from California and New Jersey

The use of alternative chemical flame retardants in consumer products is increasing as the result of the phase-out of polybrominated diphenyl ethers. Today, the most commonly detected alternatives in residential furniture include the organophosphate flame retardants (PFRs) and the Firemaster (R) 550 mixture (FM550). Urinary levels of dialkyl and diaryl phosphate esters, and 2-ethylhexyl tetrabromobenzoate (EH-TBB) have been used as biomarkers of human exposure to PFRs and FM550, respectively. In a previous study, we demonstrated that toddlers had significantly higher levels of PFRs relative to their mothers in a cohort from New Jersey; however, it is unclear if there are regional differences in exposure. It is possible that exposure to PFRs may be higher in California relative to other US States due to the California flammability standard, as was seen previously observed for PBDEs. In the current study, we examined urinary levels of PFR metabolites and TBBA in 28 mother-child pairs from California, USA, collected in 2015, and compared them with levels measured in our previous study from New Jersey. Urine samples were extracted using solid-phase extraction and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Diphenyl phosphate (DPHP), isopropyl-phenyl phenyl phosphate (ip-PPP), bis(1,3-dichloro-2propyl) phosphate (BDCIPP) and BCIPHIPP conjugates were detected in 100% of mother and child urine samples, while bis(1-chloro-2-propyl) phosphate (BCIPP), tert-butyl-phenyl phenyl phosphate (tb-PPP) and TBBA were detected in <50% of samples. Interestingly, BCIPHIPP conjugates were detected in 100% of the urine samples, suggesting ubiquitous exposure to the parent compound, tris(1-chloro-2-propyl) phosphate (TCIPP). The current study found significantly higher BDCIPP levels in California toddlers and higher and ip-PPP levels in mothers as compared to the New Jersey cohort, which may be reflective of California's furniture flammability standard. For example, BDCIPP levels in California children were 2.4 times higher than those in New Jersey children. Consistent with our previous work, the current study showed higher PFR and EH-TBB exposure in children, likely due to increased hand-mouth behavior. Children's DPHP and BDCIPP levels, on average, were 5.9 times and 15 times those of their mothers. Positive correlations between paired mothers and their children were shown for DPHP and BCIPHIPP conjugates but not BDCIPP or ip-PPP. In the children, several predictors of hand-mouth behavior were associated with BDCIPP, DPHP and ip-PPP urine levels, but no associations were observed with BCIPHIPP conjugates.

High Exposure to Organophosphate Flame Retardants in Infants: Associations with Baby Products.

Infant products containing polyurethane foam are commonly treated with organophosphate flame retardants (PFRs), including tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) and triphenyl phosphate (TPHP). Infants may have greater exposure due to greater contact with these products, yet little is known about levels of exposure or the factors contributing to higher exposure. We recruited children age 2-18 months from North Carolina to investigate PFR exposure (n = 43; recruited 2014-2015). Parents provided information on potential sources and modifiers of exposure, and reported whether they owned common infant products. We measured five PFR metabolites in urine samples collected from children. TDCIPP and TPHP metabolites (bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and diphenyl phosphate (DPHP)) were most commonly detected (>93% detect). Other metabolites were detected infrequently (<35% detect). Although we did not observe a clear age trend for infants, BDCIPP levels were substantially higher than those reported for adults (geometric mean = 7.3 ng/mL). The number of infant products owned was strongly associated with BDCIPP; children with >16 products had BDCIPP levels that were 6.8 times those with <13 (p = 0.02). Infants attending daycare centers also had higher BDCIPP levels (3.7 times those of others; p = 0.07), suggesting time spent in this microenvironment contributes to higher exposure. In contrast, DPHP levels were not related to products owned, time in different microenvironments, or behavior.

Assessment of human hair as an indicator of exposure to organophosphate flame retardants. Case study on a Norwegian mother–child cohort

A major challenge of non-invasive human biomonitoring using hair is to assess whether it can be used as an indicator of exposure to Flame Retardants, such as Organophosphate Flame Retardants (PFRs), since the contribution of atmospheric deposition (air and/or dust) cannot be neglected. Therefore, the aim of this study was to evaluate the suitability of using human hair more thoroughly by comparison of (i) levels of PFRs in human hair (from 48 mothers and 54 children), with levels measured in dust and air in their respective households; and (ii) levels of selected PFRs in hair with the levels of corresponding PFR metabolites in matching urine samples collected simultaneously. Most PFRs (tri-n-butyl phosphate (TNBP), 2-ethyl-hexyldiphenyl phosphate (EHDPHP), tri-phenyl phosphate (TPHP), tri-iso-butyl phosphate (TIBP), and tris(2-butoxyethyl) phosphate (TBOEP)) were detected in all human hair samples, tris(2-ethylhexyl) phosphate (TEHP) and tris(1,3-dichloro-iso-propyl) phosphate (TDCIPP) in 93%, tri-cresyl-phosphate (TCP) in 69% and tris(2-chloroethyl) phosphate (TCEP) in 21% of the samples. Levels of individual PFRs ranged between <1 and 3744ng/g hair and were lower than in indoor dust from the participants' homes. Several statistically significant associations between PFR levels in human hair and PFR levels in house dust and/or air were found, e.g. Spearman correlation (rS=0.561, p<0.05) between TBOEP in children's hair and in indoor air. Also, associations were found between TDCIPP in hair and its metabolite bis(1,3-dichloro-iso-propyl) phosphate (BDCIPP) in urine; they were stronger for children (e.g. Pearson correlation rP=0.475; p=0.001) than for mothers (rP=0.395, p=0.01). Levels of diphenyl phosphate (DPHP) in mothers' and children's urine were slightly correlated (rS=0.409, p=0.008), suggesting similar sources of exposure. To the best of our knowledge, this is the first study with such design and our findings might help to understand human exposure to and body burdens of PFRs.