Evaluating Mixtures of Urinary Phthalate Metabolites and Serum Per-/Polyfluoroalkyl Substances in Relation to Adolescent Hair Cortisol: The HOME Study.

Results of toxicological studies indicate that phthalates and per-/polyfluoroalkyl substances (PFAS), 2 classes of endocrine-disrupting chemicals, may alter the functioning of the hypothalamic-pituitary-adrenocortical (HPA) axis. We evaluated the associations of urinary phthalate metabolites and serum PFAS during gestation and childhood with adolescent hair cortisol concentrations (pg/mg hair) at age 12 years, an integrative marker of HPA axis activity (n = 205 mother-child pairs; Cincinnati, Ohio; enrolled 2003-2006). We used quantile-based g-computation to estimate associations between mixtures of urinary phthalate metabolites or serum PFAS and hair cortisol. We also examined whether associations of individual phthalate metabolites or PFAS with cortisol varied by the timing of exposure. We found that a 1-quartile increase in all childhood phthalate metabolites was associated with 35% higher adolescent hair cortisol (phthalate mixture ψ = 0.13; 95% confidence interval: 0.03, 0.22); these associations were driven by monoethyl phthalate, monoisobutyl phthalate, and monobenzyl phthalate. We did not find evidence that phthalate metabolites during gestation or serum PFAS mixtures were related to adolescent hair cortisol concentrations. We found suggestive evidence that higher childhood concentrations of individual PFAS were related to higher and lower adolescent hair cortisol concentrations. Our results suggest that phthalate exposure during childhood may contribute to higher levels of chronic HPA axis activity.

Temporal Trends in Phthalate Metabolite Exposure of Girls in the United States Across Sociodemographic Factors and Intersectional Social Identities: National Health and Nutrition Examination Survey 2001-2018.

BACKGROUND: Exposure to phthalates during the pubertal window impacts chronic disease risk and temporal trends in exposure can inform public health initiatives. OBJECTIVE: Characterize temporal trends in phthalate metabolite exposure for adolescent girls overall and by sociodemographic characteristics. METHODS: We used the cross-sectional data from each cycle of the National Health and Nutrition Examination Survey from years 2001 to 2018. We restricted participants to ages of 8-14 with at least one urinary measurement of the selected 12 phthalate metabolites within the study period (n=2,063). We used multivariable linear regression to assess temporal trends for selected individual phthalate metabolite concentrations (ng/ml) and source groupings of parent metabolites (sum low and high molecular weight phthalates; ∑LMW and ∑HMW) overall and individually by sociodemographic characteristics (race/ethnicity), nativity, socioeconomic status (SES), intersection of race/ethnicity-SES) to assess for modification. RESULTS: Overall ∑HMW and ∑LMW concentrations declined between 2001 and 2018; however, only ∑LMW consistently differed by all sociodemographic characteristics. Trends in ∑LMW concentration were significantly higher across all racial/ethnic groups, ranging from an average of 35% (Other Hispanic) to 65% (Mexican American and non-Hispanic Black) higher than non-Hispanic White (all p-values<0.0001). Compared to non-Hispanic White, we observed an average decrease of 15% in MiBP for non-Hispanic Black (ßSpline=-0.16, p<0.0001) and 28% for Other Hispanic (ßSpline=-0.33, p=0.01) in 2011-2018 vs. 2001-2010. Summary and individual LMW metabolite phthalate concentrations were 11%-49% higher among low vs. high SES girls. LMW metabolites MBP and MiBP were on average 22% and 35% higher; respectively, among foreign born vs. U.S. born. Compared to non-Hispanic Whites, all racial/ethnic groups had statistically significant higher trends in ∑LMW concentration irrespective of SES status. SIGNIFICANCE: Girls identifying with a historically disadvantaged racial/ethnic group have elevated ∑LMW concentrations irrespective of SES class; suggesting the need for interventions to mitigate exposure among the most historically disadvantaged strata.

Assessment of baby disposable diapers application for urine collection and determination of phthalate metabolites.

The baby disposable diapers were investigated as a sampling material for urine collection and validated for the evaluation of the exposure of children to xenobiotics. Phthalate metabolites detected in urine samples were chosen as proof-of-concept analytes. For the determination of phthalate metabolites in children's urine samples, high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) was used. Two sampling approaches were compared, namely sterile containers and baby disposable diapers. Thirty urine samples from infants and toddlers were analyzed by both methods in parallel and the results were compared. It was found that for diaper sampling, lower concentrations of the metabolites were observed, however, the general distribution for particular metabolites remains the same for both methods. For most of the metabolites high determination coefficients were obtained, namely 0.9929 for MEHHP, 0.9836 for MMP, 0.9796 for MECPP, and 0.9784 for 2-cx-MMHP. For MEOHP the determination correlation coefficient was 0.9154, while for MBP was - 0.7771 and MEHP was - 0.5228. In general, for diaper sampling an underestimation for 2-cx-MMHP and MEOHP was observed, while for MMP diaper-based approach provides overestimation. However, the proposed procedure confirms the possibility of using baby disposable diapers as a material for the collection of urine samples for biomonitoring purposes and fast screening of phthalates exposure.

Assessment of phthalate exposure at a fire site in Korean firefighters.

To determine phthalate exposure in 32 firefighters, the concentrations of urinary phthalate metabolites, immediately (exposure day) and three weeks (control day) after fire suppression, were compared. Mono-(2-ethyl-5-carboxypentyl) phthalate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, mono-n-butyl phthalate (MBP), mono-n-benzyl phthalate (MBzP), and total phthalates (∑phthalates) levels, and creatinine-adjusted levels of MBP, MBzP, and ∑phthalates were significantly higher on exposure day than on control day. Phthalate concentration was significantly higher in firefighters who performed the fire extinguishing tasks (geometric mean [GM], 149.9 µg/L) than in those who performed other tasks (GM 70.8 µg/L) (p = .012). The GM concentration of firefighters who were active ≤ 50 m from the fire was 119.0 µg/L, and 37.6 µg/L for those who were > 50 m away (p = .012). The GM concentration was significantly different (p = .039) in firefighters with subjective symptoms after fire suppression (151.9 µg/L) compared to those without symptoms (81.6 µg/L). This study showed that firefighters were exposed to phthalate.

Influence of data acquisition modes and data analysis approaches on non-targeted analysis of phthalate metabolites in human urine.

Humans are often exposed to phthalates and their alternatives, on account of their widespread use in PVC as plasticizers, which are associated with harmful human effects. While targeted biomonitoring provides quantitative information for exposure assessment, only a small portion of phthalate metabolites has been targeted. This results in a knowledge gap in human exposure to other unknown phthalate compounds and their metabolites. Although the non-targeted analysis (NTA) approach is capable of screening a broad spectrum of chemicals, there is a lack of harmonized workflow in NTA to generate reproducible data within and between different laboratories. The objective of this study was to compare two different NTA data acquisition modes, the data-dependent (DDA) and independent (DIA) acquisition (DDA), as well as two data analysis approaches, based on diagnostic ions and Compound Discoverer software for the prioritization of candidate precursors and identification of unknown compounds in human urine. Liquid chromatography coupled to high-resolution mass spectrometry was used for sample analysis. The combination of three-diagnostic-ion extraction and DDA data acquisition was able to improve data filtering and data analysis for prioritizing phthalate metabolites. With DIA, 25 molecular features were identified in human urine, while 32 molecular features were identified in the same urine samples using DDA data. The number of molecular features identified with level 1 confidence was 11 and 9 using DIA and DDA data, respectively. The study demonstrated that besides sample preparation, the impact of data acquisition must be taken into account when developing a NTA method and a consistent protocol for evaluating such an impact is necessary.

Persistent high exposure to exogenous phthalates and endogenous sex hormones associated with early pubertal onset among children: A 3.5-year longitudinal cohort study in China.

BACKGROUND: Early onset of puberty could have significant impacts on childhood health, but the extent to which it was affected by phthalate esters (PAEs) and sex hormone disruption was not understood. The aim of this study is to investigate the associations between exposure to PAEs and sex hormone disruption and early onset of puberty in children. METHODS: A longitudinal cohort study was conducted in China from May 2017 to Oct 2020, involving 740 children during consecutive visits. The onset of puberty was evaluated using Tanner definition, and early puberty was defined as an onset age less than the first 25 %, with cut-offs of 10.33 and 8.97 years for boys and girls, respectively. Serum testosterone (TT), estradiol (E2) and urinary PAE metabolites were measured during three visits. Generalized linear models were used to explore the associations between PAE and sex hormones with the age of puberty onset, while log-binomial regressions were applied to assess the associations of persistent exposure to PAEs and sex hormones with early pubertal onset. RESULTS: Approximately 86.0 % of boys and 90.2 % of girls completed puberty onset from pre-puberty, and more than 95 % of participants had PAE concentrations higher than the limit of detection. Boys showed higher exposure to PAE pollutants and higher TT levels. Persistent exposure to PAEs was positively associated with early pubertal onset in girls (ARR = 1.97, 95 %CI = 1.12, 3.46). Moreover, persistent exposure to PAEs and E2 had synergistic associations with early pubertal onset in both boys (ARR = 4.77, 95 %CI = 1.06, 21.54) and girls (ARR = 7.07, 95 %CI = 1.51, 33.10). However, PAEs and TT had antagonistic associations only in boys (ARR = 0.44, 95 %CI = 0.07, 2.58). CONCLUSION: Long-term exposure to PAEs might increase the risk of early pubertal onset, and it appears to work in synergy with E2, while in antagonism with TT in boys' early pubertal onset. Reducing PAEs exposure might promote pubertal health.

A Study of the Relationship between Phthalate Exposure and the Occurrence of Adult Asthma in Taiwan.

Although phthalate esters contribute to airway remodeling by increasing bronchial cells' migration and proliferation, the relationship between human exposure to phthalates and asthma is not understood. We measured phthalate exposure in the human body and evaluated its effect on asthma. Asthma (n = 123) and asthma-free (n = 139) participants were, respectively, recruited from an asthma clinic and the community in Taiwan. The urine levels of six phthalate metabolites were determined by liquid chromatography tandem mass spectrometry. Compared with the controls, male asthma patients had higher means of mono-(2-ethylhexyl) phthalate (MEHP) (116.3 nmol/g), monobutyl phthalate (MBP) (850.3 nmol/g) and monoethyl phthalate (MEP) (965.8 nmol/g), and female patients had greater MBP (2902.4 nmol/g). Each 10-fold increase in the level of these phthalate metabolites was correspondingly associated with a 5.0-, 5.8-, 4.2- and 5.3-fold risk of contracting asthma. Male asthma patients were identified to have a higher proportion of MEHP exposure (32.5%) than the controls (25.3%). In asthma patients, an increase in urine MEHP levels and the total phthalate metabolite concentration were notably linked to increased risks of emergency room visits and being hospitalized. For the occurrence and acute clinical events of adult asthma, phthalate exposures and MEHP retention may contribute to higher risks of contracting this respiratory disorder.

Urinary phthalate metabolites and their mixtures are associated with advanced sperm epigenetic aging in a general population.

INTRODUCTION: We have recently shown that sperm epigenetic age (SEA), a surrogate measure of biological aging in sperm, is associated with couples' time-to-pregnancy (TTP). Advanced SEA was also observed among smokers, suggesting its susceptibility to environmental exposures. Therefore, we assessed the association between urinary phthalate metabolites and SEA in male partners of couples planning to conceive among the general population. METHOD: The Longitudinal Investigation of Fertility and the Environment (LIFE) Study was a prospective multi-site and general population cohort study of couples who were interested in becoming pregnant. Among male partners (n = 333), eleven urinary phthalate metabolites were measured and SEA was previously developed using Super Learner ensemble algorithm. Multivariable linear regression was used to evaluate associations of SEA with individual metabolites. Bayesian kernel machine regression (BKMR), quantile g-computation (qgcomp) and weighted quantile sum (WQS) models were used for mixture analyses. Covariates included were BMI, cotinine, race and urinary creatinine. RESULT: In the single metabolite multivariate analyses, nine (82%) phthalate metabolites displayed positive trends with SEA (range: 0.05-0.47 years). Of these metabolites, advanced SEA was significantly associated with interquartile range increases in exposure of three phthalates [MEHHP (ß = 0.23, 95% CI: 0.03, 0.43, p = 0.03), MMP (ß = 0.24, 95% CI: 0.01, 0.47, p = 0.04), and MiBP (ß = 0.47, 95% CI: 0.14, 0.81, p = 0.01)]. Additionally, in BKMR and qgcomp (p = 0.06), but not WQS models, phthalate mixtures showed an overall positive trend with SEA, with MiBP, MMP and MBzP as major drivers of the mixture effects. CONCLUSION: This is the first study that combined single exposure and mixture models to associate male phthalate exposures with advanced epigenetic aging of sperm in men planning to conceive among the general population. Our findings suggest that phthalate exposure may contribute to the acceleration of biological aging of sperm.

Levels and health risks of urinary phthalate metabolites and the association between phthalate exposure and unexplained recurrent spontaneous abortion: a large case-control study from China.

Phthalate acid esters (PAEs) are environmental endocrine disruptors that can interfere with endocrine processes and cause adverse reproductive outcomes. The link between PAE exposure and unexplained recurrent spontaneous abortion (URSA) remains unknown. In this study, nine urinary metabolites of PAEs (mPAEs) were measured in 594 URSA cases and 569 healthy controls. The measured mPAEs were ubiquitously detected and present at higher levels (median: 203 ng/mL) in the URSA cases than in the controls (median: 161 ng/mL). Multiple logistic regression analysis showed that URSA was associated with higher concentrations of mono (2-ethyl-5-hydroxyhexyl) phthalate (mEHHP), mono (2-ethylhexyl) phthalate (mEHP), and mono-ethyl phthalate (mEP) and lower concentrations of mono-isobutyl phthalate (miBP). Moreover, a quantile-based g-computation (QGC) model revealed a positive association between mPAEs mixture and URSA. The URSA cases showed significantly higher concentrations of di-(2-ethylhexyl) phthalate (DEHP) than the controls. This was consistent with the health risk assessment, which suggested that DEHP is the main contributors to potential non-carcinogenic risk. DEHP accounted for over 80% of total risk. The large case-control study results suggest that PAE exposure may increase the risk of URSA, and that policy-makers and public health experts should pay more attention to DEHP exposure.

Association of urinary phthalate metabolites with renal function among 9989 US adults.

PURPOSE: This study aimed to investigate the relationship between phthalate metabolites and renal function. METHODS: We analyzed data from 9989 participants who took part in the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. Renal function was reflected by estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and hypertension. We used generalized linear regression to estimate the correlation between covariate-adjusted creatinine-normalized phthalate metabolites and renal function. In addition, subgroup analysis was used to further compare the effect differences between various populations. RESULTS: In the adjusted model, we found differential associations between phthalates and plasticizers metabolites and renal function. We found that Mono-benzyl phthalate, Mono-(3-carboxypropyl) phthalate, and Mono-(2-ethyl-5-oxohexyl) phthalate were positively associated with lower eGFR with odds ratios (95% confidence intervals) of 1.38 (1.14, 1.67), 1.30 (1.09, 1.57), and 1.27 (1.04, 1.53). While Mono-ethyl phthalate, Mono-(2-ethyl)-hexyl phthalate, Mono-isononyl phthalate and Mono-isobutyl phthalate were negatively associated with lower eGFR with OR values of 0.79 (0.69, 0.90), 0.64 (0.52, 0.78), 0.65 (0.51, 0.82) and 0.80 (0.63, 1.00), respectively. In addition, we found that Mono(carboxyoctyl) phthalate and Mono-isobutyl phthalate were negatively associated with hypertension with ORs of 0.86 (0.78, 0.96) and 0.84 (0.72, 0.98). But phthalates and plasticizers metabolites were not associated with UACR. CONCLUSION: This study found differences in the effects of phthalates and plasticizers metabolites on kidney function, which may raise concerns about possible changes in kidney function resulting from exposure to current levels of plasticizers.

The association of serum phthalate metabolites with biomarkers of ovarian reserve in women of childbearing age.

Phthalates (PAEs) are widely used plasticizers drawing increasing concern due to reproductive toxicity. However, studies on serum PAEs metabolites (mPAEs) and their associations with human ovarian function remain very scarce. In this study, from April 2019 to August 2020, a total of 297 women of childbearing age were recruited in Tianjin, China. Eleven mPAEs were analyzed in serum samples and eight mPAEs were detected at frequencies > 65% with median concentrations of 0.43-15.3 ng/mL. In multinomial logistic analysis, an increase in serum mono (2-isobutyl) phthalate (miBP) was associated with decline in antral follicle count (AFC) (OR=1.26, 95% CI: 0.99, 1.61) and 5-mono-(2-ethyl-5-hydroxyhexyl) phthalate (mEHHP) was significantly associated with AFC increase (OR=1.43, 95% CI: 1.06, 1.92), which were aligned with the associations found between mPAEs and AMH through generalized linear regression. In multiple linear regression models, per 10% increase in serum mono (2-ethylhexyl) phthalate (mEHP), mono (2-ethyl-5-oxohexyl) phthalate (mEOHP) (oxo-mEHP), and principal component 1 featured for high concentrations of mono-n-butyl phthalate (mBP), miBP and mEHP were associated with 0.15 (95% CI: -0.29, -0.02), 0.01 (95% CI: -0.01, 0.00) and 0.01 (95% CI: -0.02, 0.00) ln-unit decrease in estradiol (E2) levels, respectively, while mono-[(2-carboxymethyl) hexyl] phthalate (mCMHP) (carboxymethyl-mEHP) was positively associated with 0.05 ln-unit increase of E2 (95% CI: 0.02, 0.08). The observed negative associations between mPAEs and the Anti-Müllerian hormone (AMH) also aligned with the change in AFC. Generalized linear regression also revealed nonlinear associations between mono-ethyl phthalate (mEP), mCMHP and follicle-stimulating hormone (FSH). Overall, serum mEHP and its metabolites were negatively associated with E2. miBP was negatively associated with AFC. The nonlinear associations between mPAEs and FSH, and AMH need further study.

Potential health risks of maternal phthalate exposure during the first trimester - The Saudi Early Autism and Environment Study (SEAES).

Phthalates are the most ubiquitous contaminants that we are exposed to daily due to their wide use as plasticizers in various consumer products. A few studies have suggested that in utero exposure to phthalates can disturb fetal growth and development in humans, because phthalates can interfere with endocrine function. We collected spot urine samples from 291 pregnant women in their first trimester (9.8 ± 2.3 gestational weeks) recruited in an ongoing prospective cohort study in Saudi Arabia. A second urine sample was collected within 1-7 d after enrollment. The aims of this study were to: (1) assess the extent of exposure to phthalates during the first trimester and (2) estimate the risk from single and cumulative exposures to phthalates. Most phthalate metabolites' urinary levels were high, several-fold higher than those reported in relevant studies from other countries. The highest median levels of monoethyl phthalate, mono-n-butyl phthalate (MnBP), mono-iso-butyl phthalate (MiBP), and mono-(2-ethylhexyl) phthalate (MEHP) in µg/l (µg/g creatinine) were 245.62 (197.23), 114.26 (99.45), 39.59 (34.02), and 23.51 (19.92), respectively. The MEHP levels were highest among three di (2-ethylhexyl) phthalate (DEHP) metabolites. %MEHP4, the ratio of MEHP to four di (2-ethylhexyl) phthalate metabolites (∑4DEHP), was 44%, indicating interindividual differences in metabolism and excretion. The hazard quotient (HQ) of individual phthalates estimated based on the reference dose (RfD) of the U.S. Environmental Protection Agency indicated that 58% (volume-based) and 37% (creatinine-based) of the women were at risk of exposure to ∑4DEHP (HQ > 1). Based on the tolerable daily intake (TDI) from the European Food Safety Authority, 35/12% (volume-/creatinine-based data) of the women were at risk of exposure to two dibutyl phthalate (∑DBP) metabolites (MiBP and MnBP). The cumulative risk was assessed using the hazard index (HI), the sum of HQs of all phthalates. The percentages of women (volume-/creatinine-based data) at health risks with an HI > 1 were 64/40% and 42/22% based on RfD and TDI, respectively. In view of these indices for assessing risk, our results for the anti-androgenic effects of exposing pregnant women to ∑4DEHP and ∑DBP early during pregnancy are alarming.

The influence of prenatal exposure to phthalates on subsequent male growth and body composition in adolescence.

Phthalates are ubiquitous environmental chemicals with predominantly anti-androgenic, and potentially obesogenic effects. We hypothesised that antenatal phthalate exposure may influence subsequent boy's growth and body composition through childhood and adolescence. Among 1399 singleton males from the Raine Study, 410 had maternal serum and at least one height, BMI or DEXA outcome available after birth and up to 20 years of age. Maternal serum collected at 18 and 34 weeks' gestation was pooled, and analyzed for concentrations of 32 metabolites of 15 phthalate diesters. Their serum concentrations were categorized into undetectable/detectable levels or tertiles. Linear mixed models were used to determine associations between maternal serum phthalate levels and longitudinal height and body mass index (BMI) z-scores in boys from birth to 20 years of age (n = 250 and n = 295 respectively). Linear regression was used to determine associations between maternal phthalate levels and deviation from mid-parental height (n = 177) and DEXA scan outcomes (n = 191) at the 20 year follow-up. Weak positive associations of participants height z-score increase were detected with exposure to some phthalate metabolites in particular to the lower molecular weight phthalate metabolites. Less consistent findings, by mixed model analyses, were detected for BMI and body composition, by dual energy X-ray absorptiometry (DEXA), with some positive associations of phthalate metabolites with BMI and some negative associations with DEXA fat tissue measures, although no consistent findings were evident. In conclusion, we derived some associations of childhood growth with prenatal phthalate exposure, particularly with respect to the lower molecular weight phthalate metabolites.

A rapid method for the quantification of urinary phthalate monoesters: A new strategy for the assessment of the exposure to phthalate ester by solid-phase microextraction with gas chromatography and tandem mass spectrometry.

In the following work, a new method for the analysis of the phthalate monoesters in human urine was reported. Phthalate monoesters are metabolites generated as a result of phthalate exposure. In compliance with the dictates of Green Analytical Chemistry, a rapid and simple protocol was developed and optimized for the quantification of phthalate monoesters (i.e., monoethyl phthalate, monoisobutyl phthalate, mono-n-butyl phthalate, mono-(2-ethylhexyl) phthalate, mono-n-octyl phthalate, monocyclohexyl phthalate, mono-isononyl phthalate) in human urine, which entails preceding derivatization with methyl chloroformate combined with the use of commercial solid phase microextraction and the analysis by gas chromatography-triple quadrupole mass spectrometry. The affinity of the derivatized analytes toward five commercial coatings was evaluated, and in terms of analyte extraction, the best results were reached with the use of the divinylbenzene/carboxen/polydimethylsiloxane fiber. The multivariate approach of experimental design was used to seek for the best working conditions of the derivatization reaction and the solid phase microextraction, thus obtaining the optimum response values. The proposed method was validated according to the guidelines issued by the Food and Drug Administration achieving satisfactory values in terms of linearity, sensitivity, matrix effect, intra- and inter-day accuracy, and precision.

[A study on the correlation of phthalate metabolites in umbilical cord blood of 161 newborns with birth indicators in Beijing].

Objective: To analyze the correlation of phthalate metabolites in neonatal umbilical cord blood with birth indicators in Beijing, 2015. Method: From February to July in 2015, 161 pregnant women and their newborns who met the criteria were recruited from the Maternal and Child Health Hospital in Haidian District, Beijing. Questionnaires were used to collect the demographic information of pregnant women such as age, smoking, drinking, and cord blood after delivery. An ultra-high performance liquid chromatography-tandem mass spectrometry was used to determine the concentration of phthalate metabolites in umbilical cord blood. The multiple linear regression model was used to analyze the correlation of phthalate metabolites in umbilical cord blood with the neonatal weight, length, and ponderal index. Result: The age of 161 pregnant women was (30.3±3.0) years. The weight, length and ponderal index of 161 newborns were (3 447.2±413.0) kg, (50.2±1.1) cm, and (26.7±2.2) kg/m3; 51.6% of newborns (83 cases) were boys. The concentrations of seven phthalate metabolites detected in umbilical cord blood, i.e., mono-methyl phthalate (MMP), mono-ethyl phthalate (MEP),mono-(2-isobutyl) phthalate (MiBP), mono-n-butyl phthalate (MBP), mono-ethylhexyl phthalate (MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), was (3.50±0.28), (2.65±0.47), (4.31±0.55), (6.26±0.57), (1.71±0.13), (1.10±0.09) and (0.47±0.06) ng/ml, respectively. The result of multiple linear regression model analysis showed that the concentrations of seven phthalate metabolites were not related to the neonatal weight, length, and ponderal index (all P values> 0.05). Conclusion: The concentrations of phthalate metabolites in neonatal umbilical cord blood are low, and they are not related to the neonatal weight, length, and ponderal index.

Identifying periods of susceptibility to the impact of phthalates on children's cognitive abilities.

BACKGROUND: Early-life phthalate exposures may adversely affect children's neurodevelopment by disrupting thyroid function, reducing gonadal hormone levels, or altering fatty acid concentrations in the brain. This study aimed to identify periods of heightened susceptibility during gestation, infancy, and childhood to the impact of phthalates on children's cognitive abilities. METHODS: We used data from 253 mother-child pairs in the Health Outcomes and Measures of the Environment (HOME) Study (Cincinnati, Ohio), a longitudinal pregnancy and birth cohort. We quantified urinary concentrations of 11 phthalate metabolites in samples collected twice during gestation and 6 times during study visits when children were aged 1-8 years using a modified method of on-line solid phase extraction coupled with isotope dilution-high performance liquid chromatography-tandem mass spectrometry. We assessed children's intelligence (IQ) at ages 5 and 8 years using the Wechsler Preschool and Primary Scale of Intelligence-III and Wechsler Intelligence Scale for Children-IV, respectively. We estimated covariate-adjusted associations between a 1-standard deviation increase in log10-transformed urinary phthalate metabolite concentrations at each visit and children's IQ, adjusting for demographic, perinatal, and child factors; we tested for differences in these associations across visits using multiple informant models. RESULTS: Associations between some phthalate metabolites and IQ varied by visit (phthalate x visit interaction p-values<0.20). The sum of di(2-ethylhexyl) phthalate metabolites (ΣDEHP), mono(3-carboxypropyl) phthalate, and monoethyl phthalate at age 3 years, and monobenzyl phthalate at 16 weeks gestation and child ages 3, 5, and 8 years were inversely associated with children's full-scale IQ. For example, each 1-standard deviation increase in ΣDEHP at age 3 was associated with a 1.9-point decrease in full-scale IQ (95% confidence interval: -3.7, -0.2). Mono-n-butyl phthalate and mono-isobutyl phthalate at age 4 years were positively associated with children's full-scale IQ. CONCLUSION: Urinary concentrations of several phthalate metabolites at age 3 years, compared to other time periods, were more strongly associated with decreased cognitive abilities in these children.

Mothers and children are related, even in exposure to chemicals present in common consumer products.

BACKGROUND: Phthalates, bisphenol A (BPA) and triclosan (TCS) are detectable in the vast majority of people. Most humans are continuously exposed to these chemicals due to their presence in food or in everyday consumer products. The measurement of these compounds in family members may help to explore the impact of major lifestyle factors on exposure. Mothers and (young) children are especially interesting to study, as they mostly share considerable parts of daily life together. MATERIALS AND METHODS: Phthalate metabolites, bisphenol A (BPA) and triclosan (TCS) were measured in first morning void urine, collected in mother-child pairs (n = 129) on the same day. The mothers (27-45y) and their children (6-11y) were recruited in the Brussels agglomeration and rural areas of Belgium in the context of the European COPHES-DEMOCOPHES human biomonitoring project. Face-to-face questionnaires gathered information on major exposure sources and lifestyle factors. Exposure determinants were assessed by multiple linear regression analysis. RESULTS: The investigated compounds were detectable in nearly all mothers (92.8-100%) and all children (95.2-100%). The range (P90 vs. P10) of differences in urinary concentrations within each age group was for most compounds around 10-20 fold, and was very high for TCS up to 35 and 350-fold in children and mothers respectively. Some participants exceeded the tolerable daily intake guidelines as far as they were available from the European Food Safety Authority (EFSA). Overall, for BPA, the urinary concentrations were similar among both age groups. Most urinary phthalate metabolites were higher in children compared to the mothers, except for monoethyl phthalate (MEP). TCS levels were generally higher in the mothers. Despite the difference in mothers' and children's urinary concentrations, the creatinine-corrected levels were correlated for all biomarkers (Spearman rank r = 0.32 to 0.66, p < 0.001). Furthermore, for phthalates, similar home and lifestyle factors were associated with the urinary concentrations in both age groups: home renovation during last two years or redecoration during the last year for di-ethyl phthalate (DEP); PVC in home for di-n-butyl phthalate (DnBP), di-iso-butyl phthalate (DiBP) and butyl benzyl phthalate (BBzP), and personal care products use for DiBP and DnBP. Based on questionnaire information on general food type consumption patterns, the exposure variability could not be explained. However, comparing the phthalate intake from the current study with earlier assessed Belgian food intake calculations for both ages, food in general was estimated to be the major intake source for di-ethyl hexyl phthalate (DEHP), with diminishing importance for BBzP, DiBP and DnBP. CONCLUSION: Our results confirm, that children and their mothers, sharing diets and home environments, also share exposure in common consumer products related chemicals. By collecting morning urine levels on the same day, and using basic questionnaires, suspected exposure routes could be unraveled.

Urinary phthalate metabolites in primary school starters in Pearl River Delta, China: Occurrences, risks and possible sources.

Assessment of children's exposure risks of phthalates before puberty is important, as phthalates are ubiquitous and are associated with reproductive development. However, relevant data in Pearl River Delta, China are scarce. Nineteen phthalate metabolites were analyzed in urine samples from 1490 primary school starters (6-8 years old) recruited in 2016-2017 using ultra-performance liquid chromatography and tandem mass spectrometry (UHPLC-MS/MS). Nine phthalate metabolites were detected more than 80% of the urine samples. Monobutyl phthalate (MnBP) was the highest metabolite (median, 212 µg/g creatinine), followed by two short chained phthalate metabolites, four secondary metabolites of di(2-ethylhexyl) phthalate (DEHP), and the primary metabolites of DEHP. The MnBP level was the third highest of those reported worldwide while other metabolites were in the lower range compared with previous studies. Significantly positive associations were found between urinary metabolite levels and family income as well as parent education levels (p < 0.05). Duration since the latest interior decoration was inversely associated with phthalate metabolites (p < 0.05). Significantly positive associations had also been found between the frequency of eating takeaway food and four DEHP metabolites (p < 0.01). The geometric mean of estimated daily intake (EDI) of di-n-butyl phthalate (DnBP), DEHP, di-iso-butyl phthalate (DiBP), dimethyl phthalate, diethyl phthalate and butylbenzyl phthalate (BBzP) were 6.24, 2.67, 1.06, 0.64, 0.44, and 0.01 µg/kg bw/day, respectively. Hazard quotient (HQ) was defined as the ratio of EDI and the tolerable daily intake (TDI). Approximately 38% children had HQ DnBP >1 indicating potential reproductive risks caused by DnBP. To evaluate cumulative exposure risks, hazard index (HI) was calculated as the sum of the HQs of DnBP, DiBP, DEHP, and BBzP. Nearly 48% children had HI > 1 suggesting extremely high cumulative risks in children in Pearl River Delta, China. To our best knowledge, this was the largest study on evaluating phthalate exposure among children in China.

Determinants of exposure levels, metabolism, and health risks of phthalates among pregnant women in Wuhan, China.

Concerns on minimizing health risks of phthalates have been raised due to their widespread exposure and well-documented endocrine disrupting properties, but the determinants of levels, metabolism, and health risks of phthalate exposures have not been thoroughly characterized among the Chinese population, particularly pregnant women. The metabolites of five phthalates were analyzed: diethyl (DEP), diisobutyl (DiBP), di-n-butyl (DnBP), di-(2-ethylhexyl) (DEHP), and benzyl butyl phthalate (BBzP) were analyzed in urine samples collected from 946 mothers in Wuhan during 2014-2015. We applied linear mixed models to investigate the relationships between biomarkers (e.g., urinary concentrations of phthalate metabolites, phthalates, and ratios of metabolites) and factors including sampling seasons and epidemiological characteristics. We calculated estimated daily intake (EDI) using average phthalate concentrations over three trimesters and hazard index (HI) by dividing EDI by tolerance daily intake. About 24.9% of participants were at health risks with HI > 1. The largest health risks were driven by one specific phthalate (DnBP or DEHP). We observed lower urinary levels of phthalate metabolites in winter. Elevated levels were found in mothers with higher education levels or those employed. Mothers who got pregnant on purpose had lower phthalate concentrations than those got pregnant by accident. More recent exposure to phthalates was observed among groups of mothers giving birth to girls, or those who got excessive gestational weight gain. Younger mothers were more susceptible to phthalate exposure. This repeated measurement study suggests that the intervention should be taken to limit application and production of DnBP and DEHP, and highlights that typical demographic factors should be taken into account in demographic studies.

The extent and predictors of phthalate exposure among couples undergoing in vitro fertilization treatment.

Phthalates are chemicals used as plasticizers and solvents in many consumer products but are suspected of disrupting the endocrine system and are known for their reproductive/developmental health risks. This study examined the extent and predictors of phthalate exposure among 599 couples undergoing in vitro fertilization. A questionnaire was administered to obtain sociodemographic, health, and lifestyle data, and two spot urine samples were collected from the couples to analyze eight phthalate metabolites, cotinine (COT) as a smoking index, and creatinine to adjust for urine dilution. Seven phthalate metabolites were detected in > 94% of the urine samples, and monobenzyl phthalate (MBzP) was found in 24% of the women and 26% of their male partners. Median phthalate levels were highest for monoethyl phthalate (MEP), at 333.26 µg/l in women and 290 µg/l in male partners, and lowest for MBzP, at 1.17 µg/l in women and 1.14 µg/l in male partners. Correlation coefficients of ≥ 0.4 between the women and their male partners for the eight urinary phthalate metabolites may indicate a shared source of exposure. A multivariate regression model was used to assess the association between predictors and each urinary phthalate metabolite. Several potential predictors for the variations in specific urinary phthalate metabolites were identified, including the body mass index, age, socioeconomic status, and regional distribution for both women and their male partners but with slightly different patterns. Women with a history of breastfeeding, using bottled water for cooking and storing food in plastic bags had lower MEP (8.7%), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) (9.2%), and both mono-iso-butyl phthalate and MECPP (8.2 and 8.1%). A history of contraceptive use was associated with an increase in MECPP (8.7%), mono-(2-ethyl-5-hydroxyhexyl) phthalate (11.4%), mono-(2-ethyl-5-oxohexyl) phthalate (7.6%), and the molar sum of bis (2-ethylhexyl) phthalate metabolites (8.9%). Urinary COT levels were associated with an increase of 10-16% in all urinary metabolites in women but of only 10.5% in mono-(2-ethylhexyl) phthalate in male partners. More than 95% of the couples reported the use of cosmetics, perfumes, and personal-care products, but we were not able to find associations with urinary phthalate metabolites, perhaps due to their short half-lives. MEP levels associated with the use of household cleaning products were 11.2% higher in male partners. Our levels were generally higher than those reported elsewhere, perhaps due to different lifestyles, cultural practices, dietary habits, use of personal-care products, and governmental legislation.