Urine Phthalate Metabolite Concentrations Research Articles

Associations between gastrointestinal infection and urinary phthalate metabolite concentrations in US children and adolescents from NHANES 2005-2016.

The purpose of this study was to evaluate at the link between gastrointestinal illness and urine phthalate metabolite concentrations in children and adolescents in the United States between 2005 and 2016. A total of 4008 National Health and Nutrition Examination Survey (NHANES) participants had urine samples obtained during the survey and self-reported their gastrointestinal functional status over the previous week. High performance liquid chromatography/tandem mass spectrometry (HPLC/MS-MS) was used to identify twelve phthalate metabolites in urine samples. The link between PAE concentrations and gastrointestinal illnesses was investigated using logistic regression, which was controlled for possible confounders. The combined and independent effects of PAEs on gastrointestinal illnesses were investigated using Bayesian Kernel Machine Regression (BKMR) and quantile-based g-computation (qgcomp). In children and adolescents, the prevalence of gastrointestinal infection was 9.0%. One log-unit increase in urinary concentrations was associated with an increased risk of gastrointestinal infection for monocarboxyoctyl phthalate (MCOP) (adjusted odd ratio (aOR) = 1.36, 95 percent confidence interval (95%ci): 1.08, 1.62), mono(2-ethylhexyl) phthalate (MEHP) (aOR = 1.18, 95 percent CI: 1.05, 1.32) and mono(2-eth The mixed exposure model findings revealed that the combined effect of PAEs was substantially linked with gastrointestinal infection; exposure to the combination of PAEs was positively associated with the risk of gastrointestinal infection. In the BKMR model, the exposure to the mixture of PAEs was positively associated with the risk of gastrointestinal infection. In qgcomp, a substantial positive correlation between PAEs and gastrointestinal illnesses was identified (OR = 1.16, 95 percent CI: 1.05, 1.28). MCOP and MEHP may be the major contributors after controlling for other PAE homologs. These associations were more pronounced in overweight and obese children and adolescents. Mixed exposure to phthalates (PAEs) in children and adolescents was significantly associated with gastrointestinal infections, with MCOP and MEHP accounting for the major proportions. These associations were more pronounced in overweight and obese children and adolescents.

Predictors of phthalate metabolites in urine and follicular fluid and correlations between urine and follicular fluid phthalate metabolite concentrations among women undergoing in vitro fertilization

BackgroundPhthalate metabolites in follicular fluid (FF) may negatively affect normal folliculogenesis; however, the predictors of phthalate metabolite concentrations in urine and FF and relationships between urine and FF phthalate metabolite concentrations among women undergoing in vitro fertilization (IVF) are poorly understood. ObjectiveTo investigate predictors of phthalate metabolites in urine and FF and correlations between urine and FF phthalate metabolite concentrations among women undergoing IVF. MethodWe recruited 305 women seeking infertility treatment at a reproductive center in Wuhan, China, from October to November 2016. Information regarding demographic characteristics, personal care product use and plastic material contact was obtained through direct interviews. Concentrations of 8 phthalate metabolites in urine and FF samples were measured using high-performance liquid chromatography and tandem mass spectrometry. Associations regarding metabolite concentrations in urine and FF samples were analysed by Spearman's correlation and linear regression. Generalized linear regression was used to examine potential predictors of phthalate metabolite concentrations in urine and FF. ResultsWeak to moderate associations between urine and FF samples were found for monoethyl phthalate (MEP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) (correlation coefficient: MEP, 0.350; MEOHP, 0.377); no associations were observed for other metabolites. The predictive powers of urinary metabolite concentrations in determining FF metabolite concentrations were uniformly low, with R2 ≤ 0.113. Body mass index (BMI) and educational level were inversely associated with the urinary concentrations of certain metabolites. Higher household income, intake of bottled drinks within 48 h, and use of shower gel and soap were frequently associated with higher urinary metabolite concentrations. BMI, higher household income and use of disposable plastic cups within 48 h were associated with higher metabolite concentrations in FF. ConclusionPhthalate metabolite concentrations in urine and FF vary according to sociodemographic characteristics and lifestyle factors. Phthalate metabolite concentrations in urine may not be appropriate for estimating ovary phthalate exposure.

Urinary Phthalate Metabolites in Common Bottlenose Dolphins (Tursiops truncatus) From Sarasota Bay, FL, USA.

Phthalates are chemical additives to common consumer goods including cleaning products, cosmetics, personal care products, and plastic. Because they are not chemically bound to these products and are widely used, the potential for environmental contamination is significant. Phthalates and their metabolites have been associated with endocrine disruption and reproductive impairment, among other adverse health effects, in laboratory animals and human epidemiologic studies. Common bottlenose dolphins (Tursiops truncatus) are vulnerable to environmental pollutants due to their apex position in the food chain, long life spans, and habitat overlap with developed coastal areas. The objective of this study was to quantify phthalate metabolite concentrations in urine collected from bottlenose dolphins in Sarasota Bay, Florida, during May 2016 (n = 7) and May 2017 (n = 10). Screening of nine phthalate monoester metabolites in bottlenose dolphin urine was performed by liquid chromatography tandem mass spectrometry using methods adapted from those used for analyzing human samples. At least one phthalate metabolite was detected in 71% of the dolphins sampled across both years, with the highest concentrations detected for monoethyl phthalate (MEP; GM = 5.4 ng/ml; 95%CI: 1.3–22.0 ng/ml) and mono‐(2‐ethylhexyl) phthalate (MEHP; GM = 1.9 ng/ml; 95%CI: 1.1–3.2 ng/ml). These data demonstrate exposure to two of the most commonly used phthalates in commercial manufacturing, diethyl phthalate (DEP) and di‐2‐ethylhexyl phthalate (DEHP). This study establishes methods for urinary detection of phthalate metabolites in marine mammals and provides baseline data to address a significant and growing, yet poorly understood, health threat to marine wildlife.

Association of phthalate exposure with anthropometric indices and blood pressure in first-grade children

We aimed to assess the relationship of urine phthalate metabolite concentrations with anthropometric indices, and blood pressure in first-grade children. We detected 11 phthalate metabolites in urine and estimated anthropometric indices, including skinfold measurements, waist circumference (WC), and body mass index (BMI) in 276 children aged 6-8years. Multivariate linear regression models were used to assess the associations between urinary phthalate metabolite levels, and anthropometric and blood pressure indices in a gender-specific manner. In boys, a 1-ng/mL increase in monobenzyl phthalate (MBzP) concentration was associated with a 0.027-cm decrease in the skinfold measurement (95% confidence interval [CI], - 0.053 to 0.001), whereas a 1-ng/mL increase in mono-ethyl-phthalate (MEP) concentration was associated with a 0.016-mmHg decrease in systolic blood pressure (95% CI, - 0.031 to 0.001). MBzP, mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), and MEOHP concentrations were also inversely associated with WC. However, in girls, MEP concentrations were positively associated with chest measurements, but were inversely associated with WC. A 1-ng/mL increase in monomethyl phthalate concentrations was associated with a 0.039-cm increase in skinfold measurements (95% CI, 0.002 to 0.076), whereas a 1-ng/mL increase in MECPP concentrations was associated with a 0.050cm decrease in skinfold measurements (95% CI, - 0.095 to - 0.005). In this exploratory, cross-sectional analysis, we identified various interesting associations between different phthalate metabolite levels and anthropometric indices, which suggest that some of phthalate metabolite should be considered in addition to the prevalence rates of overweight and obesity.

Predictors and correlations of phthalate metabolite concentrations in urine and seminal plasma among reproductive-aged men

BackgroundCertain phthalates are suspected to be endocrine disruptors that are adversely associated with male reproductive health. However, the predictors and correlations of phthalate metabolite concentrations in urine and seminal plasma among reproductive-aged men have not been thoroughly studied. ObjectiveTo investigate the predictors and correlations of phthalate metabolite concentrations in urine and seminal plasma among adult Chinese males. MethodWe measured mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), monomethyl phthalate (MMP), monoethyl phthalate (MEP), mono-n-octyl phthalate (MOP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) concentrations in seminal plasma and repeated spot-urine samples from 687 men who visited a reproductive center. Mixed-effect models were used to examine the associations of sociodemographic, lifestyle and medical factors with urinary metabolite concentrations. Linear regression models were used to identify predictors of metabolite concentrations in seminal plasma and correlations between metabolite concentrations in spot urine samples and seminal plasma. ResultsMeasurements taken from spot urine samples poorly predicted same-day seminal plasma concentrations (all R2<0.10). Inverse associations were observed between education level and urinary MBP and MEOHP and between household income and urinary MMP; receiving intravenous infusion therapy was associated with increased urinary MBP, MEHHP and MEOHP, use of facial cleanser/cream was associated with increased MEP, and smoking was associated with increased MEHP. The predictors of metabolite concentrations in seminal plasma differed from those in urine, except for the association of intravenous infusion therapy with MBP. BMI was associated with increased seminal plasma MBP, MEHP and MEOHP, smoking was associated with increased MEP, and contact with plastics was associated with increased MEOHP. ConclusionsPhthalate metabolite concentrations in adult men varied in accordance with sociodemographic variables, lifestyle factors and intravenous therapy. Measures of metabolite levels in urine may not directly reflect the exposure status of the male reproductive system.

Oxidative Stress-Related Genetic Variants May Modify Associations of Phthalate Exposures with Asthma.

Background: Phthalate exposure may increase the risk of asthma. Little is known about whether oxidative-stress related genes may alter this association. First, this motivated us to investigate whether genetic polymorphisms of the oxidative-stress related genes glutathione S-transferase Mu 1 (GSTM1), glutathione S-transferase pi 1 (GSTP1), superoxide dismutase 2 (SOD2), catalase (CAT), myeloperoxidase (MPO), and EPHX1 in children are associated with phthalate urine concentrations. Second, we addressed the question whether these genes may affect the influence of phthalates on asthma. Methods: In a case-control study composed of 126 asthmatic children and 327 controls, urine phthalate metabolites (monoethyl phthalate (MEP), monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), and mono(2-ethyl-5-hydroxyhexyl)phthalate (MEHHP) were measured by UPLC-MS/MS at age 3. Genetic variants were analyzed by TaqMan assay. Information on asthma and environmental exposures was also collected. Analyses of variance and logistic regressions were performed. Results: Urine MEHHP levels were associated with asthma (adjusted OR 1.33, 95% CI (1.11–1.60). Children with the GSTP1 (rs1695) AA and SOD2 (rs5746136) TT genotypes had higher MEHHP levels as compared to GG and CC types, respectively. Since only SOD2 TT genotype was significantly associated with asthma (adjusted OR (95% CI): 2.78 (1.54–5.02)), we estimated whether SOD2 variants modify the association of MEHHP levels and asthma. As MEHHP concentrations were dependent on GSTP1 and SOD2, but the assessment of interaction requires independent variables, we estimated MEHHP residuals and assessed their interaction, showing that the OR for SOD2 TT was further elevated to 3.32 (1.75–6.32) when the residuals of MEHHP were high. Conclusions: Urine phthalate metabolite concentrations are associated with oxidative-stress related genetic variants. Genetic variants of SOD2, considered to be reflect oxidative stress metabolisms, might modify the association of phthalate exposure with asthma.

Cumulative risk assessment of phthalates associated with birth outcomes in pregnant Chinese women: A prospective cohort study

A prospective cohort study of a Chinese population of mother–neonate pairs (n = 3103) was conducted to investigate the relationship between the cumulative hazard index (HI) of combined diethyl phthalate (DEP), dibutyl phthalate (DBP), dibenzyl phthalate (BBzP) and di(2-ethylhexyl) phthalate (DEHP) exposure and birth outcomes. The estimated HI for phthalates was based on phthalate metabolite concentrations in urine collected between 5th and 14th gestational weeks. The median HI values according to the European Food Safety Authority tolerable daily intake (HITDI) and U.S. Environmental Protection Agency reference dose (HIRfD) were 0.358 and 0.187, respectively. A total of 16.3% and 1.9% of the women exhibited HITDI and HIRfD exceeding the value of one, respectively. In unadjusted models, the categories (low < P25, median P25–P50, high > P75) of HITDI were associated with decreased birth weight (β = −26.34 g, p = 0.021) and head circumference (β = −0.09 cm, p = 0.029), whereas those for HIRfD were negatively associated with birth weight (β = −31.74 g, p = 0.005), birth length (β = −0.11 cm, p = 0.032), head circumference (β = −0.13 cm, p = 0.003) and chest circumference (β = −0.10 cm, p = 0.021) in all neonates. Adjustment for potential confounders revealed that HIRfD was inversely associated with head circumference (β = −0.10 cm, p = 0.020). Stratification by gender indicated that HIRfD was associated with decreased birth length (β = −0.17 cm, p = 0.041) in infant boys and HITDI was associated with decreased birth weight (β = −33.12 g, p = 0.036) and head circumference (β = −0.13 cm, p = 0.027) in girls. This is the first study on the cumulative risk assessment of phthalate exposures in pregnant Chinese women. We found that the HI values of multiple phthalate co-exposure were sex-specifically related to birth outcomes.

Association between phthalate exposure and lower handgrip strength in an elderly population: a repeated-measures study.

BackgroundDecreased muscle strength can lead to adverse health outcomes in the elderly. A potential association between phthalate exposure and muscle strength was suggested previously, but has not been investigated directly. We hypothesized that phthalate exposure is associated with lower handgrip strength and that the association is modified by the dietary omega-6 to omega-3 ratio.MethodsWe analyzed 1,228 participants (≥60 years of age) recruited in Seoul and Asan, Republic of Korea. The study participants were surveyed up to three times between 2012 and 2015. At every survey, we collected urine samples and measured handgrip strength twice for each hand. The associations between urine phthalate metabolite concentrations and handgrip strength were evaluated using linear mixed models. Based on dietary information from 391 individuals who participated in the first survey in Seoul, we evaluated the heterogeneity of the association for those with high and low omega-6 to omega-3 ratios, using 8.81 (the 75th quantile) as a cutoff value.ResultsLog-transformed creatinine-adjusted concentrations of mono-(2-ethyl-5-oxohexyl phthalate (MEOHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-n-butyl phthalate (MnBP) were inversely associated with all measured handgrip strengths (β = −0.69 to −0.42, all p-values < 0.05). Associations between phthalate biomarkers and handgrip strength did not differ by sex. When the dietary subgroup was stratified by the omega-6 to omega-3 ratio, the associations were stronger among participants with high ratios.ConclusionsWe found inverse associations between phthalate biomarkers and handgrip strength in the elderly; this association was modified by the dietary omega-6 to omega-3 ratio.Electronic supplementary materialThe online version of this article (doi:10.1186/s12940-016-0176-2) contains supplementary material, which is available to authorized users.

Association of current phthalate exposure with neurobehavioral development in a national sample.

Previous studies have indicated that phthalate exposure may influence the development of children, but the current data are limited, and controversy remains regarding the sex-specific and age-specific effects of phthalate exposure. We investigated the sex- and age-specific associations of current phthalate exposure with neurobehavioral development scores in a nationally representative sample of 6-18-year-olds participating in the Korean Environmental Health Survey in Children and Adolescents (KorEHS-C). Neurobehavioral development was assessed using the Korean Child Behavior Checklist (CBCL, N=1723) and the Korean Attention Deficit Hyperactivity Disorder Rating Scale (ARS, N=867). We measured the concentrations of phthalate metabolites in urine samples using high-performance liquid chromatography tandem mass spectrometry. The associations between urine phthalate metabolite concentrations and neurobehavioral development were examined by survey regression analysis for complex sampling and penalized regression splines using a generalized additive model. Survey regression analysis revealed that a higher mono-n-butyl phthalate (MnBP) level was associated with social (β=0.60; 95% confidence interval=0.15-1.05), thought (0.55; 0.08-1.03), and attention (0.68; 0.21-1.14) problems on the CBCL. A significant association was found between the MnBP level and the ARS hyperactivity subscale score (0.42; 0.05-0.58). Higher levels of MnBP (0.87; 0.20-1.54), mono-2-ethyl-5-oxohexyl phthalate (MEOHP, 0.61; 0.11-1.11) and mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP, 0.51; 0.04-0.97) were associated with an increase in thought problems among the girls. Among the younger children aged 6-11 years, significant positive associations between the MnBP (0.71; 0.09-1.33), MECPP (0.74, 0.14-1.34), MEOHP (0.65; 0.10-1.20), and MEHHP (0.71; 0.21-1.21) levels and social problems and between the MnBP (1.11; 0.37-1.84), MEOHP (0.64; 0.13-1.15), and MEHHP (0.66; 0.18-1.14) levels and attention problems were observed. The penalized regression splines for the age-specific relationships between the urinary MnBP, MEOHP, and MEHHP levels and social and attention problems exhibited positive supralinear relationships with downward curvature in the 6-11 year age group. In contrast, the score for social problems exhibited nearly linear relationships with these levels in the 12-18 year age group. In this national sample, increased phthalate exposure exhibited supralinear associations with social, thought and attention problems in children aged 6-11 years, who showed greater vulnerability to phthalate exposure. The results highlight the need for the environmental regulation of phthalate exposure in younger children, even at low dosages.

Association between phthalates and externalizing behaviors and cortical thickness in children with attention deficit hyperactivity disorder.

Previous studies have implicated the relationship between environmental phthalate exposure and attention deficit hyperactivity disorder (ADHD) symptoms of childhood, but no studies have been conducted in children who have a confirmed diagnosis of ADHD obtained through meticulous diagnostic testing. We aimed to determine whether phthalate metabolites in urine would be higher in children with ADHD than in those without ADHD and would correlate with symptom severity and cortical thickness in ADHD children. A cross-sectional examination of urine phthalate metabolite concentrations was performed; scores for ADHD symptoms, externalizing problems, and continuous performance tests were obtained from 180 children with ADHD, and brain-imaging data were obtained from 115 participants. For the control group, children without ADHD (N = 438) were recruited. Correlations between phthalate metabolite concentrations and clinical measures and brain cortical thickness were investigated. Concentrations of phthalate metabolites, particularly the di(2-ethylhexyl) phthalate (DEHP) metabolite, were significantly higher in boys with ADHD than in boys without ADHD. Concentrations of the di-n-butyl phthalate (DBP) metabolite were significantly higher in the combined or hyperactive-impulsive subtypes compared to the inattentive subtype, and the metabolite was positively correlated with the severity of externalizing symptoms. Concentrations of the DEHP metabolite were negatively correlated with cortical thickness in the right middle and superior temporal gyri. The results of this study suggest an association between phthalate concentrations and both the diagnosis and symptom severity of ADHD. Imaging findings suggest a negative impact of phthalates on regional cortical maturation in children with ADHD.

Association between Urine Phthalate Levels and Poor Attentional Performance in Children with Attention-Deficit Hyperactivity Disorder with Evidence of Dopamine Gene-Phthalate Interaction

Although there is some evidence supporting the existence of an association between prenatal maternal or postnatal child’s urine phthalate metabolite concentrations and poor attentional performances, the interaction between urine phthalate metabolite levels and genetic variation for neuropsychological deficit of attention-deficit hyperactivity disorder (ADHD) has not been examined. The aim of this study was to determine whether phthalate metabolites in urine are associated with poor neuropsychological performance in children with ADHD, and whether such association is affected by genotype-phthalate interaction. A cross-sectional examination of urine phthalate metabolite concentrations and the continuous performance test (CPT) were performed in 179 Korean children with ADHD recruited from department of psychiatry of university hospital. Correlations between urine phthalate metabolite concentrations and the CPT scores were investigated, and the interaction of phthalate metabolite levels with the selected polymorphisms at major candidate genes for ADHD, namely dopamine receptor D4 (DRD4), dopamine transporter, α-2A-adrenergic receptor, and norepinephrine transporter genes. For the subjects with the DRD4 4/4 genotype, there were significant associations of the urine phthalate metabolite concentrations with the number of omission errors, the number of commission errors, and the response time variability scores on the CPT. However, for the subjects without the DRD4 4/4 genotype, no significant associations were found. The results of this study suggest a possible association between phthalate metabolite concentrations and poor attentional performances of ADHD as well as a genetic influence on this association. Further prospective and epigenetic studies are needed to investigate causality and pathophysiological mechanisms.

Phthalates and other additives in plastics: human exposure and associated health outcomes

Concern exists over whether additives in plastics to which most people are exposed, such as phthalates, bisphenol A or polybrominated diphenyl ethers, may cause harm to human health by altering endocrine function or through other biological mechanisms. Human data are limited compared with the large body of experimental evidence documenting reproductive or developmental toxicity in relation to these compounds. Here, we discuss the current state of human evidence, as well as future research trends and needs. Because exposure assessment is often a major weakness in epidemiological studies, and in utero exposures to reproductive or developmental toxicants are important, we also provide original data on maternal exposure to phthalates during and after pregnancy (n = 242). Phthalate metabolite concentrations in urine showed weak correlations between pre- and post-natal samples, though the strength of the relationship increased when duration between the two samples decreased. Phthalate metabolite levels also tended to be higher in post-natal samples. In conclusion, there is a great need for more human studies of adverse health effects associated with plastic additives. Recent advances in the measurement of exposure biomarkers hold much promise in improving the epidemiological data, but their utility must be understood to facilitate appropriate study design.