Low Molecular Weight Phthalates Research Articles

Phthalate exposure and pubertal development in a longitudinal study of US girls.

Does phthalate exposure during early childhood alter the timing of pubertal development in girls? Urinary concentrations of high-molecular weight phthalate (high-MWP) metabolites are associated with later pubarche. Phthalates are anti-androgenic environmental agents known to alter early development, with possible effects on pubertal onset. This multi-ethnic study included 1239 girls from New York City, greater Cincinnati, and the San Francisco Bay Area who were 6-8 years old at enrollment (2004-2007) and who were followed until 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS Phthalate metabolites were measured in urine collected at enrollment from 1170 girls; concentrations ranged from <1 to >10,000 µg/l. Breast and pubic hair stages and body size were assessed one to two times annually to determine the age at transition from stage 1 to 2 for breast and pubic hair development. Associations between exposures and pubertal ages were estimated using Cox proportional hazard ratios (HR) with 95% confidence intervals (CI) and survival analyses. Associations were examined with respect to age-specific body mass-index percentile, one of the strongest predictors of pubertal onset. Urinary concentrations of high-MWP including di(2-ethylhexyl) phthalate (ΣDEHP) metabolites were associated with later pubic hair development during 7 years of observation. The relationship was linear and was stronger among normal-weight girls. Among normal-weight girls, age at pubic hair stage 2 (PH2) was 9.5 months older for girls in the fifth compared with the first quintile of urinary ΣDEHP (medians: 510 and 59 µg/g creatinine, respectively; adjusted HR 0.70, CI 0.53-0.93, P-trend 0.005. Age at first breast development was older for fifth quintile of mono-benzyl phthalate versus first (HR 0.83, CI 0.68-1.02; P-trend 0.018). No associations were observed between low-molecular weight phthalate urinary metabolite concentrations and age at pubertal transition in adjusted analyses. While there is evidence that phthalate exposures are fairly consistent over time, the exposure measure in this study may not reflect an earlier, more susceptible window of exposure. We investigated alternative explanations that might arise from exposure misclassification or confounding. Phthalates are widespread, hormonally active pollutants that may alter pubertal timing. Whether exposures delay or accelerate pubertal development may depend on age at exposure as well as other factors such as obesity and exposures earlier in life. Whether exposures act independently or as part of real life mixtures may also change their effects on maturation from birth through childhood. This project was supported by the US National Institutes of Health, Environmental Protection Agency, New York State Empire Clinical Research Investigator Program and the Avon Foundation. L.H.K. is employed by Kaiser Permanente. The remaining authors declare they have no actual or potential competing financial interests.

Urinary phthalates are associated with higher blood pressure in childhood.

To examine associations of urinary phthalate levels with blood pressure (BP) and serum triglyceride and lipoprotein levels in children. We performed a cross-sectional analysis of a subsample of US children aged 6-19 years who participated in the National Health and Nutrition Examination Survey between 2003 and 2008. We quantified exposure to 3 families of phthalates--low molecular weight, high molecular weight and di-2-ethylhexylphthalate (DEHP)--based on molar concentration of urinary metabolites. We assessed descriptive, bivariate, and multivariate associations with BP and lipid levels. Controlling for an array of sociodemographic and behavioral factors, as well as diet and body mass index, levels of metabolites of DEHP, a phthalate commonly found in processed foods, were associated with higher age-, sex-, and height-standardized BP. For each log unit (roughly 3-fold) increase in DEHP metabolites, a 0.041 SD unit increase in systolic BP z-score was identified (P = .047). Metabolites of low molecular weight phthalates commonly found in cosmetics and personal care products were not associated with BP. Phthalate metabolites were not associated with triglyceride levels, high-density lipoprotein level, or prehypertension. Dietary phthalate exposure is associated with higher systolic BP in children and adolescents. Further work is needed to confirm these associations, as well as to evaluate opportunities for intervention.

Identifying sources of phthalate exposure with human biomonitoring: Results of a 48h fasting study with urine collection and personal activity patterns

Human biomonitoring studies measuring phthalate metabolites in urine have shown widespread exposure to phthalates in the general population. Diet is thought to be a principle route of exposure to many phthalates. Therefore, we studied urinary phthalate metabolite patterns over a period of strict fasting and additionally recorded personal activity patterns with a diary to investigate non-dietary routes of exposure. Five individuals (3 female, 2 male, 27-47 years of age) fasted on glass-bottled water only over a 48-h period. All urine void events were captured in full, and measured for metabolites of the high molecular weight (HMW) di-(2-ethylhexyl) phthalate (DEHP), di-isononyl phthalate (DINP) and di-isodecyl phthalate (DiDP), and the low molecular weight (LMW) di-n-butyl phthalate (DnBP), di-iso-butyl phthalate (DiBP), butylbenzyl phthalate (BBzP), dimethyl phthalate (DMP), and diethyl phthalate (DEP). In all, 21 metabolites were measured in a total of 118 urine events, including events before and after the fasting period. At the onset of the study all phthalate metabolite concentrations were consistent with levels found in previous general population studies. Metabolites of the HMW phthalates (DEHP, DiNP and DiDP) showed a rapid decline to levels 5-10 times lower than initial levels within 24h of the fast and remained low thereafter. After food consumption resumed, levels rose again. By contrast, metabolites of the LMW phthalates including DMP, DEP, BBzP, DnBP and DiBP showed a cyclical pattern of rising and declining concentrations suggestive of ongoing non-food exposures. Furthermore, metabolites of most of the LMW phthalates (BBzP, DnBP and DiBP) tracked each other remarkably well, suggesting concurrent exposures. Diary entries could not help explain exposure sources for these phthalates, with one exception: rises in MEP concentrations around males' showers suggest personal care products as a major source of DEP. Exposure to HMW phthalates in this cohort appears to be driven by dietary intake, while non-dietary routes such as use of personal care products and ubiquitous sources including dust and indoor air appear to explain exposure to LMW phthalates.

Does perinatal exposure to endocrine disruptors induce autism spectrum and attention deficit hyperactivity disorders? Review

To provide an overview of studies on perinatal exposure in humans to endocrine disrupting chemicals (EDCs) in relation to autism spectrum (ASD) and attention deficit hyperactivity (ADHD) disorders. A review of the literature (PubMed) was performed. Exposure-related keywords, including various chemicals, were matched with keywords describing outcome. Animal studies as well as publications not written in English were excluded. In total, 834 titles were retrieved. The final selection included 21 publications. Positive associations were found for ASD in relation to exposure to all chemicals investigated, which included hazardous air pollutants, pesticides and bisphenol A (BPA). Increased risks of ADHD or positive associations were found for exposure to polychlorinated biphenyls (PCBs), dialkyl phosphate (DAP) and chlorpyrifos. BPA, polybrominated diphenylethers (PBDEs) and low molecular weight (LMW) phthalates were positively associated with externalizing behaviour. Five of 17 studies did not find any association between exposure and ADHD. Perinatal exposure to EDCs appears to be associated with the occurrence of ASD as well as ADHD. Disruption of thyroid hormone function and gamma-aminobutyric acid (GABA)ergic mechanisms may offer an explanation for the observed relations; though, conclusive evidence in humans is limited.

Associations between phthalate metabolite urinary concentrations and body size measures in New York City children

ObjectiveTo examine prospectively associations between urinary phthalate metabolite concentrations and body size measures in children. MethodsUrinary concentrations of nine phthalate metabolites: monoethyl (MEP); mono-n-butyl (MBP); mono-(3-carboxypropyl) (MCPP); monobenzyl (MBzP); mono-isobutyl (MiBP); mono-(2-ethylhexyl) (MEHP); mono-(2-ethyl-5-oxohexyl) (MEOHP); mono-(2-ethyl-5-carboxypentyl) (MECPP); and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and the molar sum of the low molecular-weight phthalate metabolites (low MWP: MEP, MBP and MiBP) and high molecular-weight phthalate metabolites (high MWP: MECPP, MEHHP, MEOHP, MEHP and MBzP) and of four di-(2-ethylhexyl) phthalate (DEHP) metabolites (ΣDEHP: MEHP, MEHHP, MEOHP, MECPP) and anthropometry, including body mass index and waist circumference were measured among 387 Hispanic and Black, New York City children who were between six and eight years at cohort enrollment (2004–2007). Relationships between baseline metabolite concentrations and body size characteristics obtained one year later were examined using multivariate-adjusted geometric means for each body size characteristic by continuous and categories of phthalate metabolite concentrations. Stratified analyses by body size (age/sex specific) were conducted. ResultsNo significant associations are reported among all girls or boys. Dose response relationships were seen with monoethyl phthalate and the sum of low molecular-weight phthalates and body mass index and waist circumference among overweight children; for increasing monoethyl phthalate concentration quartiles among girls, adjusted mean body mass indexes were as follows: 21.3, 21.7, 23.8, 23.5 and adjusted mean waist circumference (cm) were as follows: 73.4, 73.5, 79.2, 78.8 (p-trend<0.001 for both). ConclusionIn this prospective analysis we identified positive relationships between urinary concentrations of monoethyl phthalate and the sum of low molecular-weight phthalates and body size measures in overweight children. These are metabolites with concentrations above 1μM.

Levels of phthalate metabolites in urine among mother–child-pairs – Results from the Duisburg birth cohort study, Germany

Phthalates are used ubiquitously and human exposure is widespread. Some phthalates are anti-androgens and have to be regarded as reproductive and developmental toxicants. In the Duisburg birth cohort study we examine the associations between hormonally active environmental agents and child development. Here we report the concentrations of 21 primary and secondary phthalate metabolites from seven low molecular weight (LMW) phthalates (DMP, DEP, BBzP, DiBP, DnBP, DCHP, DnPeP) and five high-molecular weight (HMW) phthalates (DEHP, DiNP, DiDP, DPHP, DnOP) in 208 urine samples from 104 mothers and their school-aged children. Analysis was performed by multidimensional liquid chromatography coupled to tandem mass spectrometry (LC/LC-MS/MS), using internal isotope-labeled standards. In both children and mothers, 18 out of 21 phthalate metabolites were detected above the limits of quantification (between 0.2 and 1.0 μg/l) in nearly all urine samples. Among the LMW phthalates, the excretion level (geometric mean) of the ΣDiBP metabolites was most prominent in children (103.9 μg/l), followed by ΣDnBP (56.5 μg/l), and MEP (39.1 μg/l). In mothers ΣDiBP (66.6 μg/l) was highest, followed by MEP (50.5 μg/l), and ΣDnBP (36.0 μg/l). Among the HMW phthalates, ΣDEHP was highest in children and mothers (55.7/28.9 μg/l). Compared to reference values derived from the German Human Biomonitoring Commission, children's metabolite concentrations were within background levels, whereas for mothers considerably higher exposure to the LMW phthalates DnBP and DiBP, and the HMW phthalate DEHP was detected (MiBP: 10.7%; MnBP: 11.7%; ΣDEHP: 23.3% of the samples were above the reference values). The LMW metabolites from DMP, DiBP, and DnBP, and the HMW metabolites from DEHP and DiNP were correlated between the mothers and children, probably indicating shared exposure in the immediate surrounding environment. Children showed higher excretion levels for most of the secondary metabolites than mothers, confirming previous findings on higher oxidized metabolite levels in children. The LMW metabolites ΣDiBP, ΣDnBP, and MMP, and the HMW metabolites ΣDEHP were negatively associated with children's age. The LMW metabolites ΣDiBP, ΣDnBP, and MBzP were inversely associated with body mass index of the children. The LMW ΣDiBP metabolites revealed a significant association with nicotine metabolites in urine from both children and mothers. Further analyses are ongoing to study long-term phthalate exposure and the associations with puberty outcome in these children.

Prenatal Phthalate Exposure Is Associated with Childhood Behavior and Executive Functioning

BackgroundExperimental and observational studies have reported biological consequences of phthalate exposure relevant to neurodevelopment.ObjectiveOur goal was to examine the association of prenatal phthalate exposure with behavior and executive functioning at 4–9 years of age.MethodsThe Mount Sinai Children’s Environmental Health Study enrolled a multiethnic prenatal population in New York City between 1998 and 2002 (n = 404). Third-trimester maternal urines were collected and analyzed for phthalate metabolites. Children (n = 188, n = 365 visits) were assessed for cognitive and behavioral development between the ages of 4 and 9 years.ResultsIn multivariate adjusted models, increased loge concentrations of low molecular weight (LMW) phthalate metabolites were associated with poorer scores on the aggression [β = 1.24; 95% confidence interval (CI), 0.15– 2.34], conduct problems (β = 2.40; 95% CI, 1.34–3.46), attention problems (β = 1.29; 95% CI, 0.16– 2.41), and depression (β = 1.18; 95% CI, 0.11–2.24) clinical scales; and externalizing problems (β = 1.75; 95% CI, 0.61–2.88) and behavioral symptom index (β = 1.55; 95% CI, 0.39–2.71) composite scales. Increased loge concentrations of LMW phthalates were also associated with poorer scores on the global executive composite index (β = 1.23; 95% CI, 0.09–2.36) and the emotional control scale (β = 1.33; 95% CI, 0.18– 2.49).ConclusionBehavioral domains adversely associated with prenatal exposure to LMW phthalates in our study are commonly found to be affected in children clinically diagnosed with conduct or attention deficit hyperactivity disorders.

Prenatal Exposure to Low Molecular Weight Phthalates and Autistic Social Impairment

ISEE-0494 Background and Objective: Prenatal phthalate exposure has been shown to affect thyroid and sex hormone metabolism. These findings suggest the possibility that phthalates may also interfere with hormone-sensitive aspects of neurodevelopment. Both fetal testosterone levels and thyroid hormone have been implicated in the etiology of autism spectrum disorders (ASD). We investigated the association between prenatal phthalate exposure and subclinical austitic symptomatology in a prospective birth cohort. Methods: The Mount Sinai Children’s Environmental Health Study enrolled a multiethnic prenatal population from 1998–2002 (n = 404). Third trimester urines were analyzed for phthalate metabolites, which were grouped by molecular weight into monoester metabolites of high (>250 Daltons) molecular weight (HMW) and low (<250 Daltons) molecular weight (LMW). At the 8 year visit, mothers (n = 153) completed the Social Responsiveness Scale (SRS), a questionnaire designed to identify characteristics of ASD, including problems with interpersonal behavior, communication, and repetitive/stereotypic behaviors. The SRS is validated for use in the general population. Results: In adjusted generalized linear models, increased log-LMW concentrations were associated with poorer SRS scores (B = 1.53, 95% CI 0.26–2.80, P-value: 0.02). SRS treatment subscale scores were also significantly poorer for cognition (B = 1.43, P = .03), communication (B = 1.80, P = .01) and awareness (B = 1.29, P = .03), but not for Mannerisms or Motivation. There were no associations for HMW phthalates, which have lower exposure levels. Conclusion: Prenatal phthalate exposure was associated with evidence of social impairment in a healthy, urban population. Impaired social functioning is a prominent feature of multiple behavior and developmental disorders, including autism spectrum disorders. These results extend our previous finding of abnormalities in neonatal behavior in relation to prenatal phthalate exposure. Our study was limited by a small sample size and substantial attrition between birth and follow-up.

Prenatal Exposure to Low Molecular Weight Phthalates and Childhood Behavior and Executive Functioning

ISEE-0016 Background and Objective: Several studies have reported possible antagonistic effects of phthalates on the thyroid gland in vivo and thyroid tissue in vitro, suggesting that phthalate exposure may have neurodevelopmental consequences. We undertook an investigation of the neurobehavioral consequences of prenatal phthalate exposure in a prospective birth cohort. Methods: The Mount Sinai Children's Environmental Health Study enrolled a multiethnic prenatal population of 404 singleton, primiparous women in New York City between 1998-2002. Maternal urine was collected in the third trimester, and children were reassessed for growth and neurodevelopment at approximately ages 4, 6 and 8 years. At their exam, mothers completed the parent-report form of the Behavioral Assessment System for Children (BASC) and the Behavior Rating Inventory of Executive Function (BRIEF). In total, 181 (45%) children returned for at least one visit (n = 343 visits). Prenatal urine was analyzed for phthalate metabolites, which were grouped by molecular weight into monoester metabolites of high- (>250 dalton) (HMW), and low- (<250 dalton) (LMW) molecular weight. Results: In multivariate adjusted generalized linear models, increased log-LMW phthalate metabolite concentrations were associated with poorer BASC scores on the Aggression (B = 1.24, 95% CI 0.15-2.34), Attention Problems (1.29, 0.16-2.41), Conduct Problems (2.40, 1.34-3.46), and Depression (1.18, 0.11-2.24) clinical scales; and Externalizing Problems (1.75, 0.61-2.88) and Behavioral Symptom Index (1.55, 0.39-2.71) composite scales. For the BRIEF, in multivariate adjusted models, increased log-LMW phthalate concentrations were associated with poorer scores on the Global Executive Composite index (1.23, 0.09-2.36), and the Emotional Control scale (1.33, 0.18-2.49). Conclusion: These associations include domains that are typically affected in childhood Conduct Disorder, ADHD, and Depression clinical groups. Given the ubiquity of phthalates in the environment, the public health impact of even small adverse effects of phthalates on neurodevelopment could be significant. Replication of these findings is needed.

Prenatal phthalate exposure and performance on the Neonatal Behavioral Assessment Scale in a multiethnic birth cohort

We investigated the relationship between prenatal maternal urinary concentrations of phthalate metabolites and neonatal behavior in their 295 children enrolled in a multiethnic birth cohort between 1998 and 2002 at the Mount Sinai School of Medicine in New York City. Trained examiners administered the Brazelton Neonatal Behavioral Assessment Scale (BNBAS) to children within 5 days of delivery. We measured metabolites of 7 phthalate esters in maternal urine that was collected between 25 and 40 weeks’ gestation. All but two phthalate metabolites were over 95% detectable. We summed metabolites on a molar basis into low and high molecular weight phthalates. We hypothesized the existence of sex-specific effects from phthalate exposure a priori given the hormonal activity of these chemicals. Overall we found few associations between individual phthalate metabolites or their molar sums and most of the BNBAS domains. However, we observed significant sex-phthalate metabolite interactions ( p < 0.10) for the Orientation and Motor domains and the overall Quality of Alertness score. Among girls, there was a significant linear decline in adjusted mean Orientation score with increasing urinary concentrations of high molecular weight phthalate metabolites ( B = −0.37, p = 0.02). Likewise, there was a strong linear decline in their adjusted mean Quality of Alertness score ( B = −0.48, p < 0.01). In addition, boys and girls demonstrated opposite patterns of association between low and high molecular weight phthalate metabolite concentrations and motor performance, with some indication of improved motor performance with increasing concentration of low molecular weight phthalate metabolites among boys. This is the first study to report an association between prenatal phthalate exposure and neurological effects in humans or animals, and as such requires replication.

Phthalate metabolites in urine of CF patients are associated with use of enteric-coated pancreatic enzymes

In metabolomic studies using liquid chromatography mass spectrometry of urine from children with cystic fibrosis (CF), high levels of metabolites of low molecular weight phthalates were found. Phthalate metabolite excretion was explained by therapy with enteric-coated pancreatic enzyme replacements. Phthalate metabolite identity was confirmed by tandem mass spectrometry. Pancreatic insufficient CF children taking Cotazym ECS ®, which is formulated with diethyl phthalate (DEP), had urinary metabolites of DEP. Children taking Creon ®, which has dibutyl phthalate (DBP), excreted DBP metabolites. The estimated concentrations of free MEP were 2–3 orders of magnitude higher than reported from environmental phthalate exposure. Enteric-coated pancreatic enzymes can expose individuals with CF to incessant, high oral intakes of phthalates. Although adverse effects have neither been shown to be present nor absent, we raise the need to consider that individuals requiring life-long therapy with some current pancreatic enzyme replacements chronically ingest high amounts of phthalates.

Phtalates (II)

The findings on the toxicological effects of twelve phthalate esters, among the most largely used, are reviewed. This review completes a previous article on six other phthalates. Phthalates are generally distributed into three categories based on their physicochemical and toxicological properties. Low molecular weight phthalates (which include methyl and ethyl phthalates) are commonly used as solvents or in cellulose acetate industry. Their water solubility is slightly greater than other phthalates. High molecular weight phthalates are used nearly exclusively as plasticizers in polyvinyl chloride. They are insoluble in water and have a very low vapour pressure. Transitional phthalates are substances with either linear or branched side chains, with the stipulation that the predominant fraction of the alkyl side chains have a linear portion with carbon numbers ranging from C4-C6. They are characterized by a greater toxicity potential compared to methyl, ethyl, and high molecular weight phthalates, especially regarding their reproductive and developmental effects.