Urinary Mono-n-butyl Phthalate Research Articles

Urinary phthalate metabolites and arterial stiffness: A panel study

The link between phthalates exposure and arterial stiffness in adults remains unclear. We aimed to investigate the associations of urinary phthalate metabolites with arterial stiffness in a longitudinal panel study involving 3 repeated visits among 127 Chinese adults. Urine samples were collected once a day for 4 consecutive days and 10 urinary phthalate metabolites were measured by gas chromatography-tandem mass spectrometry (GC-MS/MS). Brachial ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI) were determined using an oscillometric device (BP-203RPEIII; Omron) in physical examinations during each visit. Linear mixed-effect (LME) models with the adaptive Least Absolute Shrinkage and Selection Operator (LASSO) method were applied to assess the associations between urinary phthalate metabolites and arterial stiffness parameters. The odds ratio (OR) for peripheral arterial disease (PAD) was estimated using generalized estimating equations. For ABI, mono-methyl phthalate (MMP) and mono-n-butyl phthalate (MBP) at lag 0 day were selected by the adaptive LASSO, whereas no phthalates were selected for baPWV. After adjusting for potential covariates and other metabolites, we found ABI reduction was associated with one-unit increase of ln-transformed urinary MBP at lag 0 day [β = 0.013 (SE = 0.006), P = 0.003)]. Stratified analysis revealed that the inverse association was more evident in males (Pinteraction = 0.025). In addition, we observed a borderline risk of PAD in relation to MBP exposure at lag 0 day (P = 0.06). Our data suggested that environmental exposure to MBP may contribute to arterial stiffness, and the effect seems to be sex-specific.

Association of urinary phthalate metabolites with sarcopenia in US adults: NHANES 1999-2006.

Phthalates have been extensively detected in environmental and biological matrices. Exposure to phthalates is implicated in various human diseases. In this study, we conducted a cross-sectional study to determine whether urinary phthalate metabolite concentrations were correlated with prevalence of sarcopenia in US adult population. We included 3562 participants with detailed information on skeletal muscle mass and urinary phthalate metabolites based on National Health and Nutrition Examination Survey (NHANES) 1999-2006 data. A total of 7 main phthalate metabolites were analyzed in the urine sample of each participant. Appendicular skeletal muscle mass (ASM) was measured using dual-energy X-ray absorptiometry. Multivariable linear regression models were conducted following adjustment for multiple covariates. ASM adjusted by body mass index (ASM/BMI) was calculated, and sarcopenia was defined as the lowest quintile for ASM/BMI value. Compared with participants in quartile 1, those in quartile 2 of urinary mono-n-butyl phthalate (MnBP) and quartile 4 of urinary monobenzyl phthalate (MBzP) had decreased ASM/BMI. Urinary MnBP in quartile 4, as well as urinary MBzP in quartile 2, was shown to be significantly correlated with higher sarcopenia prevalence. In subgroup analysis, negative association of MBzP with ASM/BMI was observed in both males and females, while this negative association was only observed in males for MnBP. Females with higher urinary monoethyl phthalate (MEP) concentrations had higher sarcopenia risk. Taken together, the present study found several urinary phthalate metabolites were positively associated with sarcopenia prevalence in US adult population. These findings indicated phthalate exposure might be an important environmental risk factor contributing to sarcopenia development.

Assessment of metabolic perturbations associated with prenatal phthalate exposure among pregnant African American women

BACKGROUND AND AIM: Phthalates have been linked with numerous harmful health effects. Limited data are available on the molecular mechanism underlying phthalate toxicity on human health. In this analysis, we measured urinary phthalate metabolites and conducted high-resolution metabolomics (HRM) to identify biological perturbations associated with phthalate exposures among pregnant African American (AA) women, who are disproportionately exposed to high phthalates levels. METHODS: We used untargeted HRM profiling to characterize serum samples collected during early (8-14 weeks gestation) and late (24-30 weeks gestation) pregnancy from 73 participants from the Atlanta AA Maternal-Child cohort. We measured 8 urinary phthalate metabolites in early and late pregnancy, including Monoethyl phthalate (MEP), Mono-n-butyl phthalate (MBP), Mono(2-ethlyhexyl) phthalate (MEHP), and Mono (2-ethyl-5-hydroxyhexyl phthalate (MEHHP), to assess maternal exposures to phthalates. Metabolite and metabolic pathway perturbation were evaluated using an untargeted HRM workflow. RESULTS:Geometric mean creatinine-adjusted levels of urinary MEP, MBP, MEHP, and MEHHP were 67.3, 6.6, 1.4, and 4.1 μg/g creatinine, respectively, with MEP and MEHP higher than the mean levels of Non-Hispanic blacks in the general US population (2015-2016). There were 814 and 1,435 metabolic features significantly associated with at least one phthalate metabolites during early and late pregnancy, respectively. Metabolic pathway enrichment analysis revealed perturbations in four inflammation- and oxidative stress-related pathways associated with phthalate metabolite levels during both early and late pregnancy, including glycerophospholipid, urea cycle, arginine, and tyrosine metabolism. We confirmed 10 metabolites associated with urinary phthalates, including thyroxine and thiamine, which were negatively associated with MEP, as well as tyramine and phenethylamine, which were positively associated with MEHP and MEHHP. CONCLUSIONS:Our results demonstrate that urinary phthalate levels are associated with perturbations in biological pathways connected with inflammation and oxidative stress. The findings support future hypothesis-testing investigations on potential molecular mechanisms underlying the impact of maternal phthalates exposure on adverse health outcomes. KEYWORDS: Phthalates, Metabolomics, Prenatal Phthalate Exposures, Biological Pathway

Associations between medication use and phthalate metabolites in urine and follicular fluid among women undergoing in vitro fertilization

BackgroundPhthalates, which are used as excipients of drugs, have been related to adverse reproductive outcomes. However, the relationships between medication use and phthalate exposure among women undergoing in vitro fertilization (IVF) have not been studied. ObjectiveTo investigate the associations between the medication intake and phthalate metabolites in urine and follicular fluid (FF). MethodEight phthalate metabolites were measured in urine and FF samples from 274 women undergoing IVF using liquid chromatography-tandem mass spectrometry. Information on recent medication intake was obtained via interview by trained staff. We constructed generalized linear regression models to examine the associations of medication intake with phthalate metabolite concentrations and dose-response relationships between the number of medicines used and metabolite concentrations in two matrices. ResultsFour of 10 drugs were used by more than 10% of the participants, including vitamins (23.0%), traditional Chinese medicine (TCM, 22.3%), antioxidants (12.4%) and amoxicillin (10.2%). Participants who had used TCM had 26.0% (95% CI: 0.0, 58.8%), 32.6% (95% CI: 4.2, 68.8%) and 32.3% (95% CI: 2.6, 70.6%) higher urinary mono-n-butyl phthalate (MBP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) concentrations, respectively, than those who had not. Antioxidant intake was associated with a 30.6% (95% CI: −48.5, −6.6%) decrease in the urinary MBP concentration. Compared with non-users, women who reported the use of medicines had 53.2% (95% CI: 2.7, 128.5%) higher concentrations of MMP and a 37.7% (95% CI: −60.7, −1.5%) lower level of MBP in FF, respectively. ConclusionOur data suggest that the intake of some medications may increase phthalate exposure among women undergoing IVF.

Associations between Preconception Phthalate Exposure and Infertility Treatment Outcomes among Couples Undergoing In Vitro Fertilization

Background/Aim: Phthalates are implicated as reproductive toxicants in animal models and human populations. We modeled associations between couples’ preconception phthalate exposures and in vitro fertilization (IVF) outcomes.Methods: Women (n=56) and their male partners (n=43) undergoing IVF were enrolled in a prospective cohort investigation of environmental exposures and reproductive outcomes. Participants provided urine samples (fasting for women) on the day of oocyte retrieval. Urine was analyzed for monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), mono-n-pentyl phthalate (MPP), mono-n-hexyl phthalate (MHxP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-isononyl phthalate (MiNP), mono-isodecyl phthalate (MiDP), monocyclohexyl phthalate (MCHP), and monobenzyl phthalate (MBzP) via liquid chromatography-tandem mass spectrometry (Agilent LC 1260-AB Sciex 5500). Modified Poisson regression models, were used to assess associations between IVF outcomes and individual urinary phthalates among women and men separately, and simultaneously in couples, adjusted for age, body mass index (for women), and cigarette smoking. Results: Individual partner models showed higher likelihoods of pregnancy and live birth associated with greater concentrations of several urinary phthalates, albeit without statistical significance, with the exception of men’s MEHP and pregnancy [RR=0.53 (95%CI: 0.24-1.17). However, most urinary phthalates were associated with lower chances of pregnancy and live birth among couples. A doubling in women’s MBP was associated with a 43% [RR=0.57 (95%CI: 0.36-0.91)] lower likelihood of a pregnancy and a 46% [RR=0.54 (95%CI: 0.27-1.08)] lower likelihood of a live birth, adjusted for the male partner. Doublings in men’s MEHP andMEP were associated with 66% [RR=0.34 (95% CI: 0.16-0.72)] and 28% [RR=0.72 (95% CI: 0.52-1.01)] lower likelihoods of a pregnancy, respectively, adjusted for the female partner. Conclusions: Greater urinary MEP, MBP, and MEHP were associated with lower probabilities of pregnancy and live birth among couples undergoing IVF. The results suggest that greater phthalate exposure in couples may be deleterious to IVF.

Associations between Potential Exposure Sources and Urinary Phthalate Concentrations among Couples Undergoing Infertility Treatment

Background/Aim: Phthalates are implicated as reproductive toxicants in experimental and observational studies. We examined associations between potential exposure sources and urinary phthalate concentrations among infertile couples.Methods: Women (n=56) and their male partners (n=43) undergoing in vitro fertilization (IVF) were enrolled in a prospective cohort investigation of environmental chemicals and IVF outcomes. On the day of oocyte retrieval, women (fasting) and their male partners provided urine samples and completed questionnaires detailing use of personal care products (PCPs), consumption of medications, and foods/beverages in the preceding 24-hours. Urine was analyzed for monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), mono-n-pentyl phthalate (MPP), mono-n-hexyl phthalate (MHxP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-isononyl phthalate (MiNP), mono-isodecyl phthalate (MiDP), monocyclohexyl phthalate (MCHP), and monobenzyl phthalate (MBzP) via liquid chromatography-tandem mass spectrometry (Agilent LC 1260-AB Sciex 5500). We employed principal component analysis (PCA) to summarize questionnaire responses as patterns of exposure and entered factors into linear regression models to evaluate associations with urinary phthalate concentrations, adjusted for specific gravity, age, BMI (for women), history of smoking, and race. Results: Among women, recent application of moisturizers, cleansers, and nail polish was associated with greater urinary MBP [β=0.08 (95% CI: 0.02-0.14)] and the molar sum of diethylhexyl phthalate (DEHP) metabolites [β=0.23 (95% CI: 0.16-0.29)]. Among men, recent supplement and allergy medication intake was positively associated with the sum of DEHP metabolites [β=0.12 (95% CI: 0.02-0.21)]. Women with a tubal factor or polycystic ovarysyndrome infertility diagnosis had higher urinary phthalate concentrations than women with other infertility diagnoses.Conclusions: Among women, recent PCP use predicted urinary phthalate concentrations, whereas in men, supplements/medications were important contributors to phthalate exposure. This difference in exposure sources among couples will be useful for developing strategies to limit phthalate exposure as part of a comprehensive strategy to help improve IVF outcomes.

The levels of phthalate exposure and associations with obesity in an elderly population in China.

Few epidemiological studies on the correlation between phthalate exposure and elderly obesity in China are available. The purpose of the present study is to assess phthalate exposure levels and explore the connections between exposure to phthalates and obesity using a sample of Chinese community-dwelling elderly individuals. Data were acquired from the baseline survey of the Cohort of Health of Elderly and Controllable Factors of Environment, which was established in Lu'an, Anhui province, China, from June to September in 2016. Urine samples were obtained to analyze the concentrations of seven phthalate metabolites, utilizing a high-performance liquid chromatography-tandem mass spectrometry method. General obesity was determined based on body mass index, and abdominal obesity based on waist circumference. Binary logistic regression models were utilized to analyze the associations of creatinine-corrected phthalate metabolite concentrations (categorized into quartiles) with general and abdominal obesity in elderly people. Moreover, a stratified analysis was performed to explore the difference between genders. Of 942 elderly individuals, 52.9% were defined as generally obese and 75.5% as abdominally obese. The detection rates of seven phthalate metabolites ranged from 90.07% to 99.80%. The highest median concentration was 44.08μg/l (for MBP), and the lowest was 0.55μg/l (for MEHP). The level of exposure to LMW(low-molecular-weight) PAEs is higher than that to HMW(high-molecular-weight) PAEs. After adjustment for confounding variables, we found a significant association between urinary MEOHP (mono-2-ethyl-5-oxohexyl phthalate), MEHP (mono-2-ethylhexyl phthalate), MBP (mono-n-butyl phthalate), MEP (mono-ethyl phthalate), and MMP (mono-methyl phthalate) levels and general obesity. MBP levels were also correlated with abdominal obesity. When stratified by gender, higher urinary levels of MEOHP, MBP, MEP, and MMP were associated with general obesity in males, whereas MBP and MMP levels were eminently correlated with general obesity in females. Higher urinary MBP levels were associated with increased abdominal obesity rates in males, but not in females. In conclusion, higher phthalate metabolite concentrations were correlated with obesity in the elderly. Moreover, a gender difference was observed in these associations.

Urinary Concentrations of Phthalate Metabolite Mixtures in Relation to Serum Biomarkers of Thyroid Function and Autoimmunity among Women from a Fertility Center.

Background:Although previous epidemiological studies have explored associations of phthalate metabolites with thyroid function, no studies to date have assessed associations of mixtures with thyroid function and autoimmunity among potentially susceptible subgroups such as subfertile women.Objective:We aimed to explore associations of mixtures of urinary phthalate metabolites with serum markers of thyroid function and autoimmunity.Methods:This cross-sectional study included 558 women attending a fertility center who provided one spot urine and one blood sample at enrollment (2005–2015). We quantified urinary concentrations of eight phthalate metabolites using mass spectrometry, and biomarkers of thyroid function [thyroid-stimulating hormone (TSH), free and total thyroxine (, ) and triiodothyronine (, ), and autoimmunity [thyroid peroxidase and thyroglobulin antibodies (TPOAb and TgAb, respectively)] in serum using electrochemiluminescence assays. We applied principal component analysis (PCA) and Bayesian kernel machine regression (BKMR) to identify the main patterns of urinary phthalate metabolites. We used linear mixed models to assess the association between PCA-derived factor scores in quintiles and serum thyroid function and autoimmunity, adjusting for age, body mass index (BMI), specific gravity (SG), and, for the PCA, other factor scores.Results:We observed two factors using PCA, one representing the di(2-ethylhexyl) (DEHP) and another non-DEHP metabolites. Compared to women in the lowest quintile of the DEHP factor scores, women in the highest quintile had significantly lower serum concentrations of , , , and [absolute difference: ; 95% confidence interval (CI): , ; ; absolute difference: ; 95% CI: , ; ; absolute difference: ; 95% CI: 0.54, ; ; and absolute difference: ; 95% CI: , ; , respectively]. Using BKMR, we observed that mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) was the primary contributor to these negative associations. DEHP and non-DEHP factor scores were not associated with serum TSH, TgAb, or TPOAb.Conclusions:Mixtures of urinary DEHP metabolites were inversely associated with serum biomarkers of thyroid function but not with autoimmunity, which were within normal ranges for healthy adult women. https://doi.org/10.1289/EHP6740

Prenatal and early childhood phthalate exposures and thyroid function among school-age children

BackgroundLimited studies have investigated the association between prenatal and early childhood phthalate exposures and thyroid function among children. ObjectivesTo investigate the association between early life phthalate exposure and thyroid function among school-age children, considering both prenatal and early childhood exposures, using longitudinal data from an established prospective cohort. MethodsWe measured urinary phthalate metabolite levels during pregnancy and at 2, 4, and 6 years of age and conducted thyroid function tests at 6 years of age. We assessed the associations between phthalate metabolite levels and thyroid function using linear regression and Bayesian kernel machine regression (BKMR) models (n = 492). ResultsIn linear regression models, a doubling of urinary mono-n-butyl phthalate (MnBP) levels, measured during pregnancy and at 4 years of age, was associated with lower thyroid-stimulating hormone (TSH) levels at 6 years of age (−5.0%, 95% confidence interval [CI]: −8.8%, −1.0% and −5.7%, 95% CI: −9.7%, −1.5%, respectively). A similar association was found between mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) levels at 4 years of age and TSH levels at 6 years of age (−5.5%, 95% CI: −9.7%, −1.1%). Urinary mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) (2.3%, 95% CI: 0.1%, 4.5%) and MEOHP levels at 2 years of age (2.2%, 95% CI: 0.1%, 4.4%) and mono-2-ethyl-5-carboxypentyl phthalate (1.4%, 95% CI: 0.1%, 2.7%) and mono-benzyl phthalate levels at 6 years of age (1.1%, 95% CI: 0.4%, 1.9%) were associated with higher triiodothyronine (T3) levels at 6 years of age. Urinary MnBP during pregnancy, MEHHP, MEOHP, and MnBP at 4 years of age were also associated with lower free thyroxine (fT4) × TSH. In BKMR models, urinary MnBP levels during pregnancy were associated with lower TSH levels and fT4 × TSH (both posterior inclusion probabilities: 0.99). ConclusionsOur findings suggest that early life phthalate exposure influences subsequent thyroid function. However, the results should be interpreted cautiously, because a single spot urine sample was used to quantify the phthalate exposures at each time point.

Exposure to Mono-n-Butyl Phthalate in Women with Endometriosis and Its Association with the Biological Effects on Human Granulosa Cells.

To study the association between urinary phthalate metabolite levels, endometriosis, and their effects on human granulosa cells, we recruited patients who underwent laparoscopy to confirm endometriosis (n = 123) and control patients (n = 78). Liquid chromatography–tandem mass spectrometry was used to measure the following five urinary phthalate metabolites: mono-n-butyl phthalate (MnBP), mono(2-ethylhexyl) phthalate, monobenzyl phthalate, mono(2-ethyl-5-oxo-hexyl) phthalate, and mono(2-ethyl-5-hydroxyhexyl) phthalate. Urinary MnBP levels were higher in patients with endometriosis than in controls after multivariable logistic regression including the number of deliveries, body mass index, and use of medicine as covariables. MnBP correlates with other phthalate metabolites. Previous studies found that endometriosis was a detrimental condition for granulosa cells. In our study, we observed whether MnBP affected granulosa cells. MnBP treatment altered the gene expression of BIRC5, BUB1B, CDC20, cyclin B1, IL-1β, TNF-α, inhibin-B, StAR, and P450ssc and attenuated the ratio of the mitochondrial membrane potential in human granulosa cells. Moreover, MnBP decreased the expression of the anti-Mullerian hormone. These findings suggest that MnBP concentration is associated with endometriosis and may affect the health and steroidogenesis of human granulosa cells.

Association between urinary phthalate metabolites and obesity in adult Korean population: Korean National Environmental Health Survey (KoNEHS), 2012-2014.

BackgroundPhthalate is a chemical that is commonly used as a plasticizer in processing plastic products and as a solvent in personal care products. Although previous experimental studies have reported that phthalate metabolites are associated with obesity, epidemiological study results have been inconsistent and insufficient. The objective of the present study was to investigate the association between urinary phthalate metabolites and obesity in adult Korean population.MethodsThe present study selected 4,752 Korean adults aged 19 years or older from the 2012–2014 Korean National Environmental Health Survey data. The concentrations of urinary di-(2-ethyl-5-carboxypentyl) phthalate (DEHP) metabolites—i.e., mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono-(2-ethyl-5-carboxypentyl) phthalate—mono-benzyl phthalate (MBzP) and mono-n-butyl phthalate (MnBP) were adjusted using the urinary creatinine. We used logistic regression analysis to investigate the association between urinary phthalate metabolite concentration and body mass index (BMI) with respect to sex and age.ResultsAmong women, urinary MEHHP and DEHP concentrations were found to have statistically significantly positive associations with obesity (Q4 versus Q1; odds ratio (OR): 1.72, 95% confidence interval (CI): 1.19–2.49 for MEHHP and OR: 1.52, 95% CI: 1.04–2.21 for DEHP). Among men, urinary MnBP concentration was found to have statistically significantly negative association with obesity (Q4 versus Q1; OR: 0.71, 95% CI: 0.50–0.99). In the analysis stratified by sex and age, women aged ≥ 50 years showed statistically significantly positive associations between the concentrations of urinary DEHP metabolites, DEHP, MBzP, and obesity (Q4 versus Q1; OR: 1.94, 95% CI: 1.28–2.94 for MEHHP, OR: 1.88, 95% CI: 1.21–2.94 for MEOHP, OR: 2.04, 95% CI: 1.31–3.18 for DEHP, and Q3 versus Q1; OR: 1.45, 95% CI: 1.02–2.05 for MBzP). Meanwhile, men aged ≥ 50 years showed no significant associations between urinary phthalate concentrations and obesity.ConclusionsIn the present study, we found differences in the associations between urinary phthalate metabolites and BMI according to sex and age. However, because the present study was cross-sectional in nature, additional support through prospective studies is needed to estimate the causal associations.

Phthalate exposure in Thai children and adolescents

Abstract Background Phthalates are found in products made of plastic. Because of concerns regarding the hazards of phthalate exposure, including endocrine disruption, many countries have regulations to restrict their use in products used by children. However, in Thailand, no such restrictions exist, and data relating to phthalate exposure are scarce. Objectives To determine the level of exposure of Thai children and adolescents to phthalates, and study its associations with sociodemographic data and the exposure to potential sources of phthalates. Methods Healthy children aged 2–18 y were enrolled into the present cross-sectional study between January 2016 and December 2016 inclusive. Their anthropometric indices and Tanner staging were determined. Urinary concentrations of the phthalate metabolites, monomethyl phthalate (MMP) and mono-n-butyl phthalate (MBP), were determined in spot samples by high-performance liquid chromatography to estimate the level of phthalate exposure. Associations between sociodemographic data, exposure to potential sources of phthalates, and phthalate metabolite concentrations were analyzed. Results We included 103 boys and 118 girls with a mean age of 9.4 ± 3.64 (range 2.8–17.1) y and detected MMP in 28.5% and MBP in 88.6%. The geometric means (interquartile range) of urinary MMP and MBP were 3400 (2489, 4642) and 214.4 (164, 279) μg/g creatinine (Cr), respectively. Significant associations were found between exposure to floor cleaning products and Cr-adjusted urinary MMP level (P < 0.05), and paint and Cr-adjusted urinary MMP and MBP levels (P < 0.05). Prepuberty was significantly associated with urinary Cr-adjusted MMP level. Conclusion Urinary phthalate metabolite levels were high in a proportion of Thai children and adolescents. Exposure to floor cleaning products and paint is associated with phthalate exposure, and advanced Tanner stage is negatively associated with urinary Cr-adjusted MBP.

Phthalate Exposure is associated with Carotid Intima-Media Thickness in Adolescents and Young Adults

Background/Aim: Exposure to phthalates has been linked to cardiovascular risk factors. However, it is unclear regarding phthalates exposure and the risk of subclinical atherosclerosis. This study investigated the association between phthalates exposure and carotid intima-media thickness (CIMT) in young population. Methods: From a nationwide mass urine screening for renal health, conducted in 1992-2000 among school children 6 to 18 years of age in Taiwan, we recruited 789 subjects to participate the cardiovascular health examination in 2006-2008. Among them, 787 received measurements of 7 urinary phthalate metabolites and CIMT. Results: Both mean and maximal values of CIMT at all segments of carotid arteries significantly increased with the urinary mono-2-ethylhexyl phthalate (MEHP), ∑MEHP, and mono-n-butyl phthalate (MnBP) in a dose-response relationship after adjustment for multiple linear regression models. Multivariate logistic regression analysis showed that higher quartiles of urinary concentrations of MEHP, ∑MEHP, and MnBP were associated with a higher risk of thicker CIMT. Compared to subjects with the lowest quartile (Q1) of urinary MEHP, the adjusted odds ratios (aORs) (95% confidence interval (CI)) for thicker CIMT among subjects with higher urinary MEHP were 2.13(1.18-3.84) at Q2, 4.02(2.26-7.15) at Q3 and 7.39(4.16-13.12) at the highest Q4. Comparing those with lowest urinary MnBP, the corresponding aORs (95% CI) were 1.84 (1.08-3.15) for subjects at Q3, and 2.80 (1.65-4.75) for subjects at the highest Q4. Conclusions: Urinary phthalate metabolites of MEHP, ∑MEHP, and MnBP are strongly associated with CIMT in adolescents and young adults in Taiwan.

Phthalate-induced oxidative stress and association with asthma-related airway inflammation in adolescents.

In Belgium, around 8.5% of the children have asthmatic symptoms. Increased asthma risk in children has been reported in relation to exposure to phthalate plasticizers but the underlying mechanisms are largely unknown. The aim of this study was to identify if oxidative stress, assessed by excision of 8-hydroxydeoxyguanosine (8-OHdG) from damaged DNA, is an intermediate marker for the association between phthalate exposure and doctor-diagnosed asthma. In 418 14-15-year-old youngsters, recruited as a representative sample of residents of Flanders (Belgium), personal exposure to phthalates was assessed by measuring phthalate metabolites in urine: mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-n-butyl phthalate (MnBP), mono-benzyl phthalate (MBzP), mono-isobutyl phthalate (MiBP) and mono-ethyl phthalate (MEP). Analysis of 8-OHdG in urine was used as a sensitive biomarker of oxidative stress at the level of DNA. The presence of doctor-diagnosed asthma was elicited by a self-administered questionnaire. Associations were assessed using multiple linear and logistic regression models. Mediation was tested using Baron and Kenny's regression approach. A significant increased risk of a youngster being diagnosed with asthma was found for both urinary MnBP (metabolite of dibutyl phthalate (DBP)) and the sum of the three di(2-ethylhexyl) phthalate metabolites (ΣDEHP=MEHP+MEHHP+MEOHP), with respective odds ratio of 1.84 [95% CI: 1.02, 3.32] for MnBP and 1.94 [95% CI: 1.07, 3.51] for ΣDEHP. In addition, we observed significant associations between all urinary phthalate metabolites and increased urinary levels of 8-OHdG. The associations were stronger in girls than in boys. We did not found evidence that 8-OHdG was associated with doctor-diagnosed asthma. The results of our study are in line with other findings from epidemiological surveys and raise further concern about DEHP and DBP as risk factors for asthma, however, the underlying mechanisms are not yet well understood.

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.

Urinary phthalate metabolites and depression in an elderly population: National Health and Nutrition Examination Survey 2005–2012

Previous animal studies have demonstrated that phthalate exposure is associated with depression-like behaviors. However, no human study has explored this relationship. We explored the association between urinary phthalate metabolite concentrations and depression in a nationally representative sample of the U.S. elderly population. We analyzed 2030 participants aged 60 years or older with available data on phthalates and depression from the 2005 to 2012 National Health and Nutrition Examination Survey (NHANES). We selected 10 urinary phthalate metabolites with a weighted detection rate >60%. Depression was defined as a 9-item Patient Health Questionnaire score ≥10. The models were adjusted for age, sex, race/ethnicity, education level, income-to-poverty ratio, health insurance coverage, marital status, smoking status, alcohol consumption, moderate physical activity, body mass index, comorbidity status, NHANEs cycle, and urinary creatinine levels. One-unit increases in log-transformed mono-(3-carboxypropyl) phthalate (MCPP) (odds ratio [OR]=1.24, 95% confidence interval [CI]=1.02–1.52) and mono(carboxynonyl) phthalate (MCNP) (OR=1.42, 95% CI=1.15–1.75) were positively associated with depression. When we stratified the urinary phthalate metabolites into quartiles, the highest quartiles (Q4) of MCNP (OR=2.57, 95% CI=1.25–5.27) and mono-n-butyl phthalate (MBP) (OR=2.40, 95% CI=1.10–5.22) were associated with depression compared with the lowest quartiles (Q1). Concentrations of urinary phthalate metabolites MCPP, MCNP, and MBP were positively associated with the risk of depression in a representative sample of the U.S. elderly population. However, the present cross-sectional study is hypothesis generating and the associations need to be investigated through further longitudinal studies.

Developing an intervention strategy to reduce phthalate exposure in Taiwanese girls

Children in Taiwan seem to be exposed to higher concentrations of phthalates than do children in Western countries. We developed intervention strategies to reduce the exposure of phthalates in Taiwanese girls. Thirty girls 4–13years old who had been exposed to high levels of phthalates were selected from prior studies. To reduce their phthalate-exposure sources, we developed seven intervention strategies: handwashing, not using plastic containers, not eating food with a plastic bag/plastic-wrap cover, not microwaving food, not taking nutrition supplements, and reducing use of cosmetics/personal care products. Pre- and post-intervention urine samples were collected during a one-week study. HPLC-MS/MS was used to analyze urinary phthalate metabolites. The dominant urinary phthalate metabolite was mono-n-butyl phthalate (MBP), followed by mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP). Post-intervention concentrations of eight urinary phthalate metabolites were significantly lower. Girls in the high-frequency handwashing group had significantly lower urinary MBP (p=0.009) and mono-methyl phthalate (MMP) (p=0.07) than did girls in the low-frequency handwashing group. Girls who drank fewer beverages from plastic cups had significantly lower urinary MBP (p=0.016), MEHHP (p=0.038), and MECPP (p=0.012). Girls who used less shampoo and shower gel also had marginally significantly lower urinary MBP (p=0.06) and mono-ethyl phthalate (MEP) (p=0.06). The intervention strategies that we set up in this study were effective for reducing exposure to phthalates in children. Handwashing and drinking fewer beverages from plastic cups were the most effective strategies for reducing phthalate metabolites in urine, especially MBP and di(2-ethylhexyl) phthalate (DEHP) metabolites. Education and voluntary self-restraint were useful for reducing the body burden of phthalates.

Health on the Factory Floor: Occupational Phthalate Exposure Reduces Testosterone

Human studies have shown widespread exposure to phthalates, compounds used in the manufacture of household, consumer, and medical products. The metabolites mono-2-ethylhexyl phthalate (MEHP) and mono-n-butyl phthalate (MBP) have shown testicular toxicity in rats, specifically damage to the cells that produce testosterone and sperm. But animal studies involve higher phthalate exposures than humans typically experience, and there is inconclusive evidence that low exposures affect testicular cells in men. Occupational phthalate exposure tends to be greater and more consistent than the highly variable low levels seen in the general population, however, and research at a Chinese manufacturing plant now reveals that such exposure can be significantly related to decreased blood testosterone concentration [EHP 114:1643–1648; Pan et al.]. The study participants included 74 men who manufactured polyvinyl chloride (PVC) flooring at a plant in Liaoning Province and 63 men employed at a construction company. All the men completed a questionnaire about lifestyle factors and provided blood and urine samples. Blood samples were analyzed for circulating amounts of free testosterone, luteinizing hormone, follicle-stimulating hormone, and estradiol. Urine analysis provided data on concentrations of MBP and MEHP, which served as biomarkers of exposure. Due to the materials involved in flooring manufacture, the men at the flooring plant were assumed to have dermal and inhalational exposure to dibutyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP), the parent compounds of MBP and MEHP. Indeed, all the participants except one construction worker had detectable levels of urinary MBP and MEHP, demonstrating that phthalate exposure was pervasive. However, PVC plant workers had up to 100-fold higher levels of MBP and MEHP and significantly lower blood testosterone concentrations, compared with construction workers. Regression analysis revealed a modest but significant decrease in testosterone as total phthalate esters increased. Based on MEHP concentrations, the investigators estimated that 40.5% of the PVC plant workers had DEHP exposure exceeding the European Union’s tolerable daily intake standard of 37.0 μg/kg body weight. The team concluded that high levels of DEHP and DBP exposure seemed to suppress testosterone production in the PVC plant workers, but it is not clear from this study what effect, if any, that might have on their fertility.

Evaluation of the effect of governmental control of human exposure to two phthalates in Japan using a urinary biomarker approach

In Japan, the use of certain phthalates has been regulated. We analyzed the effectiveness of these measures using an analytical biomarker approach. We measured two phthalate metabolites, mono- n-butyl phthalate (MBP) and mono-2-ethylhexyl phthalate (MEHP) in urine samples from 36 participants using enzymatic deconjugation, offline solid phase extraction, and HPLC-ESI-MS/MS. From the levels measured and individual values of creatinine excretion rate the daily intake was determined and compared to each corresponding tolerable daily intake (TDI). The levels of urinary MBP and MEHP were <1.8–280 and 0.76–25 μg/l, respectively. The ranges of the estimated daily intake of di- n-butyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP) from 35 adult urine samples were 0.22–4.5 and 0.37–7.3 μg/kg/day, respectively. These values were lower than the corresponding TDIs. After comparing these values to previous exposure assessment data on DEHP in Japan, it could be seen that the DEHP intake dropped over the period from 1998 to 2001. Children were not covered in the present study, so the results may only be applicable to adults, not to the Japanese population at large. Even so, the small number of people in one specific geographic area cannot be considered representative of the adult Japanese population. In addition to MEHP, the secondary metabolites of DEHP, which are more suitable biomarkers should be measured in the future.

Exposure of nursery school children and their parents and teachers to di-n-butylphthalate and butylbenzylphthalate

Some phthalates, among them di-n-butylphthalate (DnBP) and butylbenzylphthalate (BBzP), are known reproductive and developmental toxicants in animals and suspected endocrine disruptors in humans. Children are probably the most susceptible to these effects. To obtain an estimate of internal exposure to DnBP and BBzP we compared the excretion of their metabolites in the urine of nursery school children with that of their teachers and parents. We measured the urinary mono-ester metabolites of DnBP, mono-n-butylphthalate (MnBP), and BBzP, monobenzylphthalate (MBzP), in first-morning voids of 36 children (median age 4.7 years) and 19 adults (37.4 years). In all samples both metabolites were detected. Urinary MnBP concentrations (in microgrammes per litre) of the children and adults were 139 and 91.8 (median), respectively. MBzP concentrations were 22.1 microg/l and 12.7 microg/l (median), respectively. Concentrations in microgrammes per gramme creatinine for MnBP were 161 for the children and 91.8 for the adults (median). The maximum concentration found for children (2249 microg/g) was approximately 15-times higher than that for adults (149 microg/g). This maximum value for children was attributed to medication that contained DnBP. If this child was excluded, the maximum concentration was 517 microg/g. MBzP concentrations for children and adults were 37.0 microg/g and 9.8 microg/g (median), respectively. The maximum concentration found for children (193 microg/g) was approximately seven-times higher than that for adults (26.7 microg/g). Creatinine-adjusted concentrations were significantly higher for children for both MBzP and MnBP (P<0.0001). MnBP and MBzP exposures were found to correlate statistically significantly within the children's cohort (r=0.723, P<0.001). Within the children's cohort we found elevated MnBP exposure to be caused by augmented use of skin-care products (P<0.05). We have shown that the internal exposure to MnBP and MBzP in children is approximately two- to four-times higher than in adults. Correlation of internal MnBP with MBzP exposure points to common sources of exposure for both phthalates. DnBP exposure seems, at least in part, to be connected with the use of body/skin care products and certain medications.