Monoisobutyl phthalic acid

Association of phthalates, parabens and phenols found in personal care products with pubertal timing in girls and boys

Study question: Are in-utero or peripubertal exposures to phthalates, parabens and other phenols found in personal care products associated with timing of pubertal onset in boys and girls? Summary answer: We found some associations of altered pubertal timing in girls, but little evidence in boys. What is known already: Certain chemicals in personal care and consumer products, including low molecular weight phthalates, parabens and phenols, or their precursors, are associated with altered pubertal timing in animal studies. Study design, size, duration: Data were from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) longitudinal cohort study which followed 338 children in the Salinas Valley, California, from before birth to adolescence. Participants/materials, setting, methods: Pregnant women were enrolled in 1999-2000. Mothers were mostly Latina, living below the federal poverty threshold and without a high school diploma. We measured concentrations of three phthalate metabolites (monoethyl phthalate [MEP], mono-n-butyl phthalate and mono-isobutyl phthalate), methyl and propyl paraben and four other phenols (triclosan, benzophenone-3 and 2,4- and 2,5-dichlorophenol) in urine collected from mothers during pregnancy and from children at age 9. Pubertal timing was assessed among 179 girls and 159 boys every 9 months between ages 9 and 13 using clinical Tanner staging. Accelerated failure time models were used to obtain mean shifts of pubertal timing associated with concentrations of prenatal and peripubertal biomarkers. Main results and the role of chance: In girls, we observed earlier onset of pubic hair development with prenatal urinary MEP concentrations and earlier menarche with prenatal triclosan and 2,4-dichlorophenol concentrations. Regarding peripubertal biomarkers, we observed: earlier breast development, pubic hair development and menarche with methyl paraben; earlier menarche with propyl paraben; and later pubic hair development with 2,5-dichlorophenol. In boys, we observed no associations with prenatal urinary biomarker concentrations and only one association with peripubertal concentrations: earlier genital development with propyl paraben. Limitations, reasons for caution: These chemicals are quickly metabolized and one to two urinary measurements per developmental point may not accurately reflect usual exposure. Associations of peripubertal measurements with parabens may reflect reverse causality: children going through puberty early may be more likely to use personal care products. The study population was limited to Latino children of low socioeconomic status living in a farmworker community and may not be widely generalizable. Wider implications of the findings: This study contributes to a growing literature that suggests that exposure to certain endocrine disrupting chemicals may impact timing of puberty in children. Study funding/competing interest(s): This study was funded by the National Institute of Environmental Health Sciences and the US Environmental Protection Agency. The authors declare no conflicts of interest. Trial registration number: N/A.

Associations between exposure to a mixture of phenols, parabens, and phthalates and sex steroid hormones in children 6-19 years from NHANES, 2013-2016

Background: Humans are typically exposed to mixtures of environmental endocrine-disrupting chemicals simultaneously, but most studies have considered only a single chemical or a class of similar chemicals.
Objectives: We examined the association of exposure to mixtures of 7 chemicals, including 2 phenols [bisphenol A (BPA) and bisphenol S (BPS)], 2 parabens [methylparaben (MeP) and propyl paraben (PrP)], and 3 phthalate metabolites [Mono-benzyl phthalate (MBzP), mono-isobutyl phthalate (MiBP), mono (carboxyoctyl) phthalate (MCOP)] with sex steroid hormones.
Methods: A total of 1179 children aged 6-19 years who had complete data on both 7 chemicals and sex steroid hormones of estradiol (E₂), total testosterone (TT), and sex hormone-binding globulin (SHBG) were analyzed from the U.S. National Health and Nutrition Examination Survey 2013-2016. Free androgen index (FAI) calculated by TT/SHBG, and the ratio of TT to E₂ (TT/E₂) were also estimated. Puberty was defined if TT ≥ 50 ng/dL in boys, E₂ ≥ 20 pg/mL in girls; otherwise prepuberty was defined. Linear regression, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) were performed to estimate the associations of individual chemical or chemical mixtures with sex hormones.
Results: The linear regression showed that 2 phenols, 2 parabens, and 3 phthalate metabolites were generally negatively associated with E₂, TT, FAI, and TT/E₂, while positively with SHBG. Moreover, these associations were more pronounced among pubertal than prepubertal children. The aforementioned associations were confirmed when further applying WQS and BKMR, and the 3 phthalates metabolites were identified to be the most heavily weighing chemicals.
Conclusions: Exposure to phenols, parabens, and phthalates, either individuals or as a mixture, was negatively associated with E₂, TT, FAI and TT/E₂, while positively with SHBG. Those associations were stronger among pubertal children.

Associations Between Prenatal Urinary Biomarkers of Phthalate Exposure and Preterm Birth: A Pooled Study of 16 US Cohorts

Importance: Phthalate exposure is widespread among pregnant women and may be a risk factor for preterm birth.
Objective: To investigate the prospective association between urinary biomarkers of phthalates in pregnancy and preterm birth among individuals living in the US.
Design, setting, and participants: Individual-level data were pooled from 16 preconception and pregnancy studies conducted in the US. Pregnant individuals who delivered between 1983 and 2018 and provided 1 or more urine samples during pregnancy were included.
Exposures: Urinary phthalate metabolites were quantified as biomarkers of phthalate exposure. Concentrations of 11 phthalate metabolites were standardized for urine dilution and mean repeated measurements across pregnancy were calculated.
Main outcomes and measures: Logistic regression models were used to examine the association between each phthalate metabolite with the odds of preterm birth, defined as less than 37 weeks of gestation at delivery (n = 539). Models pooled data using fixed effects and adjusted for maternal age, race and ethnicity, education, and prepregnancy body mass index. The association between the overall mixture of phthalate metabolites and preterm birth was also examined with logistic regression. G-computation, which requires certain assumptions to be considered causal, was used to estimate the association with hypothetical interventions to reduce the mixture concentrations on preterm birth.
Results: The final analytic sample included 6045 participants (mean [SD] age, 29.1 [6.1] years). Overall, 802 individuals (13.3%) were Black, 2323 (38.4%) were Hispanic/Latina, 2576 (42.6%) were White, and 328 (5.4%) had other race and ethnicity (including American Indian/Alaskan Native, Native Hawaiian, >1 racial identity, or reported as other). Most phthalate metabolites were detected in more than 96% of participants. Higher odds of preterm birth, ranging from 12% to 16%, were observed in association with an interquartile range increase in urinary concentrations of mono-n-butyl phthalate (odds ratio [OR], 1.12 [95% CI, 0.98-1.27]), mono-isobutyl phthalate (OR, 1.16 [95% CI, 1.00-1.34]), mono(2-ethyl-5-carboxypentyl) phthalate (OR, 1.16 [95% CI, 1.00-1.34]), and mono(3-carboxypropyl) phthalate (OR, 1.14 [95% CI, 1.01-1.29]). Among approximately 90 preterm births per 1000 live births in this study population, hypothetical interventions to reduce the mixture of phthalate metabolite levels by 10%, 30%, and 50% were estimated to prevent 1.8 (95% CI, 0.5-3.1), 5.9 (95% CI, 1.7-9.9), and 11.1 (95% CI, 3.6-18.3) preterm births, respectively.
Conclusions and relevance: Results from this large US study population suggest that phthalate exposure during pregnancy may be a preventable risk factor for preterm delivery.

Association of urinary phthalate metabolites with cardiovascular disease among the general adult population

Objective: This study aims to explore the relationship between urinary phthalate metabolites and total and specific cardiovascular disease (CVD) among the general adult population.
Methods: This cross-sectional study analyzed 11 urinary phthalates in the general population from the 2005-2016 National Health and Nutrition Examination Survey (NHANES) (n = 10,427). Multivariate logistic regression and weighted quantile sum (WQS) regression were applied to examine the relationship between phthalate metabolites and mixtures and the prevalence rates of total and specific CVD.
Results: Compared to the lowest quartile, mono-isobutyl phthalate (MiBP) (OR 1.37; 95% CI 1.03-1.83, P for trend = 0.032) and mono-benzyl phthalate (MBzP) (OR 1.44; 95% CI 1.10-1.88, P for trend = 0.013) in the highest quartile were independently associated with increased total CVD. The WQS index of phthalate mixtures was independently correlated with total CVD (adjusted OR 1.17; 95% CI 1.01-1.36, P = 0.039), and MBzP (weight = 0.392) was the most heavily weighted component. In addition, restricted cubic spline regression demonstrated that the MBzP level had a positive correlation and linear association with total CVD (P for nonlinearity = 0.182).
Conclusions: Our findings suggest that high phthalate mixture levels are associated with an increased prevalence of CVD, with the greatest influence coming from MBzP.

Environmental estrogen-like endocrine disrupting chemicals and breast cancer

Background: Estrogen-mimicking endocrine disruptors (EEDs) such as polychlorinated biphenyls (PCBs), bisphenol A (BPA), and phthalates have been found ubiquitously throughout our environment. Although exposure to EEDs has the ability to interfere with endocrine control of reproductive function and development in both humans and wildlife, inconsistent reports have made it difficult to draw conclusions concerning the hypothesized increased risk of breast cancer associated with EEDs.
Objectives: The purpose of this study was to examine the cross-sectional relationship between exposure to PCBs, BPA or phthalates; and risk of breast cancer in U.S. women using the Centers for Disease Control and Prevention's National Health and Nutrition Examination Survey (NHANES) data between 1999 and 2004.
Methods: We analyzed data from female participants (20 years of age and older) collected by NHANES between 1999 and 2004 for exposure assessment based on lipid adjusted serum levels of 6 individual PCB congeners (PCB 074, 099, 118, 138, 153, and 180), the sum of dioxin-like PCBs (074 and 118), and the sum of non-dioxin-like PCBs (099 + 138 + 153 + 187). Levels of urinary BPA and seven phthalate metabolites mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), mono-ethyl phthalate (MEP), mono-(3-caroxypropyl) phthalate (MCPP), mono-benzyl phthalate (MZP), and three metabolites of di (2-ehtylhexyl) phthalate (DEHP): [mono-2-ethylhexyl phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP)] were obtained from the 2003-2010 yearly survey cycles in participants aged 6 years and older. Assessments of EEDs or their metabolites were analyzed in conjunction with medical and reproductive health questionnaire data. Age, race/ethnicity, age at menarche, body mass index (BMI; kg/m²), and lactation were considered as potential confounders in our final models. Geometric means (GM) were calculated to compare PCB, BPA or phthalate concentrations in women who self-reported a breast cancer diagnosis versus women who self-reported never being diagnosed with breast cancer. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the association between PCB, BPA or phthalate measurements and breast cancer.
Results: In age, race/ethnicity, and BMI adjusted models, PCB138 was the only congener found to be significantly associated with breast cancer [OR of 3.16; 95% CI: 1.14-8.76]. We also found the sum of non-dioxin-like PCBs to be significantly associated with breast cancer [OR of 1.14; 95% CI: 1.00-1.29]. Risk of breast cancer, however, was not found to be significantly associated with phthalate, phthalate metabolites, and BPA in unadjusted or adjusted logistic regression models.
Conclusions: Our results suggest a link between environmental exposures to PCB 138 and breast cancer. There were no significant associations between phthalates or BPA and breast cancers. These findings should be interpreted with caution because of the use of cross-sectional self-reported data and a small sample size of breast cancer subjects. Nonetheless, our finding emphasizes a need of comprehensive environmental molecular epidemiologic study to determine the potential role of environmental exposures to PCBs, phthalates, and BPA in the development of breast cancer.