Kelly K. Ferguson

Distribution, Variability, and Predictors of Urinary Concentrations of Phenols and Parabens among Pregnant Women in Puerto Rico

Puerto Rico has higher rates of a range of endocrine-related diseases and disorders compared to the United States. However, little is known to date about human exposures to known or potential endocrine disrupting chemicals (EDCs) in Puerto Rico. We recruited 105 pregnant women in Northern Puerto Rico who provided urine samples and questionnaire data at three times (18 ± 2, 22 ± 2, and 26 ± 2 weeks) during gestation. We measured the urinary concentrations of five phenols and three parabens: 2,4-dichlorophenol (24-DCP), 2,5-dichlorophenol (25-DCP), benzophenone-3 (BP-3), bisphenol A (BPA), triclosan (TCS), butyl paraben (B-PB), methyl paraben (M-PB), and propyl paraben (P-PB). The frequent detection of these chemicals suggests that exposure is highly prevalent among these Puerto Rican pregnant women. Urinary concentrations of TCS, BP-3, and 25-DCP were higher than among women of reproductive age in the US general population, while concentrations of BPA, 24-DCP, and parabens were similar. Intraclass correlation coefficients (ICC) varied widely between biomarkers; BPA had the lowest ICC (0.24) and BP-3 had the highest (0.62), followed by 25-DCP (0.49) and TCS (0.47). We found positive associations between biomarker concentrations with self-reported use of liquid soap (TCS), sunscreen (BP-3), lotion (BP-3 and parabens), and cosmetics (parabens). Our results can inform future epidemiology studies and strategies to reduce exposure to these chemicals or their precursors.

Relationship between Urinary Phthalate and Bisphenol A Concentrations and Serum Thyroid Measures in U.S. Adults and Adolescents from the National Health and Nutrition Examination Survey (NHANES) 2007–2008

Background: Limited animal, in vitro, and human studies have reported that exposure to phthalates or bisphenol A (BPA) may affect thyroid signaling. Objective: We explored the cross-sectional relationship between urinary concentrations of metabolites of di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), and BPA with a panel of serum thyroid measures among a representative sample of U.S. adults and adolescents. Methods: We analyzed data on urinary biomarkers of exposure to phthalates and BPA, serum thyroid measures, and important covariates from 1,346 adults (ages ≥ 20 years) and 329 adolescents (ages 12–19 years) from the National Health and Nutrition Examination Survey (NHANES) 2007–2008 using multivariable linear regression. Results: Among adults, we observed significant inverse relationships between urinary DEHP metabolites and total thyroxine (T4), free T4, total triiodothyronine (T3), and thyroglobulin, and positive relationships with thyroid-stimulating hormone (TSH). The strongest and most consistent relationships involved total T4, where adjusted regression coefficients for quintiles of oxidative DEHP metabolites displayed monotonic dose-dependent decreases in total T4 (p-value for trend < 0.0001). Suggestive inverse relationships between urinary BPA and total T4 and TSH were also observed. Conversely, among adolescents, we observed significant positive relationships between DEHP metabolites and total T3. Mono(3-carboxypropyl) phthalate, a secondary metabolite of both DBP and di-n-octyl phthalate, was associated with several thyroid measures in both age groups, whereas other DBP metabolites were not associated with thyroid measures. Conclusions: These results support previous reports of associations between phthalates—and possibly BPA—and altered thyroid hormones. More detailed studies are needed to determine the temporal relationships and potential clinical and public health implications of these associations.

Environmental Phthalate Exposure and Preterm Birth

IMPORTANCE Preterm birth is a leading cause of neonatal mortality, with a variety of contributing causes and risk factors. Environmental exposures represent a group of understudied, but potentially important, factors. Phthalate diesters are used extensively in a variety of consumer products worldwide. Consequently, exposure in pregnant women is highly prevalent. OBJECTIVE To assess the relationship between phthalate exposure during pregnancy and preterm birth. DESIGN, SETTING, AND PARTICIPANTS This nested case-control study was conducted at Brigham and Womens Hospital, Boston, Massachusetts. Women were recruited for a prospective observational cohort study from 2006-2008. Each provided demographic data, biological samples, and information about birth outcomes. From within this group, we selected 130 cases of preterm birth and 352 randomly assigned control participants, and we analyzed urine samples from up to 3 time points during pregnancy for levels of phthalate metabolites. EXPOSURE Phthalate exposure during pregnancy. MAIN OUTCOMES AND MEASURES We examined associations between average levels of phthalate exposure during pregnancy and preterm birth, defined as fewer than 37 weeks of completed gestation, as well as spontaneous preterm birth, defined as preterm preceded by spontaneous preterm labor or preterm premature rupture of the membranes (n = 57). RESULTS Geometric means of the di-2-ethylhexyl phthalate (DEHP) metabolites mono-(2-ethyl)-hexyl phthalate (MEHP) and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), as well as mono-n-butyl phthalate (MBP), were significantly higher in cases compared with control participants. In adjusted models, MEHP, MECPP, and  Σ DEHP metabolites were associated with significantly increased odds of preterm birth. When spontaneous preterm births were examined alone, MEHP, mono-(2-ethyl-5-oxohexyl) phthalate, MECPP,  Σ DEHP, MBP, and mono-(3-carboxypropyl) phthalate metabolite levels were all associated with significantly elevated odds of prematurity. CONCLUSIONS AND RELEVANCE Women exposed to phthalates during pregnancy have significantly increased odds of delivering preterm. Steps should be taken to decrease maternal exposure to phthalates during pregnancy.

Urinary Phthalate Metabolites in Relation to Biomarkers of Inflammation and Oxidative Stress: NHANES 1999-2006

Phthalate esters are a class of compounds utilized extensively in widely-distributed consumer goods, and have been associated with various adverse health outcomes in previous epidemiologic research. Some of these health outcomes may be the result of phthalate-induced increases in oxidative stress or inflammation, which have been demonstrated in animal studies. The aim of this study was to explore the relationship between urinary phthalate metabolite concentrations and serum markers of inflammation and oxidative stress (C-reactive protein (CRP) and gamma glutamyltransferase (GGT), respectively). Subjects were participants in the National Health and Nutrition Examination Survey (NHANES) between the years 1999 and 2006. In multivariable linear regression models, we observed significant positive associations between CRP and mono-benzyl phthalate (MBzP) and mono-isobutyl phthalate (MiBP). There were CRP elevations of 6.0% (95% confidence interval (CI) 1.7-10.8%) and 8.3% (95% CI 2.9-14.0%) in relation to interquartile range (IQR) increases in urinary MBzP and MiBP, respectively. GGT was positively associated with mono(2-ethylhexyl) phthalate (MEHP) and an MEHP% variable calculated from the proportion of MEHP in comparison to other di(2-ethylhexyl) phthalate (DEHP) metabolites. IQR increases in MEHP and MEHP% were associated with 2.5% (95% CI 0.2-4.8%) and 3.7% (95% CI 1.7-5.7%) increases in GGT, respectively. CRP and GGT were also inversely related to several phthalate metabolites, primarily oxidized metabolites. In conclusion, several phthalate monoester metabolites that are detected in a high proportion of urine samples from the US general population are associated with increased serum markers of inflammation and oxidative stress. On the other hand, several oxidized phthalate metabolites were inversely associated with these markers. These relationships deserve further exploration in both experimental and observational studies.

Urinary phthalate metabolite concentrations among pregnant women in Northern Puerto Rico: Distribution, temporal variability, and predictors

BACKGROUND Phthalate contamination exists in the North Coast karst aquifer system in Puerto Rico. In light of potential health impacts associated with phthalate exposure, targeted action for elimination of exposure sources may be warranted, especially for sensitive populations such as pregnant women. However, information on exposure to phthalates from a variety of sources in Puerto Rico is lacking. The objective of this study was to determine concentrations and predictors of urinary phthalate biomarkers measured at multiple times during pregnancy among women living in the Northern karst area of Puerto Rico. METHODS We recruited 139 pregnant women in Northern Puerto Rico and collected urine samples and questionnaire data at three separate visits (18 ± 2 weeks, 22 ± 2 weeks, and 26 ± 2 weeks of gestation). Urine samples were analyzed for eleven phthalate metabolites: mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-hydroxyhexyl phthalate, mono-2-ethyl-5-oxohexyl phthalate, mono-2-ethyl-5-carboxypentyl phthalate, mono-ethyl phthalate (MEP), mono-n-butyl phthalate, mono-benzyl phthalate, mono-isobutyl phthalate, mono-3-carboxypropyl phthalate (MCPP), mono carboxyisononyl phthalate (MCNP), and mono carboxyisooctyl phthalate (MCOP). RESULTS Detectable concentrations of phthalate metabolites among pregnant women living in Puerto Rico was prevalent, and metabolite concentrations tended to be higher than or similar to those measured in women of reproductive age from the general US population. Intraclass correlation coefficients ranged from very weak (MCNP; 0.05) to moderate (MEP; 0.44) reproducibility among all phthalate metabolites. We observed significant or suggestive positive associations between urinary phthalate metabolite concentrations and water usage/storage habits (MEP, MCNP, MCOP), use of personal care products (MEP), and consumption of certain food items (MCPP, MCNP, and MCOP). CONCLUSIONS To our knowledge this is the first study to report concentrations, temporal variability, and predictors of phthalate biomarkers among pregnant women in Puerto Rico. Preliminary results suggest several potentially important exposure sources to phthalates in this population and future analysis from this ongoing prospective cohort will help to inform targeted approaches to reduce exposure.

Relationship between urinary triclosan and paraben concentrations and serum thyroid measures in NHANES 2007–2008

Triclosan and parabens are broad spectrum antimicrobials used in a range of consumer products. In vitro and animal studies have suggested the potential for these compounds to disrupt thyroid function, though studies in humans have been limited. The objective of the study was to assess the relationship of urinary concentrations of triclosan and parabens with serum thyroid measures in a large, representative sample of the US population. We conducted an exploratory, cross-sectional analysis of data on urinary biomarkers of triclosan and paraben exposure and serum thyroid measures obtained from 1831 subjects (ages≥12 years) as part of the 2007-2008 National Health and Nutrition Examination Survey (NHANES). We found evidence of some inverse associations between parabens and circulating thyroid hormone levels in adults, with the strongest and most consistent associations among females. We also observed a positive association between triclosan and total triiodothyonine (T3) concentrations in adolescents. These results, in accordance with the in vitro and animal literature, suggest that paraben, and potentially triclosan, exposures may be associated with altered thyroid hormone levels in humans. Further research is needed for confirmation and to determine the potential clinical and public health significance of these findings.

Variability in urinary phthalate metabolite levels across pregnancy and sensitive windows of exposure for the risk of preterm birth

BACKGROUND Preterm birth is a significant public health problem, affecting over 1 in 10 live births and contributing largely to infant mortality and morbidity. Everyday exposure to environmental chemicals such as phthalates could contribute to prematurity, and may be modifiable. In the present study we examine variability in phthalate exposure across gestation and identify windows of susceptibility for the relationship with preterm birth. METHODS Women were recruited early in pregnancy as part of a prospective, longitudinal birth cohort at the Brigham and Womens Hospital in Boston, Massachusetts. Urine samples were collected at up to 4 time points during gestation for phthalate measurement, and birth outcomes were recorded at delivery. From this population we selected all 130 cases of preterm birth, defined as delivery before 37 weeks of completed gestation, as well as 352 random controls. RESULTS Urinary phthalate metabolite levels were moderately variable over pregnancy, but levels measured at multiple time points were associated with increased odds of preterm birth. Adjusted odds ratios (aOR) for spontaneous preterm birth were strongest in association with phthalate metabolite concentrations measured at the beginning of the third trimester (aOR for summed di-2-ethylhexyl phthalate metabolites [∑DEHP]=1.33, 95% confidence interval [CI]=1.02, 1.73). Odds ratios for placental preterm birth, defined as delivery with presentation of preeclampsia or intrauterine growth restriction, were slightly elevated in the first trimester for DEHP metabolites (aOR for ∑DEHP=1.33, 95% CI=0.99, 1.78). CONCLUSIONS Pregnant women with exposure to phthalates both early and late in pregnancy are at an increased risk of delivering preterm, but mechanisms may differ based on etiology.

Environmental Contaminant Exposures and Preterm Birth: A Comprehensive Review

Preterm birth is a significant public health concern, as it is associated with high risk of infant mortality, various morbidities in both the neonatal period and later in life, and a significant societal economic burden. As many cases are of unknown etiology, identification of the contribution of environmental contaminant exposures is a priority in the study of preterm birth. This is a comprehensive review of all known studies published from 1992 through August 2012 linking maternal exposure to environmental chemicals during pregnancy with preterm birth. Using PubMed searches, studies were identified that examined associations between preterm birth and exposure to five categories of environmental toxicants, including persistent organic pollutants, drinking-water contaminants, atmospheric pollutants, metals and metalloids, and other environmental contaminants. Individual studies were summarized and specific suggestions were made for future work in regard to exposure and outcome assessment methods as well as study design, with the recommendation of focusing on potential mediating toxicological mechanisms. In conclusion, no consistent evidence was found for positive associations between individual chemical exposures and preterm birth. By identifying limitations and addressing the gaps that may have impeded the ability to identify true associations thus far, this review can guide future epidemiologic studies of environmental exposures and preterm birth.

Urinary Phthalate Metabolites Are Associated With Decreased Serum Testosterone in Men, Women, and Children From NHANES 2011–2012

CONTEXT There is evidence of declining trends in T levels among men in recent decades, as well as trends in related conditions at multiple life stages and in both sexes. There is also animal and limited human evidence that exposure to phthalates, chemicals found in plastics and personal care products, is associated with reduced androgen levels and associated disorders. OBJECTIVE To explore relationships between urinary concentrations of 13 phthalate metabolites and serum total T levels among men, women, and children when adjusting for important confounders and stratifying by sex and age (6-12, 12-20, 20-40, 40-60, and 60-80 y). DESIGN A cross-sectional study. SETTING US National Health and Nutrition Examination Survey, 2011-2012. PATIENTS OR OTHER PARTICIPANTS US general population. INTERVENTIONS None. MAIN OUTCOME MEASURES Serum total T measured by isotope dilution-liquid chromatography-tandem mass spectrometry. RESULTS Multiple phthalates were associated with significantly reduced T in both sexes and in differing age groups. In females, the strongest and most consistent inverse relationships were found among women ages 40-60 years. In boys 6-12 years old, an interquartile range increase in metabolites of di-2-ethylhexyl phthalate was associated with a 29% (95% confidence interval, 6, 47) reduction in T. In adult men, the only significant or suggestive inverse associations between phthalates (metabolites of di-2-ethylhexyl phthalate and dibutyl phthalate) and T were observed among men ages 40-60 years. CONCLUSIONS Because T plays an important role in all life stages for both sexes, future efforts should focus on better defining these relationships and their broader impacts.

Exploration of Oxidative Stress and Inflammatory Markers in Relation to Urinary Phthalate Metabolites: NHANES 1999–2006

Phthalate exposure has been associated with a wide range of adverse health outcomes in limited epidemiologic studies, and inflammation and oxidative stress have been hypothesized as potential mechanisms involved. In the present study we investigated associations between urinary concentrations of phthalate metabolites and potential blood markers of oxidative stress (bilirubin) and inflammation (alkaline phosphatase [ALP], absolute neutrophil count [ANC], ferritin [adjusted for iron status], and fibrinogen), using data from 10,026 participants in the National Health and Nutrition Examination Survey (NHANES) recruited between 1999 and 2006. After adjustment for covariates we found that bilirubin was inversely associated with several phthalate metabolites (all p-values <0.0001), including the metabolites of di-2-ethylhexyl phthalate (DEHP) and dibutyl phthalate (DBP), in addition to monobenzyl phthalate (MBzP) and mono-(3-carboxypropyl) phthalate (MCPP). Since bilirubin is a potent antioxidant these relationships suggest that phthalates may be associated with increased oxidative stress. Many of the same metabolites were also significantly and positively related with ANC, ALP, and ferritin, suggesting phthalates may be associated with increased inflammation. These markers may be useful in other studies of low-dose exposure to environmental contaminants.