Lauren E. Johns

Exposure assessment issues in epidemiology studies of phthalates

PURPOSE The purpose of this paper is to review exposure assessment issues that need to be addressed in designing and interpreting epidemiology studies of phthalates, a class of chemicals commonly used in consumer and personal care products. Specific issues include population trends in exposure, temporal reliability of a urinary metabolite measurement, and how well a single urine sample may represent longer-term exposure. The focus of this review is on seven specific phthalates: diethyl phthalate (DEP); di-n-butyl phthalate (DBP); diisobutyl phthalate (DiBP); butyl benzyl phthalate (BBzP); di(2-ethylhexyl) phthalate (DEHP); diisononyl phthalate (DiNP); and diisodecyl phthalate (DiDP). METHODS Comprehensive literature search using multiple search strategies. RESULTS Since 2001, declines in population exposure to DEP, BBzP, DBP, and DEHP have been reported in the United States and Germany, but DEHP exposure has increased in China. Although the half-lives of various phthalate metabolites are relatively short (3 to 18h), the intraclass correlation coefficients (ICCs) for phthalate metabolites, based on spot and first morning urine samples collected over a week to several months, range from weak to moderate, with a tendency toward higher ICCs (greater temporal stability) for metabolites of the shorter-chained (DEP, DBP, DiBP and BBzP, ICCs generally 0.3 to 0.6) compared with those of the longer-chained (DEHP, DiNP, DiDP, ICCs generally 0.1 to 0.3) phthalates. Additional research on optimal approaches to addressing the issue of urine dilution in studies of associations between biomarkers and different type of health effects is needed. CONCLUSIONS In conclusion, the measurement of urinary metabolite concentrations in urine could serve as a valuable approach to estimating exposure to phthalates in environmental epidemiology studies. Careful consideration of the strengths and limitations of this approach when interpreting study results is required.

Associations between Repeated Measures of Maternal Urinary Phthalate Metabolites and Thyroid Hormone Parameters during Pregnancy

Background: Maintaining thyroid homeostasis during pregnancy is essential for normal fetal growth and development. Growing evidence suggests that phthalates interfere with normal thyroid function. Few human studies have investigated the degree to which phthalates may affect thyroid hormone levels in particularly susceptible populations such as pregnant women. Objectives: We examined the associations between repeated measures of urinary phthalate metabolites and plasma thyroid hormone levels in samples collected at up to four time points per subject in pregnancy. Additionally, we investigated the potential windows of susceptibility to thyroid hormone disturbances related to study visit of sample collection. Methods: Data were obtained from pregnant women (n = 439) participating in a nested case–control study of preterm birth with 116 cases and 323 controls. We measured 9 phthalate metabolite concentrations in urine samples collected at up to four study visits per subject during pregnancy (median = 10, 18, 26, and 35 weeks of gestation, respectively). We also measured a panel of thyroid function markers in plasma collected at the same four time points per subject during pregnancy. Results: Although our results were generally null, in repeated measures analyses we observed that phthalate metabolites were largely inversely associated with thyrotropin and positively associated with free and total thyroid hormones. Cross-sectional analyses by study visit revealed that the magnitude and/or direction of these relationships varied by timing of exposure during gestation. Conclusions: These results support previous reports showing the potential for environmental phthalate exposure to alter circulating levels of thyroid hormones in pregnant women. Citation: Johns LE, Ferguson KK, McElrath TF, Mukherjee B, Meeker JD. 2016. Associations between repeated measures of maternal urinary phthalate metabolites and thyroid hormone parameters during pregnancy. Environ Health Perspect 124:1808–1815; http://dx.doi.org/10.1289/EHP170

Serum Biomarkers of Exposure to Perfluoroalkyl Substances in Relation to Serum Testosterone and Measures of Thyroid Function among Adults and Adolescents from NHANES 2011-2012

Perfluoroalkyl substances (PFASs) are a group of environmentally-persistent chemicals that have been widely used in many industrial applications. There is human and animal evidence that PFASs may alter levels of reproductive and thyroid-related hormones. However, human studies on the potential age-related effects of PFASs on these outcomes among males and females are limited. We explored the relationship between serum PFASs and serum total testosterone (T), thyroid stimulating hormone (TSH), and free and total triiodothyronine (FT3, TT3) and thyroxine (FT4, TT4) among males and females 12 to 80 years of age from the 2011–2012 cycle of the National Health and Nutrition Examination Survey. Associations were assessed using multiple linear regression models that were stratified on sex and age categories. Effect estimates from the majority of the adjusted models were not statistically significant. However, exposure to PFASs may be associated with increases in FT3, TT3, and FT4 among adult females, but during adolescence, PFASs may be related to increases in TSH among males and decreases in TSH among females. No significant relationships were observed between PFASs and T in any of the models. These findings suggest that exposure to PFASs may disrupt thyroid hormone homeostasis.

Thyroid hormone parameters during pregnancy in relation to urinary bisphenol A concentrations: A repeated measures study ☆

BACKGROUND Maternal supply of thyroid hormones during pregnancy serves a critical role in fetal development. Although animal and in vitro studies provide evidence for thyroid hormone disruption as a result of bisphenol A (BPA) exposure, there is still a lack of evidence in human studies, particularly in the context of pregnancy. OBJECTIVES We aimed to explore the associations between urinary BPA concentrations and plasma thyroid hormone parameters during gestation in pregnant women, and also investigated potential windows of vulnerability during gestation. METHODS Our study population included 116 cases of preterm birth and 323 controls from a nested case-control study. We measured BPA in urine and thyroid hormone parameters in plasma samples collected at up to four study visits during pregnancy (median for each visit: 9.64, 17.9, 26.0, and 35.1weeks gestation). We used linear mixed models for repeated measures analyses, and multivariate linear regression models stratified by study visit to explore potential windows of susceptibility. RESULTS In our repeated measures analysis, BPA and thyrotropin (TSH) were inversely associated. An interquartile range (IQR) increase in BPA was associated with an 8.21% decrease in TSH (95% confidence interval [CI]: -14.2, -1.83), and a 4.79% increase in free T4 (95% CI: 0.82, 8.92). BPA and TSH were also inversely associated in our cross-sectional analyses at visits 3 and 4. CONCLUSIONS Our results suggest that TSH is inversely associated with urinary BPA in a consistent manner across pregnancy. Disruption of TSH levels during pregnancy can potentially impact child development and interfere with normal birth outcomes.

Longitudinal profiles of thyroid hormone parameters in pregnancy and associations with preterm birth

Introduction Overt thyroid disease in pregnancy is associated with numerous maternal and neonatal complications including preterm birth. Less is known about the contribution of trimester-specific subclinical alterations in individual thyroid hormones, especially in late gestation, on the risk of preterm birth. Herein, we examined the associations between subclinical changes in maternal thyroid hormone concentrations (TSH, total T3, free and total T4), measured at multiple time points in pregnancy, and the odds of preterm birth in pregnant women without clinical thyroid disease. Participants and Methods Data were obtained from pregnant women participating in a nested case-control study of preterm birth within on ongoing birth cohort study at Brigham and Women’s Hospital in Boston, MA (N = 439; 116 cases and 323 controls). We measured thyroid hormones in plasma collected at up to four time points in pregnancy (median = 10, 18, 26, and 35 weeks). We used multivariate logistic regression models stratified by study visit of sample collection to examine associations. To reveal potential biological pathways, we also explored these relationships by obstetric presentation of preterm birth (e.g., spontaneous preterm delivery) that have been previously hypothesized to share common underlying mechanisms. Results In samples collected at median 10 and 26 weeks of gestation, we found inverse associations between FT4 and the odds of overall preterm birth (odds ratio [OR] = 0.57, 95% confidence interval (CI) = 0.33, 1.00; and OR = 0.53, 95% CI = 0.34, 0.84, respectively). Positive associations were detected for total T3 at these same time points (OR = 2.52, 95% CI = 1.20, 5.31; and OR = 3.40, 95% CI = 1.56, 7.40, respectively). These effect estimates were stronger for spontaneous preterm birth. Conclusions Our results suggest that subclinical alterations in individual maternal thyroid hormones may influence the risk of preterm birth, and the strength of these associations vary by gestational age.

Urinary BPA and phthalate metabolite concentrations and plasma vitamin D levels in pregnant women: A repeated measures analysis

Background: In addition to its well-established role in maintaining skeletal health, vitamin D has essential regulatory functions in female reproductive and pregnancy outcomes. Phthalates and bisphenol A (BPA) are endocrine disruptors, and previous research has suggested that these chemical agents may disrupt circulating levels of total 25(OH)D in adults. Objectives: We investigated the relationships between repeated measures of urinary phthalate metabolites and BPA and circulating total 25(OH)D in a prospective cohort of pregnant women. Methods: The present study population includes participants (n=477) in a nested case–control study of preterm birth drawn from a prospective birth cohort of pregnant women at Brigham and Women’s Hospital in Boston, Massachusetts. Urine and blood samples were collected for biomarker measurements at median 10 wk and 26 wk of gestation. Results: In repeated measures analysis, we observed that an interquartile range (IQR) increase in urinary mono-3-carboxypropyl phthalate (MCPP) was associated with a 4.48% decrease [95% confidence interval (CI): −7.37, −1.58] in total 25(OH)D. We also detected inverse associations for metabolites of di(2-ethylhexyl) phthalate (DEHP) [percent difference (%Δ)=−2.83 to −2.16]. For BPA, we observed a nonsignificant inverse association with total 25(OH)D in the overall population. Our sensitivity analysis revealed that the associations for some metabolites (e.g., MEHP) varied by race/ethnicity, which may reflect potential differences in susceptibility. In agreement with findings from repeated measures analysis, we reported that DEHP metabolites and BPA were significantly associated with an approximate 20% increase in the odds of vitamin D deficiency (≤20 ng/mL) [odds ratio (95% CI): 1.19 (1.06, 1.35) for molar sum of DEHP metabolites and 1.22 (1.01, 1.47) for BPA] at median 10 wk and 26 wk, respectively. Conclusions: Our results provide suggestive evidence of the potential for environmental exposure to phthalates and/or BPA to disrupt circulating vitamin D levels in pregnancy. https://doi.org/10.1289/EHP1178

Associations between maternal phenol and paraben urinary biomarkers and maternal hormones during pregnancy: A repeated measures study

BACKGROUND A number of phenols and parabens are added to consumer products for a variety of functions, and have been found at detectable levels in the majority of the U.S. POPULATION Among other functions, thyroid hormones are essential in fetal neurodevelopment, and could be impacted by the endocrine disrupting effects of phenols and parabens. The present study investigated the association between ten maternal urinary phenol and paraben biomarkers (bisphenol S, triclosan, triclocarban, benzophenone-3, 2,4-dichlorophenol, 2,5-dichlorophenol, and ethyl, butyl, methyl and propyl paraben) and four plasma thyroid hormones in 439 pregnant women in a case-control sample nested within a cohort study based in Boston, MA. METHODS Urine and blood samples were collected from up to four visits during pregnancy (median weeks of gestation at each visit: Visit 1: 9.64, Visit 2: 17.9, Visit 3: 26.0, Visit 4: 35.1). Linear mixed models were constructed to take into account the repeated measures jointly, followed by multivariate linear regression models stratified by gestational age to explore potential windows of susceptibility. RESULTS We observed decreased total triiodothyronine (T3) in relation to an IQR increase in benzophenone-3 (percent change [%Δ] = -2.07; 95% confidence interval [CI] = -4.16, 0.01), butyl paraben (%Δ = -2.76; 95% CI = -5.25, -0.26) and triclosan (%Δ = -2.53; 95% CI = -4.75, -0.30), and triclocarban at levels above the LOD (%Δ = -5.71; 95% CI = -10.45, -0.97). A 2.41% increase in T3 was associated with an IQR increase in methyl paraben (95% CI = 0.58, 4.24). We also detected a negative association between free thyroxine (FT4) and propyl paraben (%Δ = -3.14; 95% CI = -6.12, -0.06), and a suggestive positive association between total thyroxine (T4) and methyl paraben (%Δ = 1.19; 95% CI = -0.10, 2.47). Gestational age-specific multivariate regression analyses showed that the magnitude and direction of some of the observed associations were dependent on the timing of exposure. CONCLUSION Certain phenols and parabens were associated with altered thyroid hormone levels during pregnancy, and the timing of exposure influenced the association between phenol and paraben, and hormone concentrations. These changes may contribute to downstream maternal and fetal health outcomes. Additional research is required to replicate the associations, and determine the potential biological mechanisms underlying the observed associations.

Exploratory analysis of the potential relationship between urinary molybdenum and bone mineral density among adult men and women from NHANES 2007–2010

Human exposure to molybdenum (Mo) may play a role in reducing bone mineral density (BMD) by interfering with steroid sex hormone levels. To begin to address gaps in the literature on this topic, the potential relationship between urinary Mo (U-Mo) and BMD at the femoral neck (FN-BMD) and lumbar spine (LS-BMD) was explored in a sample of 1496 adults participating in the 2007-2010 cycles of the National Health and Nutrition Examination Survey. Associations were assessed using multiple linear regression models stratified on sex and age. In adjusted models for 50-80+ year-old women, there was a statistically significant inverse relationship between natural log-U-Mo and LS-BMD (p-value: 0.002), and a statistically significant dose-dependent decrease in LS-BMD with increasing U-Mo quartiles (trend p-value: 0.002). A suggestive (trend p-value: 0.08), dose-dependent decrease in FN-BMD with increasing U-Mo quartiles was noted in this group of women as well. All other adjusted models revealed no statistically significant or suggestive relationships between U-Mo and FN-BMD or LS-BMD. Bone health is important for overall human health and well-being and, given the exploratory nature of this work, additional studies are needed to confirm the results in other populations, and clarify the potential underlying mechanisms of Mo on BMD.

Subclinical Changes in Maternal Thyroid Function Parameters in Pregnancy and Fetal Growth

Context Overt thyroid disease in pregnancy is a known risk factor for abnormal fetal growth and development. Data on the effects of milder forms of variation in maternal thyroid function on intrauterine growth are less well examined. Objective We explored these associations using repeated thyroid hormone and ultrasound measurements. Design, Setting, and Participants Data were obtained from 439 pregnant women without diagnosed thyroid disease who were participants in a case-control study of preterm birth nested within an ongoing prospective birth cohort in Boston, Massachusetts. Main Outcome Measures Ultrasound and delivery indices of fetal growth were standardized to those measured in a larger population. Results At median 10, 18, and 26 weeks of gestation, we observed significant inverse associations between free thyroxine (FT4) and birth weight z scores, with the strongest association detected at median 10 weeks, at which time a 10% increase in FT4 was associated with a 0.02 z score decrease (∼8.5 g) in birth weight (β = -0.41 for ln-transformed FT4; 95% confidence interval, -0.64 to -0.18). FT4 was also inversely associated with repeated measurements of estimated fetal weight, head circumference, and abdominal circumference. We observed weaker inverse associations for total T4 and a positive relationship between total triiodothyronine and birth weight z scores. We did not observe any associations for thyroid-stimulating hormone. Conclusion In pregnant women without overt thyroid disease, subclinical changes in thyroid function parameters may influence fetal growth.