BPA, Parabens, and Phthalates in Relation to Endometrial Cancer Risk: A Case–Control Study Nested in the Multiethnic Cohort

Danja Sarink,1 Adrian A. Franke,1 Kami K. White,1 Anna H. Wu,2 Iona Cheng,3 Brandon Quon,1 Loïc Le Marchand,1 Lynne R. Wilkens,1 Herbert Yu,1 and Melissa A. Merritt1 Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA


Introduction
Bisphenol A (BPA), phthalates, parabens, and triclosan are endocrine disrupting chemicals (EDCs); that is, they are exogenous substances that alter functions of the endocrine system and may cause adverse health effects. BPA and phthalates are plasticizers, whereas parabens and triclosan are antimicrobial chemicals or preservatives (Giulivo et al. 2016). Nuclear estrogen and progesterone receptors are EDC targets and BPA, selected phthalates, and parabens can bind to the estrogen receptor (ER) (Mallozzi et al. 2017;Nowak et al. 2018;Zacharewski et al. 1998). Because exposure to estrogen unopposed by progesterone is key to endometrial cancer development (Key and Pike 1988), we investigated whether BPA, triclosan, parabens, and phthalate metabolites were associated with endometrial cancer risk among participants in the prospective Multiethnic Cohort (MEC).

Methods
The MEC has been described previously (Kolonel et al. 2000). A baseline questionnaire was completed by participants in Hawaii and California in 1993-1996. In 2001-2006, biospecimens and a short questionnaire were collected. The study was approved by institutional review boards at the participating institutions, and participants provided written informed consent at biospecimen collection. This study included postmenopausal women from five main racial/ethnic groups included in the MEC, each of whom provided an overnight or first morning urine sample and had no previous hysterectomy or diagnosis of endometrial or breast cancer. Incident invasive endometrial cancers (International Classification of Diseases for Oncology 3rd revision codes C54.0-C54.9) diagnosed after urine collection, and through 2017, were identified by linkage to Hawaii and California Surveillance, Epidemiology, and End Results cancer registries. Controls were selected from participants who were alive and endometrial/breast cancer-free at the time of diagnosis of their index case. Controls were matched 1:1 on race/ethnicity and birth year, as well as on urine type, time of day, year, fasting hours, and current postmenopausal hormone use at biospecimen collection.
Observations with urinary EDC concentrations below the limit of detection (LOD) for butyl paraben (35%) and BPA, triclosan, methyl paraben, ethyl paraben, MEP, monoisobutyl phthalate (MiBP), and monomethyl phthalate (MMP) (≤8% each) were set to half of their respective LOD values. Urinary concentrations of benzyl paraben and monocyclohexyl phthalate were below the LOD for ≥95% of participants, and these markers were excluded from analysis. We used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between EDC metabolite excretion (in nanograms per milligram creatinine; tertiles based on the distribution in controls) and endometrial cancer risk, adjusted for body mass index (BMI), diabetes, and Mediterranean Diet Score. A two-tailed p < 0:05 was considered statistically significant. Analyses were performed using SAS (version 9.4; SAS Institute Inc.).

Results
In 139 case-control sets, comparisons of the crude creatinineadjusted EDC excretion showed similar median values and overlapping interquartile ranges (Table 1). BMI at urine collection was higher in cases than controls (42% vs. 22% ≥ 30 kg=m 2 BMI), whereas diabetes prevalence was lower (12% vs. 22%). Endometrial cancer cases were diagnosed a median of 6.6 y after urine collection. Most cases were diagnosed with endometrioid histology (75%) and localized disease (71%).

Discussion
In this case-control study nested in the MEC, prediagnostic urinary DBP metabolite excretion was positively associated with endometrial cancer risk. Trend tests showed no clear indication of linearly increasing endometrial cancer risk for any of the EDCs in our study; associations for MnBP were limited to the second (vs. the first) tertile, whereas ORs were similar but nonsignificant when comparing extreme tertiles. The authors declare they have no actual or potential competing financial interests.
Note to readers with disabilities: EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact ehponline@niehs.nih.gov. Our staff will work with you to assess and meet your accessibility needs within 3 working days. MiBP and MnBP are metabolites of low-molecular-weight DBP, and have been found to be weakly estrogenic in vitro (Zacharewski et al. 1998). A previous cross-sectional study observed no significant association between urinary excretion of MiBP, MnBP, or other phthalate metabolites (above vs. below the median) with a self-reported history of uterine cancer (n = 3,003 National Health and Nutrition Examination Survey participants; 27 cases) (Morgan et al. 2016). High exposure to DBP, estimated using redeemed prescriptions for phthalate-containing drug products, has been associated with increased ER-receptor-positive breast cancer risk in a Danish nationwide cohort (Ahern et al. 2019).
A limitation of the current study is the use of a single urine specimen. In the Nurses' Health Study (NHS)/NHSII there was a fair within-person reproducibility over 1-3 y for urinary phthalate excretion (Townsend et al. 2013). Reproducibility of urinary methyl and propyl paraben (median = 6:7 y) was poor in the Shanghai Women's Health Study (Engel et al. 2014). Both studies reported poor reproducibility over time for BPA, indicating that a single measurement may not reflect usual exposure. Although we included all postmenopausal incident endometrial cancer cases with an available prediagnosis urine sample in our study, estimates were imprecise owing to the small number of observations and were not adjusted for coexposure to related metabolites. In addition, 35% of observations for butyl paraben were below the LOD.
EDC exposures differ between racial/ethnic groups (Nguyen et al. 2020), and it is important to study health outcomes in diverse populations. As far as we are aware, this study is the first to investigate prediagnosis EDC excretion in relation to endometrial cancer risk using prospectively collected urine samples. This work highlights new avenues for collaborative research that aim to explain observed racial/ethnic disparities in endometrial cancer risk.