Research Letter A Section 508–conformant HTML version of this article

is available at https://doi.org/10.1289/EHP8998.

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
1
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA
2
Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA
3
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA

https://doi.org/10.1289/EHP8998
Introduction Franke 2015; Townsend et al. 2013); creatinine (in milligrams
Bisphenol A (BPA), phthalates, parabens, and triclosan are endo- per milliliter) was measured using a clinical autoanalyzer (Cobas
crine disrupting chemicals (EDCs); that is, they are exogenous MiraPlus; Roche), all in the Analytical Biochemistry Shared
substances that alter functions of the endocrine system and may Resource, University of Hawaii Cancer Center. Personnel were
cause adverse health effects. BPA and phthalates are plasticizers, blinded to sample status. Case–control sets were analyzed in the
whereas parabens and triclosan are antimicrobial chemicals or same batch. Intrabatch coefficients of variation (CVs) were
preservatives (Giulivo et al. 2016). Nuclear estrogen and proges- <14% except for butyl paraben (24%) and BPA (22%); interbatch
terone receptors are EDC targets and BPA, selected phthalates, CVs were <16% except for methyl paraben (30%) and monoethyl
and parabens can bind to the estrogen receptor (ER) (Mallozzi phthalate (MEP) (23%).
et al. 2017; Nowak et al. 2018; Zacharewski et al. 1998). Observations with urinary EDC concentrations below the limit
Because exposure to estrogen unopposed by progesterone is key of detection (LOD) for butyl paraben (35%) and BPA, triclosan,
to endometrial cancer development (Key and Pike 1988), we methyl paraben, ethyl paraben, MEP, monoisobutyl phthalate
investigated whether BPA, triclosan, parabens, and phthalate (MiBP), and monomethyl phthalate (MMP) (≤8% each) were set
metabolites were associated with endometrial cancer risk among to half of their respective LOD values. Urinary concentrations of
participants in the prospective Multiethnic Cohort (MEC). benzyl paraben and monocyclohexyl phthalate were below the
LOD for ≥95% of participants, and these markers were excluded
Methods from analysis. We used conditional logistic regression to estimate
The MEC has been described previously (Kolonel et al. 2000). A odds ratios (ORs) and 95% confidence intervals (CIs) for associa-
baseline questionnaire was completed by participants in Hawaii tions between EDC metabolite excretion (in nanograms per milli-
and California in 1993–1996. In 2001–2006, biospecimens and a gram creatinine; tertiles based on the distribution in controls) and
short questionnaire were collected. The study was approved by endometrial cancer risk, adjusted for body mass index (BMI), dia-
institutional review boards at the participating institutions, and par- betes, and Mediterranean Diet Score. A two-tailed p < 0:05 was
ticipants provided written informed consent at biospecimen collec- considered statistically significant. Analyses were performed using
tion. This study included postmenopausal women from five main SAS (version 9.4; SAS Institute Inc.).
racial/ethnic groups included in the MEC, each of whom provided
an overnight or first morning urine sample and had no previous Results
hysterectomy or diagnosis of endometrial or breast cancer. In 139 case–control sets, comparisons of the crude creatinine-
Incident invasive endometrial cancers (International Classification adjusted EDC excretion showed similar median values and over-
of Diseases for Oncology 3rd revision codes C54.0-C54.9) diag- lapping interquartile ranges (Table 1). BMI at urine collection
nosed after urine collection, and through 2017, were identified by was higher in cases than controls (42% vs. 22% ≥ 30 kg=m2
linkage to Hawaii and California Surveillance, Epidemiology, and BMI), whereas diabetes prevalence was lower (12% vs. 22%).
End Results cancer registries. Controls were selected from partici- Endometrial cancer cases were diagnosed a median of 6.6 y after
pants who were alive and endometrial/breast cancer–free at the urine collection. Most cases were diagnosed with endometrioid
time of diagnosis of their index case. Controls were matched 1:1 on histology (75%) and localized disease (71%).
race/ethnicity and birth year, as well as on urine type, time of day, All estimates had wide 95% CIs, reflecting the modest sample
year, fasting hours, and current postmenopausal hormone use at size, with no significant trends (Table 2). However, mono-n-butyl
biospecimen collection. phthalate (MnBP) excretion was positively associated with endo-
Urinary concentrations (in nanograms per milliliter) of BPA, metrial cancer risk (second vs. first tertile: OR = 2:35 (95% CI:
triclosan, parabens, and phthalate metabolites were measured 1.19, 4.65), and a nonsignificant association was observed for the
using liquid chromatography high-resolution accurate-mass mass third vs. first tertile: OR = 1:82 (95% CI: 0.81, 4.10). Associations
spectrometry (Model Q-Exactive; Thermo Scientific) (Li and were similar for dibutyl phthalate [DBP (sum of MiBP and MnBP
excretion)], with corresponding ORs = 2:09 (95% CI: 1.05, 4.16)
and 1.77 (95% CI: 0.75, 4.17). No other associations were statisti-
Address correspondence to Melissa A. Merritt, Cancer Epidemiology Program, cally significant.
University of Hawaii Cancer Center, 701 Ilalo St, Honolulu, HI 96813, USA.
Telephone: Phone: (808) 564-5830. Email: [email protected]
The authors declare they have no actual or potential competing financial Discussion
interests. In this case–control study nested in the MEC, prediagnostic uri-
Note to readers with disabilities: EHP strives to ensure that all journal nary DBP metabolite excretion was positively associated with en-
content is accessible to all readers. However, some figures and Supplemental dometrial cancer risk. Trend tests showed no clear indication of
Material published in EHP articles may not conform to 508 standards due to
linearly increasing endometrial cancer risk for any of the EDCs
the complexity of the information being presented. If you need assistance
accessing journal content, please contact [email protected]. Our staff in our study; associations for MnBP were limited to the second
will work with you to assess and meet your accessibility needs within 3 (vs. the first) tertile, whereas ORs were similar but nonsignificant
working days. when comparing extreme tertiles.

Environmental Health Perspectives 057702-1 129(5) May 2021

Table 1. Population characteristics in postmenopausal endometrial cancer cases and matched controls nested within the Multiethnic Cohort.
Controls Cases
Characteristic n = 139 n = 139
Creatinine-adjusted EDC excretion [median (IQR)]
BPAa 1.54 (0.81–2.95) 1.62 (1.01–2.93)
Triclosana 9.70 (2.94–32.67) 9.29 (2.52–37.99)
Methyl parabena 98.73 (28.37–246.26) 78.64 (21.30–229.18)
Ethyl parabena 3.23 (0.48–12.19) 1.47 (0.33–11.75)
Propyl paraben 20.16 (4.18–82.67) 11.30 (2.54–41.62)
Butyl parabena 0.36 (0.00–2.83) 0.15 (0.00–1.29)
Total parabensb 137.13 (36.93–358.83) 111.55 (29.01–323.44)
MBzP 13.65 (8.77–23.41) 14.17 (9.03–19.76)
MECPP 33.03 (21.23–63.80) 34.40 (22.79–59.59)
MEHHP 33.57 (23.30–55.40) 34.74 (21.76–57.97)
MEHP 8.02 (5.46–12.18) 7.97 (4.42–13.65)
MEOHP 19.47 (13.45–32.35) 20.97 (13.14–39.63)
MEPa 64.53 (28.36–133.23) 51.51 (31.70–116.34)
MiBPa 4.22 (3.05–7.23) 5.38 (3.44–7.89)
MMPa 7.17 (5.21–11.50) 7.09 (4.69–10.06)
MnBP 22.01 (15.10–42.21) 22.44 (17.36–41.78)
PA 58.94 (40.28–91.89) 54.24 (39.05–98.34)
DBPc 27.90 (19.46–50.11) 30.00 (22.04–55.58)
DEHPd 90.81 (67.34–161.01) 95.33 (66.25–157.6)
Total phthalatese 259.37 (181.45–387.84) 253.07 (176.75–450.75)
Creatinine 0.53 (0.33–0.76) 0.54 (0.32–0.80)

Population characteristics [n (%) or median (IQR)]

Age at urine collection (y)f 62 (59–69) 62 (59–69)
Race/ethnicityf
White 35 (25) 35 (25)
African American 9 (6) 9 (6)
Native Hawaiian 26 (19) 26 (19)
Japanese American 52 (37) 52 (37)
Latina 17 (12) 17 (12)
Parity at baseline
Nulliparous 28 (20) 26 (19)
Parous 111 (80) 113 (81)
Oral contraceptive use at baseline
Never 55 (40) 64 (46)
Former 84 (60) 75 (54)
Postmenopausal hormone use at urine collectiona
Not current 114 (82) 114 (82)
Current 25 (18) 25 (18)
BMI at urine collection (kg=m2 )g
<25 56 (40) 43 (31)
25–29 52 (37) 37 (27)
≥30 31 (22) 59 (42)
Diabetes prevalenceh
No 108 (78) 122 (88)
Yes 31 (22) 17 (12)

Case characteristics [n (%) or median (IQR)]

Age at diagnosis (y) — 69 (65–75)
Years from urine collection to diagnosis — 6.6 (3.4–9.4)
Tumor histology
Endometrioidi — 104 (75)
Serous — 15 (11)
Other — 20 (14)
Disease stagej
Localized — 99 (71)
Regional and distant — 36 (26)
Tumor grade
1 — 46 (33)
2 — 27 (19)
3 — 42 (30)
4 — 24 (17)
Note: —, not applicable; BMI, body mass index; BPA, bisphenol A; DBP, dibutyl phthalate; DEHP, di (2-ethylhexyl) phthalate; EDC, endocrine disrupting chemical; IQR, interquar-
tile range; LOD, limit of detection; MBzP, mono-benzyl phthalate; MECPP, mono(2-ethyl-5-carboxypentyl) phthalate; MEHHP, mono(2-ethyl-5-hydroxyhexyl) phthalate; MEHP,
mono(2-ethylhexyl) phthalate; MEOHP, mono(2-ethyl-5-oxohexyl) phthalate; MEP, monoethyl phthalate; MiBP, monoisobutyl phthalate; MMP, monomethyl phthalate; MnBP,
mono-n-butyl phthalate; PA, phthalic acid.
a
Including observations with concentrations below the LOD of the assay, set to half the LOD: butyl paraben (35%) and BPA, triclosan, methyl paraben, ethyl paraben, MEP, MiBP,
and MMP (≤8% each).
d
Sum of butyl, ethyl, methyl, and propyl paraben excretion.
c
Sum of MiBP and MnBP excretion.
d
Sum of MECPP, MEHHP, MEHP, and MEOHP excretion.
e
Sum of MBzP, MECPP, MEHHP, MEHP, MEOHP, MEP, MiBP, MMP, and MnBP excretion.
f
Matching factor.
g
BMI at baseline used for three cases missing BMI at urine collection.
h
Self-reported diabetes at baseline and/or diabetes medication use at biospecimen collection.
i
Including adenocarcinoma with squamous cell differentiation and adenocarcinoma not otherwise specified.
j
n = 4 (3%) cases missing stage.

Environmental Health Perspectives 057702-2 129(5) May 2021

Table 2. Number (cases/controls) and odds ratios with 95% confidence inter- A limitation of the current study is the use of a single urine
vals for associations between creatinine-adjusted urinary EDC metabolite specimen. In the Nurses’ Health Study (NHS)/NHSII there was a
excretion (ng/mg) and endometrial cancer risk in 139 matched case–control fair within-person reproducibility over 1–3 y for urinary phthalate
sets nested within the Multiethnic Cohort.
excretion (Townsend et al. 2013). Reproducibility of urinary
EDC metabolite Tertile 1 Tertile 2 Tertile 3 pTrend a methyl and propyl paraben (median = 6:7 y) was poor in the
BPA 44/47 45/46 50/46 Shanghai Women’s Health Study (Engel et al. 2014). Both studies
0.50
Ref 0.86 (0.44, 1.67) 1.21 (0.60, 2.44) reported poor reproducibility over time for BPA, indicating that a
Triclosan 49/47 45/46 45/46
Ref 1.09 (0.53, 2.25) 0.97 (0.47, 2.01)
0.80 single measurement may not reflect usual exposure. Although we
Methyl paraben 50/47 46/46 43/46 included all postmenopausal incident endometrial cancer cases
0.83 with an available prediagnosis urine sample in our study, estimates
Ref 1.36 (0.68, 2.73) 1.17 (0.60, 2.28)
Ethyl paraben 62/47 36/46 41/46
0.85
were imprecise owing to the small number of observations and
Ref 0.65 (0.33, 1.28) 0.95 (0.48, 1.89) were not adjusted for coexposure to related metabolites. In addi-
Propyl paraben 54/47 55/46 30/46 tion, 35% of observations for butyl paraben were below the LOD.
0.25
Ref 1.35 (0.70, 2.61) 0.80 (0.39, 1.65)
Butyl paraben 55/47 43/46 41/46
EDC exposures differ between racial/ethnic groups (Nguyen
0.67 et al. 2020), and it is important to study health outcomes in diverse
Ref 0.80 (0.40, 1.61) 0.78 (0.38, 1.63)
Total parabensb 51/47 48/46 40/46 populations. As far as we are aware, this study is the first to investi-
0.81
Ref 1.36 (0.71, 2.60) 1.03 (0.52, 2.02) gate prediagnosis EDC excretion in relation to endometrial cancer
MBzP 43/47 51/46 45/46 risk using prospectively collected urine samples. This work high-
0.97
Ref 1.20 (0.62, 2.33) 1.07 (0.55, 2.11) lights new avenues for collaborative research that aim to explain
MECPP 45/47 46/46 48/46
Ref 1.24 (0.64, 2.41) 1.52 (0.74, 3.13)
0.28 observed racial/ethnic disparities in endometrial cancer risk.
MEHHP 50/47 42/46 47/46
0.78
Ref 1.14 (0.62, 2.10) 0.95 (0.48, 1.87) Acknowledgments
MEHP 46/47 44/46 49/46
Ref 1.27 (0.64, 2.52) 1.43 (0.75, 2.75)
0.30 The project described here was supported by grants
MEOHP 55/47 33/46 51/46 U54MD007601 from the National Institute on Minority Health
0.42 and Health Disparities [NIMHD; primary investigator (PI):
Ref 0.68 (0.35, 1.35) 1.17 (0.57, 2.42)
MEP 47/47 49/46 43/46
0.92 M.A.M.] and P30CA71789-03 from the National Cancer Institute
Ref 0.85 (0.43, 1.68) 0.93 (0.43, 2.00) (NCI; PI: R. Holcombe.). Both the NIMHD and the NCI are
MiBP 36/47 49/46 54/46 components of the National Institutes of Health (NIH). The
0.13
Ref 1.51 (0.75, 3.01) 1.85 (0.90, 3.82)
MMP 54/47 46/46 39/46 Multiethnic Cohort is supported by NCI grant U01CA164973
0.21 (L.L.M., C. Haiman, L.R.W.). The content is solely the responsibility
Ref 0.77 (0.38, 1.55) 0.59 (0.27, 1.31)
MnBP 32/47 63/46 44/46 of the authors and does not represent the official view of the NIMHD
0.44
Ref 2.35 (1.19, 4.65) 1.82 (0.81, 4.10) or NIH. For information on applications to gain access to data from
PA 47/47 50/46 42/46 the Multiethnic Cohort please see https://www.uhcancercenter.org/
0.84
Ref 1.39 (0.72, 2.67) 1.00 (0.45, 2.22) for-researchers/mec-data-sharing. For queries relating to the data
c
DBP 33/47 63/46 43/46
0.54 included in this manuscript, please contact the corresponding author.
Ref 2.09 (1.05, 4.16) 1.77 (0.75, 4.17)
DEHPd 52/47 39/46 48/46
0.65
Ref 0.99 (0.51, 1.89) 1.15 (0.56, 2.36)
Total phthalates e
47/47 46/46 46/46
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