Article

Variability and Predictors of Urinary Bisphenol A Concentrations during Pregnancy

Department of Environmental Health, Harvard University, Boston, Massachusetts, USA.
Environmental Health Perspectives (Impact Factor: 7.98). 01/2011; 119(1):131-7. DOI: 10.1289/ehp.1002366
Source: PubMed

ABSTRACT

Prenatal bisphenol A (BPA) exposure may be associated with developmental toxicity, but few studies have examined the variability and predictors of urinary BPA concentrations during pregnancy.
Our goal was to estimate the variability and predictors of serial urinary BPA concentrations taken during pregnancy.
We measured BPA concentrations during pregnancy and at birth in three spot urine samples from 389 women. We calculated the intraclass correlation coefficient (ICC) to assess BPA variability and estimated associations between log10-transformed urinary BPA concentrations and demographic, occupational, dietary, and environmental factors, using mixed models.
Geometric mean (GM) creatinine-standardized concentrations (micrograms per gram) were 1.7 (16 weeks), 2.0 (26 weeks), and 2.0 (birth). Creatinine-standardized BPA concentrations exhibited low reproducibility (ICC = 0.11). By occupation, cashiers had the highest BPA concentrations (GM: 2.8 μg/g). Consuming canned vegetables at least once a day was associated with higher BPA concentrations (GM = 2.3 μg/g) compared with those consuming no canned vegetables (GM = 1.6 μg/g). BPA concentrations did not vary by consumption of fresh fruits and vegetables, canned fruit, or store-bought fresh and frozen fish. Urinary high-molecular-weight phthalate and serum tobacco smoke metabolite concentrations were positively associated with BPA concentrations.
These results suggest numerous sources of BPA exposure during pregnancy. Etiological studies may need to measure urinary BPA concentrations more than once during pregnancy and adjust for phthalates and tobacco smoke exposures.

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Environmental Health Perspectives
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Research
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Children’s Health
Bisphenol A (BPA) is an estrogenic monomer
used to produce polycarbonate plastics and res-
ins that can be used in medical equipment,
children’s toys, water supply pipes, carbonless
paper, cigarette filters, and food container lin-
ings (Chapin et al. 2008; Jackson and Darnell
1985). More than 6 billion pounds of BPA
were manufactured in 2003, making it one of
the highest-volume production chemicals in the
world (Burridge 2003). e U.S. population,
including children and pregnant women, have
nearly ubiquitous exposure to BPA (Calafat
et al. 2008; Vandenberg et al. 2010), likely
because of its pervasiveness in the environment
and its ability to leach from food and beverage
containers under conditions of normal use.
Growing concern over BPA exposure
is reflected in a report from the National
Toxicology Program (NTP) and an ongo-
ing risk assessment of BPA by the U.S. Food
and Drug Administration (FDA) (Chapin
et al. 2008; FDA 2010; vom Saal et al. 2007).
e NTP report and others have concluded
that prenatal BPA exposure has the potential
to alter neurodevelopmental, reproductive,
and metabolic end points throughout the
life span (Chapin et al. 2008; Palanza et al.
2008; vom Saal et al. 2007). ese end points
may be sensitive to prenatal BPA exposure,
because the developing fetus may be suscep-
tible to environmental toxicants (Mendola
et al. 2002). Consequently, understanding
predictors and variability of BPA exposure in
pregnancy is essential for future studies of the
health effects of BPA.
Although pharmacokinetic studies in
humans show that BPA has a biological half-
life of < 6 hr (Volkel et al. 2002), recent data
suggest that BPA has a longer half-life as well
as sources of nonoral exposure and may deposit
in fat tissue (Fernandez et al. 2007; Stahlhut
et al. 2009; Vandenberg et al. 2010). Because
of a variety of factors, including the pharma-
cokinetic properties of BPA and lifestyle fac-
tors, serial urinary BPA concentrations show
low to modest correlations over 1–6 months
(Mahalingaiah et al. 2008; Nepomnaschy et al.
2009; Teitelbaum et al. 2008). Given the rapid
elimination of BPA from the body and low
degree of within- person correlation, the timing
of urine collection may influence the observed
BPA concentration and may fail to reflect the
dose of BPA that could be related to health
end points.
It is estimated that almost 99% of BPA
exposure comes from dietary sources in
children (Wilson et al. 2007), but comparable
studies have not been conducted in pregnant
women or adults. Food containers lined with
BPA-based resins are a likely source of expo-
sure, and multiple studies have measured BPA
in canned foods (Chapin et al. 2008; Lim et al.
2009; omson and Grounds 2005). However,
no studies have documented a relationship
between canned food consumption and uri-
nary BPA concentrations. Sociodemographic
factors may influence food choices and act dif-
ferentially across various populations (Calafat
et al. 2008; He et al. 2009; Ye et al. 2008).
Little is known about the variability and
determinants of BPA exposure in pregnant
women. Thus, we examined the correlation
and predictors of urinary BPA concentrations
in three serial samples taken over the latter two-
thirds of pregnancy from 389 pregnant women
in Cincinnati, Ohio. Specifically, we estimated
the within- and between-woman variability of
urinary BPA concentrations and examined the
association between sociodemographic, occu-
pational, dietary, and environmental factors
and urinary BPA concentrations.
Methods
Study sample. We used data collected from
pregnant women participating in the Health
Address correspondence to J.M. Braun, 401 Park
Dr., 3rd Floor East, Boston, MA 02215 USA.
Telephone: (617) 849-8681. Fax: (617) 384-8994.
E-mail: jbraun@hsph.harvard.edu
Supplemental Material is available online
(doi:10.1289/ehp.1002366 via http://dx.doi.org/).
We acknowledge A. Bishop, T. Jia, E. Samandar,
and J. Preau for measuring the urinary concentra-
tions of BPA and phthalate metabolites.
is study was funded by a grant from the National
Institute of Environmental Health Sciences (NIEHS)
and the U.S. Environmental Protection Agency (PO1
ES11261). Additional support came from National
Institute of Child Health and Human Development
training grant T32-HD052468-01, NIEHS grant
P30ES10126, the University of Washington K–12
Male Reproductive Health Research Training Grant,
and NIEHS Training Grant T32 ES007018.
The findings and conclusions in this report are
those of the authors and do not necessarily represent
the views of the Centers for Disease Control and
Prevention.
e authors declare they have no actual or potential
competing financial interests.
Received 29 April 2010; accepted 27 September
2010.
Variability and Predictors of Urinary Bisphenol A Concentrations
during Pregnancy
Joe M. Braun,
1
Amy E. Kalkbrenner,
2
Antonia M. Calafat,
3
John T. Bernert,
3
Xiaoyun Ye,
3
Manori J. Silva,
3
Dana Boyd Barr,
4
Sheela Sathyanarayana,
5
and Bruce P. Lanphear
6,7
1
Department of Environmental Health, Harvard University, Boston, Massachusetts, USA;
2
Department of Epidemiology, University of
North Carolina–Chapel Hill, Chapel Hill, North Carolina, USA;
3
National Center for Environmental Health, Centers for Disease Control and
Prevention, Atlanta, Georgia, USA;
4
Rollins School of Public Health, Emory University, Atlanta, Georgia, USA;
5
Department of Pediatrics,
University of Washington/Seattle Children’s Hospital, Seattle, Washington, USA;
6
Department of Pediatrics, Division of General and
Community Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA;
7
Simon Fraser University, Vancouver,
British Columbia, Canada
Ba c k g r o u n d : Prenatal bisphenol A (BPA) exposure may be associated with developmental toxicity,
but few studies have examined the variability and predictors of urinary BPA concentrations during
pregnancy.
oB j e c t i v e : Our goal was to estimate the variability and predictors of serial urinary BPA concentra-
tions taken during pregnancy.
Me t h o d s : We measured BPA concentrations during pregnancy and at birth in three spot urine
samples from 389 women. We calculated the intraclass correlation coefficient (ICC) to assess BPA
variability and estimated associations between log
10
-transformed urinary BPA concentrations and
demographic, occupational, dietary, and environmental factors, using mixed models.
re s u l t s : Geometric mean (GM) creatinine-standardized concentrations (micrograms per gram)
were 1.7 (16 weeks), 2.0 (26 weeks), and 2.0 (birth). Creatinine-standardized BPA concentrations
exhibited low reproducibility (ICC = 0.11). By occupation, cashiers had the highest BPA concentra-
tions (GM: 2.8 μg/g). Consuming canned vegetables at least once a day was associated with higher
BPA concentrations (GM = 2.3 μg/g) compared with those consuming no canned vegetables (GM
= 1.6 μg/g). BPA concentrations did not vary by consumption of fresh fruits and vegetables, canned
fruit, or store-bought fresh and frozen fish. Urinary high-molecular-weight phthalate and serum
tobacco smoke metabolite concentrations were positively associated with BPA concentrations.
co n c l u s i o n s : These results suggest numerous sources of BPA exposure during pregnancy.
Etiological studies may need to measure urinary BPA concentrations more than once during preg-
nancy and adjust for phthalates and tobacco smoke exposures.
ke y w o r d s : bisphenol A, dietary, occupational, predictors, pregnancy, prenatal, variability. Environ
Health Perspect 119:131–137 (2011). doi:10.1289/ehp.1002366 [Online 8 October 2010]
Page 1
Braun et al.
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Outcomes and Measures of the Environment
Study, an ongoing prospective birth cohort
in the Cincinnati, Ohio, metropolitan area
designed to examine low-level environmen-
tal toxicant exposure (Dietrich et al. 2005).
Eligibility criteria and participant recruitment
have been described previously (Braun et al.
2009). Of the 1,263 eligible women, 468
enrolled in our study (37%), 67 dropped out
before delivery, and 3 had stillbirths. e cur-
rent analyses were further restricted to 389
mothers who delivered singleton children
between March 2003 and January 2006. We
excluded one woman whose 26-week BPA
concentration (1,250 μg/L) was 3 orders of
magnitude higher than the median 26-week
BPA concentration.
Urinary BPA concentration. Women
provided spot urine samples around 16 and
26 weeks of gestation and within 24 hr of
delivery. Urine was collected in polyethylene
containers and stored at –20
o
C until shipped
to the U.S. Centers for Disease Control and
Prevention (CDC) for analysis. e concen-
tration of total (free plus conjugated) species
of urinary BPA was quantified using modi-
fied high-performance liquid chromatography-
isotope dilution tandem mass spectrometry
(HPLC-MS/MS) analytical methods described
previously (Ye et al. 2005). Concentrations
below the limit of detection (LOD) of 0.4 μg/L
were given a value of LOD/
2
for the statistical
analyses (Hornung and Reed 1990).
Urinary creatinine, measured using previ-
ously described methods (Larsen 1972), was
used to control for urine dilution. We stan-
dardized urinary BPA concentration (micro-
grams BPA per gram creatinine) to avoid
having multiple time-dependent variables in
our statistical models.
Predictors of BPA concentrations. We
examined the association between urinary
BPA concentrations and demographic, peri-
natal, occupational, dietary, and environmen-
tal variables collected from questionnaires and
biological samples. We evaluated demographic
and perinatal factors that may be associated
with neurodevelopmental outcomes that are
typically included as covariates in epidemio-
logical studies. We also examined urinary BPA
concentrations according to occupation and
diet. Women may be exposed to BPA in occu-
pational settings from BPA-containing medical
supplies, food, or cash register receipts. Dietary
factors were examined because food is consid-
ered the major source of BPA exposure (von
Goetz et al. 2010; Wilson et al. 2007). Finally,
we examined the association between tobacco
smoke and phthalate exposures and urinary
BPA concentrations because they may share
common sources of exposure [He et al. 2009;
National Research Council (NRC) 2008].
Demographic factors included maternal
age, education, race, marital status, household
income, and occupation. Women self-reported
occupation twice for the periods of concep-
tion to 20 weeks of gestation and 20 weeks to
birth. We categorized women’s occupations
using their employer, description of their type
of work, and job title. We hierarchically clas-
sified women as cashiers, health care workers
(e.g., nurse, physical therapist), food service
workers (e.g., waitress, cook, fast-food worker),
industrial or janitorial workers (factory work
or janitor), teachers (including other faculty or
staff working in a school), office workers, sales
or service workers, other, and unemployed
(reference) to avoid having women in more
than one occupation category. For example, a
woman who worked as a cashier in a fast-food
restaurant would be classified as a cashier.
Perinatal and maternal factors included
parity, depressive symptoms at 20 weeks of ges-
tation, maternal IQ, and child sex. Parity was
abstracted from medical records. Depressive
symptoms were measured with the Beck
Depression Inventory (BDI-II) (Beck et al.
1996). Maternal IQ was measured using the
Wechsler Abbreviated Scales of Intelligence
when mothers and children returned for a
1-year postpartum study visit (Wechsler 1999).
Women were interviewed by trained
research staff twice during pregnancy about
how frequently they consumed certain foods
during the periods of conception to 20 weeks
and 20 weeks to birth. ese foods included
store-bought fresh or frozen fish, fresh fruits
or vegetables, canned fruits, and canned veg-
etables. Women also reported the approximate
proportion of organic food they ate during the
two periods of pregnancy and whether they
were strict, partial, or nonvegetarians. These
questionnaires were originally designed to assess
gestational exposure to mercury and pesticides.
We also examined whether the time of
day or fasting status at the time of sample
collection influenced urinary BPA concen-
trations. Fasting status was derived from the
time since a woman last consumed any food.
We did not include samples taken around
birth in these analyses, because the time of
day (55%) and fasting time (70%) were miss-
ing from a substantial proportion of women.
Serum cotinine and urinary phthalate con-
centrations were measured in samples collected
at 16 and 26 weeks of gestation and within
24 hr of birth. Serum samples were analyzed
for cotinine, a biomarker of nicotine exposure,
using HPLC-MS/MS (LOD = 0.015 ng/mL)
(Bernert et al. 2000). Serum cotinine concen-
trations were examined as categorical variables
[active (> 3 ng/mL), secondhand (0.015–3
ng/mL), or no (< 0.015 ng/mL) exposure]
(Benowitz et al. 2009).
We measured nine phthalate metabo-
lites from the same urine samples used to
quantify BPA [see Supplemental Material,
Table 1 (doi:10.1289/ehp.1002366) for a
list of individual phthalate metabolites]. e
HPLC-MS/MS analytical methods and quality
control procedures used have been described
previously (Silva et al. 2007). To simplify our
analysis of the phthalates–BPA association, we
grouped phthalate metabolites into categories
based on the molecular weight of their parent
compounds or parent metabolite as follows:
low molecular weight (< 250 Da), high molec-
ular weight (> 250 Da), and di(2-ethylhexyl)
phthalate (DEHP) metabolites (Engel et al.
2010).
Statistical analysis. We compared the
demographic characteristics of the 389
women with at least one urine measurement
with those with all three urine measurements
(n = 332). Among the 57 women missing one
or more urine measurements, 54 had a valid
measurement at 16 weeks.
We used two methods to evaluate the
reproducibility of urinary BPA concentrations
across pregnancy. First, we calculated Pearson
correlation coefficients between pairs of BPA
and creatinine-standardized BPA concentra-
tions from the 16-week and 26-week and birth
urine samples. To determine whether these
correlations decayed between pairs of study
visits further apart in time, we stratified the
Pearson correlation coefficients between log
10
-
transformed urinary BPA concentrations taken
at 16 and 26 weeks and 26 weeks and birth by
the time (in weeks) between measurements.
Next, we calculated intraclass correlation
coefficients (ICC) using a one-way random-
effects models with unstructured symmetry
covariance matrices (Proc Mixed version 9.2;
SAS Institute Inc., Cary, NC, USA) to esti-
mate the between- and within-subject vari-
ability of urinary BPA, creatinine-standardized
BPA, and creatinine concentrations. e ICC
can be interpreted as a measure of the repro-
ducibility of the same measurement within
an individual. Values can range from 0 (no
reproducibility) to 1 (perfect reproducibil-
ity) (Rosner 2000). We also calculated these
variability measures using just the first two
(16- and 26-week) and last two (26-week and
birth) urine measurements.
We examined the association between
the prenatal urinary BPA concentrations and
demographic, perinatal, occupational, dietary,
temporal, and environmental factors using lin-
ear mixed models because our data involved
multiple measurements on the same individual
(Fitzmaurice et al. 2004). Demographic and
perinatal factors were included as fixed effects in
our mixed models. Occupation, dietary, time of
sample collection, fasting status, and concentra-
tions of serum cotinine and urinary phthalates
metabolites variables were modeled as time-de-
pendent factors to coincide with the temporally
relevant urine measurement. Log
10
-transformed
creatinine-standardized urinary BPA concentra-
tions (in micrograms BPA per gram creatinine)
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Urinary BPA concentrations during pregnancy
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were the outcome in mixed models with sep-
arate models for each predictor. These mod-
els were used to calculate the geometric mean
(GM) creatinine-standardized urinary BPA
concentration by category of predictor variables
to appropriately include all three urine measure-
ments. Beta coefficients from the mixed models
were exponentiated to produce the ratio of BPA
concentrations between categories of predictor
variables. us, estimates > 1.0 or < 1.0 indi-
cate that the mean creatinine-standardized BPA
concentrations were higher/lower for women
in that category compared with the reference
category. Occupational, dietary, and environ-
mental predictors were additionally adjusted
for maternal age, race, education, household
income, and marital status.
We conducted secondary analyses that
adjusted for urinary dilution by modeling log
10
-
transformed urinary creatinine concentrations
as a time-dependent covariate instead of using
creatinine-standardized BPA concentrations.
Ethical considerations. e institutional
review boards of Cincinnati Children’s
Hospital and Medical Center, participat-
ing hospitals and obstetric practices, and the
CDC approved this study. All mothers pro-
vided written informed consent before enroll-
ing in the study.
Results
Women with all three urinary BPA measure-
ments were more likely to be married (69%
vs. 40%), older (30 vs. 27 years of age), and
wealthier (median household income: $61,000
vs. $40,000 per year) than women missing one
or more measurements. However, 16-week
creatinine-standardized urinary BPA concentra-
tions were almost identical among women with
all three measurements [GM = 1.9 μg/g; SE of
the geometric mean (GSE) = 1.0)] and at least
one (GM = 1.9 μg/g; GSE = 1.1) measurement.
On average (± SD), prenatal urine samples
were collected at 16 ± 2.0, 26 ± 2.0, and 39 ±
1.8 weeks. Urine measurements at 39 weeks
were taken around the time of delivery. More
than 90% of women had detectable urinary
BPA concentrations at 16 and 26 weeks of
gestation, and 87.1% had detectable concen-
trations at birth. Unstandardized urinary BPA
and creatinine concentrations decreased across
pregnancy, but creatinine-standardized uri-
nary BPA concentrations changed little over
the latter two-thirds of gestation (Figure 1).
Log
10
-transformed urinary BPA concen-
trations were weakly correlated at 16 and
26 weeks (r = 0.28), 26 weeks and birth (r =
0.28), and 16 weeks and birth (r = 0.21).
Correlations between creatinine-standardized
urinary BPA concentrations were even lower
at 16 and 26 weeks (r = 0.12), 26 weeks and
birth (r = 0.12), and 16 weeks and birth (r =
0.06). ere was no distinguishable pattern
of correlations between either pair of urinary
BPA measurements when we stratified by the
time interval between collections.
e ICC for serial urinary BPA measure-
ments indicated poor reproducibility in analy-
ses using unstandardized (ICC = 0.25) and
creatinine-standardized concentrations (ICC
= 0.10). ere was no substantial difference in
the components of variance when we only used
the 16-week and 26-week or the 26-week and
birth concentrations (Table 1). Unstandardized
and creatinine-standardized BPA concen-
trations varied by the time of day the urine
sample was collected (Table 2). Creatinine-
standardized BPA concentrations decreased
Figure 1. Distribution of prenatal BPA (A),
creatinine-standardized BPA (B), and creatinine
concentrations (C) during the latter two-thirds of
pregnancy. Blue dots represent median values,
black and white hatch marks the 25th and 75th per-
centiles, and whiskers the 5th and 95th percentiles.
10.00
8.00
6.00
4.00
2.00
0
10.00
8.00
6.00
4.00
2.00
0
300.0
250.0
200.0
150.0
100.0
50.0
0
16 week
(n = 386)
26 week
(n = 370)
Birth
(n = 344)
Prenatal BPA (ng/mL)
Creatinine-standardized BPA
(µg BPA/g creatinine)
Creatinine concentration (mg/dL)
2.0
2.0
2.0
1.7
111.9
88.2
75.7
1.8
1.3
Table 1. Proportion of variability in serial urinary BPA concentrations attributed to within-woman and
between-woman variation.
a
Components of variance
Outcome in mixed model Between-woman (SE) Within-woman (SE) ICC
b
Unstandardized BPA concentrations
16 and 26 weeks 0.06 (0.01) 0.15 (0.01) 0.28
26 weeks and birth 0.05 (0.01) 0.15 (0.01) 0.26
16 weeks, 26 weeks, and birth 0.05 (0.01) 0.15 (0.01) 0.25
Creatinine-standardized BPA concentrations
16 and 26 weeks 0.01 (0.01) 0.11 (0.01) 0.11
26 weeks and birth 0.01 (0.01) 0.10 (0.01) 0.12
16 weeks, 26 weeks, and birth 0.01 (0.00) 0.11 (0.01) 0.10
Creatinine concentrations
16 and 26 weeks 0.06 (0.01) 0.06 (0.00) 0.49
26 weeks and birth 0.03 (0.01) 0.08 (0.01) 0.30
16 weeks, 26 weeks, and birth 0.04 (0.01) 0.08 (0.00) 0.35
a
Includes only women who have all three urinary BPA measurements (n = 332).
b
Computed by dividing the between-
woman variation by the total variation (between-woman plus within-woman).
Table 2. GM mean urinary BPA and creatinine concentrations during pregnancy according to the time of
urine collection and fasting time.
Variable
n
16 weeks
n
26 weeks
BPA (μg/L)
GM (GSE)
Creatinine
(mg/dL)
GM (GSE)
Creatinine-standardized
BPA (μg/mg)
GM (GSE)
Time of day
0700–0859 19 32 1.8 (1.2) 91.6 (1.1) 2.1 (1.1)
0900–1059 90 116 1.7 (1.1) 90.3 (1.1) 1.9 (1.1)
1100–1259 84 48 1.5 (1.1) 94.0 (1.1) 1.7 (1.1)
1300–1459 73 81 2.0 (1.1) 95.0 (1.1) 2.2 (1.1)
1500–1659 66 56 1.9 (1.1) 79.8 (1.1) 2.5 (1.1)
1700–1900 27 5 2.1 (1.2) 94.6 (1.1) 2.3 (1.2)
Fasting time
0 to < 2 hr 51 47 1.7 (1.7) 85.7 (1.1) 2.1 (1.1)
2 to < 4 hr 83 90 1.6 (1.6) 83.8 (1.1) 2.1 (1.1)
4 to < 6 hr 131 107 1.7 (1.7) 86.9 (1.1) 2.1 (1.1)
6 to < 12 hr 45 30 2.9 (2.9) 130.6 (1.1) 2.1 (1.1)
12 to 24 hr 22 26 1.9 (1.9) 104.7 (1.1) 1.8 (1.1)
Log
10
-transformed urinary BPA, creatinine, or creatinine-standardized BPA concentrations at 16 and 26 weeks of gesta-
tion are the outcome in a linear mixed model.
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across the morning hours, reaching a nadir of
1.7 μg/g between 1100 and 1259 hours, and
increased in the afternoon, reaching a peak
of 2.5 μg/g between 1500 and 1659 hours.
Urinary creatinine concentrations were rel-
atively stable in the early morning hours,
decreased between 1500 and 1659 hours, and
increased again between 1700 and 1900 hours.
Urinary BPA concentrations did not
vary by most demographic factors, except for
higher concentrations among women with
lower education (≤ 12 years) compared with
women with higher education (> 12 years;
Table 3). In contrast, BPA concentrations
varied by occupation. Prenatal urinary BPA
concentrations were highest among women
who reported being cashiers (GM = 2.8 μg/g;
GSE = 1.1) and lowest among women who
reported working in teaching (GM = 1.8
μg/g; GSE = 1.1) and industrial (GM = 1.2
μg/g; GSE = 1.2) occupations.
Frequency of canned vegetable consump-
tion was positively associated with urinary BPA
concentrations (Table 4). Strict vegetarians had
lower urinary BPA concentrations compared
with nonvegetarians, but estimates were based
on a sample of only five women. Creatinine-
standardized urinary BPA concentrations were
similar among women who reported fasting
for ≤ 12 hr but were lower among women who
had been fasting > 12 hr (Table 2).
Urinary BPA concentrations were posi-
tively associated with serum cotinine concen-
trations (Table 5). Urinary concentrations of
creatinine-standardized DEHP metabolite
concentrations and high-molecular-weight
phthalates were more positively associated
with urinary BPA concentrations than con-
centrations of metabolites of low-molec-
ular-weight phthalates (Table 5). Among
individual phthalate metabolites, mono-2-eth-
ylhexyl phthalate and mono-3-carboxypropyl
phthalate had the strongest associations with
creatinine-standardized urinary BPA concen-
trations [see Supplemental Material, Table 2
(doi:10.1289/ehp.1002366)].
Adjustment for socioeconomic factors
did not appreciably change the association
between dietary or environmental factors and
urinary BPA concentrations (Tables 4 and
5). However, adjustment did attenuate the
association between cashier work and urinary
BPA concentrations [ratio = 1.15; 95% confi-
dence interval (CI), 0.84–1.57]. is attenu-
ation was due primarily to confounding by
household income. Our results were not sub-
stantially different when we included log
10
-
transformed urinary creatinine concentrations
as a time-dependent covariate instead of
creatinine-standardized BPA concentrations.
Discussion
Serial urinary BPA concentrations were highly
variable, had a low degree of reproducibil-
ity, and varied according to time of day of
sample collection in the latter two-thirds of
pregnancy. Occupational, dietary, and envi-
ronmental factors were associated with urinary
BPA concentrations. Working as a cashier,
canned vegetables consumption, tobacco
smoke exposure, and exposure to high-mo-
lecular-weight phthalates were positively
associated with urinary BPA concentrations.
Differences in prenatal urinary BPA concen-
trations among categories of some of these fac-
tors were of similar magnitude to differences
in prenatal urinary BPA concentrations associ-
ated with externalizing behaviors in 2-year-old
females in a prior study (Braun et al. 2009).
Our reported ICC (0.11) for repeated
urinary BPA concentrations is lower than
previous reports. Nepomnaschy et al. (2009)
reported an ICC of 0.43 for three urinary
BPA concentrations taken at 14-day inter-
vals from 60 women of childbearing age.
Teitelbaum et al. (2008) reported ICCs of
0.220.35 for urinary BPA concentrations
among children 6–10 years of age over a
6-month period. Consistent with our find-
ings, Adibi et al. (2008) reported a decreased
ICC of urinary concentrations of phthalate
metabolites in pregnant women when they
adjusted for urine dilution using creatinine.
Variations in the ICCs across studies could be
related to differences in time between urine
collections or increased creatinine excretion
during pregnancy (Williams 2005).
Among demographic and perinatal fac-
tors, only maternal education was inversely
associated with creatinine-standardized uri-
nary BPA concentrations during pregnancy.
A study using data from the National Health
and Nutrition Examination Survey reported
that income was inversely associated with
urinary BPA concentrations (Calafat et al.
2008). However, two studies from China and
the Netherlands documented higher urinary
BPA concentrations among persons from
higher social class (He et al. 2009; Ye et al.
2008). Women from lower social classes in
the United States may consume more canned
foods or live in neighborhoods where more
canned fruits and vegetables are available than
do women with higher socioeconomic sta-
tus, but these relationships may be different
in other countries (Morland and Filomena
2007). Furthermore, associations between uri-
nary BPA concentrations and maternal educa-
tion may be influenced by shared covariance
with occupation or tobacco smoke exposure.
e frequency of consumption of canned
vegetables, but not canned fruit, was positively
Table 3. GM urinary BPA concentrations (µg BPA/g creatinine) according to demographic, perinatal, and
maternal factors.
a
Variable n (%)
b
GM (GSE) Ratio (95% CI)
Maternal race
Non-Hispanic white 237 (62) 2.1 (1.0) Reference
Non-Hispanic black 120 (31) 2.1 (1.0) 1.01 (0.90–1.14)
Other 26 (7) 1.9 (1.1) 0.94 (0.75–1.16)
Maternal education (years)
> 12 288 (75) 2.0 (1.0) Reference
12 54 (14) 2.3 (1.1) 1.14 (0.98–1.33)
< 12 41 (11) 2.4 (1.1) 1.19 (1.00–1.41)
Marital status
Married 248 (65) 2.0 (1.0) Reference
Unmarried 134 (35) 2.2 (1.0) 1.08 (0.96–1.20)
Maternal age (years)
25–34 230 (59) 2.0 (1.0) Reference
< 25 96 (25) 2.1 (1.1) 1.05 (0.92–1.19)
> 35 62 (16) 2.0 (1.1) 0.97 (0.84–1.12)
Income (per year)
> $80,000 103 (28) 2.0 (1.1) Reference
$40,000 to < $80,000 120 (32) 2.0 (1.0) 1.04 (0.91–1.19)
$20,000 to < $40,000 65 (17) 2.0 (1.1) 1.02 (0.86–1.20)
< $20,000 87 (23) 2.2 (1.1) 1.13 (0.97–1.31)
Depression Score at 20 weeks
Minimal (< 13) 290 (78) 2.1 (1.0) Reference
Moderate (13–19) 54 (14) 2.1 (1.1) 1.01 (0.86–1.18)
Severe (> 19) 30 (8) 1.9 (1.1) 0.90 (0.74–1.09)
Parity
0 171 (44) 2.1 (1.0) Reference
1 123 (32) 2.0 (1.0) 0.97 (0.86–1.09)
> 1 92 (24) 2.1 (1.1) 0.98 (0.86–1.12)
Maternal IQ (per 10 points) 318 0.97 (0.93–1.01)
Child sex
Female 208 (54) 2.1 (1.0) Reference
Male 180 (46) 2.0 (1.0) 0.96 (0.86–1.06)
a
Ratios are the exponentiated beta coefficients from a linear mixed model with 16-week, 26-week, and birth creatinine-
standardized BPA measurements as the outcome. Ratios represent the multiplicative difference in creatinine-standardized
urinary BPA concentrations from the reference category. Each predictor is run in a separate model.
b
At 16-week visit.
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associated with urinary BPA concentrations.
We are not aware of any prior studies docu-
menting this association, but this finding is not
surprising because BPA can migrate from con-
sumer goods into food and has been detected
in canned foods (Cao et al. 2010; Kang and
Kondo 2002; omson and Grounds 2005).
A recent risk assessment suggests that canned
vegetables contribute 1040% of the daily
BPA intake, whereas canned fruits contrib-
ute 36% (von Goetz et al. 2010). e rela-
tive contribution of canned vegetables to total
BPA dose may vary according to the canning
process, food variety, type of resin used, and,
as shown here, frequency of consumption.
Dietary patterns such as vegetarianism may
influence BPA exposure, as suggested by the
different concentrations among strict, partial,
and nonvegetarians. However, we had a small
number of women following a vegetarian diet,
and the higher exposure among partial veg-
etarians is inconsistent with the lower concen-
tration among strict vegetarians.
Compared with other occupations, cashiers
had the highest urinary BPA concentrations.
Most carbonless paper receipts used in conve-
nience and grocery stores contain BPA, which
could be dermally absorbed, orally ingested,
or inhaled (vom Saal and Myers 2008).
ese results should be interpreted cautiously
because estimates from cashiers were based on
17 women and were attenuated with adjust-
ment for socioeconomic factors. Additional
studies should validate our findings and, if they
are validated, determine the primary route of
exposure and if personal protective equipment
(e.g., gloves) could prevent exposure.
Two common environmental exposures,
phthalates and tobacco smoke, were positively
associated with urinary BPA concentrations.
Women with secondhand or active tobacco
smoke exposure had urinary BPA concentra-
tions about 20% higher than women with
no tobacco smoke exposure. is finding is
consistent with a prior study reporting higher
urinary BPA concentrations among self-
reported smokers (He et al. 2009). Inhaled
and exhaled tobacco smoke may be a source
of BPA because BPA comprises 25% of the
weight of some cigarette filters (Jackson and
Darnell 1985). Although socioeconomic fac-
tors may be partly responsible for the asso-
ciation between serum cotinine and urinary
BPA concentrations, our estimates were not
attenuated after adjustment for socioeconomic
factors. Shared sources of BPA and high-mo-
lecular-weight phthalates, including DEHP,
may be responsible for the positive correlation
between urinary BPA and phthalate metabo-
lite concentrations. ese phthalates and BPA
may be used in the same products (e.g., food
packaging), whereas low-molecular-weight
phthalates are used in cosmetics and beauty
products (NRC 2008 ). Future studies should
Table 4. GM urinary BPA concentrations (µg BPA/g creatinine) according to dietary and occupational factors.
a
Variable n (%)
b
GM (GSE) Unadjusted ratio (95% CI) Adjusted ratio (95% CI)
c
Frequency of fish consumption
Not at all 57 (15) 2.1 (1.1) Reference Reference
< Once/month 113 (30) 2.1 (1.0) 1.01 (0.86–1.18) 1.03 (0.88–1.20)
1–3 times/month 131 (34) 2.0 (1.0) 0.94 (0.80–1.10) 0.97 (0.83–1.13)
Weekly or more 77 (19) 2.1 (1.1) 1.00 (0.84–1.20) 1.04 (0.87–1.24)
Frequency of canned fruit consumption
Not at all 45 (12) 2.0 (1.1) Reference Reference
< Once/month 55 (14) 2.0 (1.1) 1.04 (0.86–1.26) 1.04 (0.85–1.26)
1–3 times/month 91 (24) 2.0 (1.1) 1.03 (0.86–1.22) 1.01 (0.85–1.21)
1–3 times/week 96 (25) 2.1 (1.1) 1.05 (0.89–1.25) 1.05 (0.88–1.25)
4–6 times/week 50 (13) 2.2 (1.1) 1.13 (0.92–1.39) 1.13 (0.92–1.39)
≥ Once/day 45 (12) 2.2 (1.1) 1.09 (0.89–1.34) 1.08 (0.88–1.33)
Frequency of canned vegetable consumption
Not at all 17 (4) 1.6 (1.1) Reference Reference
< Once/month 30 (8) 2.0 (1.1) 1.24 (0.90–1.69) 1.42 (1.03–1.97)
1–3 times/month 58 (15) 2.1 (1.1) 1.29 (0.97–1.71) 1.44 (1.07–1.93)
1–3 times/week 133 (35) 2.0 (1.0) 1.22 (0.93–1.59) 1.38 (1.04–1.83)
4–6 times/week 88 (23) 2.2 (1.1) 1.38 (1.05–1.82) 1.56 (1.17–2.09)
≥ Once/day 56 (15) 2.3 (1.1) 1.39 (1.04–1.86) 1.52 (1.13–2.06)
Frequency of fresh fruit and vegetable consumption
> Once/day 77 (20) 2.0 (1.0) Reference Reference
About once a day 73 (19) 1.7 (1.2) 0.84 (0.57–1.22) 1.02 (0.88–1.19)
4–6 times/week 104 (27) 2.2 (1.1) 1.09 (0.94–1.25) 1.07 (0.93–1.23)
1–3 times/week 83 (22) 2.0 (1.1) 0.97 (0.84–1.13) 0.96 (0.82–1.12)
1–3 times/month 39 (10) 2.2 (1.1) 1.09 (0.89–1.35) 1.03 (0.83–1.29)
< Once/month or not at all 6 (2) 2.4 (1.2) 1.22 (0.84–1.76) 1.19 (0.80–1.77)
Vegetarian
No 363 (95) 2.1 (1.0) Reference Reference
Partial 14 (4) 2.4 (1.1) 1.16 (0.88–1.52) 1.17 (0.89–1.55)
Strict 5 (1) 1.3 (1.3) 0.64 (0.41–1.00) 0.64 (0.40–1.00)
Organic fruit and vegetable consumption
None 225 (59) 2.1 (1.0) Reference Reference
Less than half 122 (32) 2.1 (1.1) 1.00 (0.89–1.12) 1.03 (0.91–1.16)
More than Half 32 (8) 2.0 (1.1) 0.99 (0.81–1.21) 0.98 (0.79–1.21)
Occupation
Unemployed 84 (22) 1.9 (1.1) Reference Reference
Cashier 17 (4) 2.8 (1.1) 1.32 (1.00–1.75) 1.15 (0.84–1.57)
Health care worker 57 (15) 2.1 (1.1) 1.00 (0.84–1.19) 1.04 (0.87–1.25)
Food service 16 (4) 2.1 (1.2) 1.01 (0.74–1.39) 1.02 (0.74–1.40)
Industrial worker 14 (4) 1.2 (1.2) 0.59 (0.40–0.87) 0.61 (0.41–0.90)
Teacher 37 (10) 1.8 (1.1) 0.84 (0.69–1.03) 0.89 (0.71–1.12)
Office worker 118 (31) 2.1 (1.0) 1.00 (0.87–1.15) 1.06 (0.91–1.24)
Sales or service worker 36 (9) 2.1 (1.1) 1.00 (0.82–1.21) 1.04 (0.85–1.28)
Other 2 (1) 1.2 (1.4) 0.59 (0.31–1.14) 0.60 (0.31–1.18)
a
Ratios are the exponentiated beta coefficients from a linear mixed model with 16-week, 26-week, and birth creatinine-
standardized BPA measurements as the outcome. Ratios represent the multiplicative difference in creatinine-standard-
ized urinary BPA concentrations from the reference category. Each predictor is run in a separate model.
b
At 16-week
visit.
c
Adjusted for maternal age, race, education, household income, and marital status.
Table 5. GM urinary BPA concentrations (µg BPA/g creatinine) by biomarkers of tobacco smoke and
phthalates exposure.
a
Variable n (%)
b
GM (GSE)
Unadjusted ratio
(95% CI)
Adjusted ratio
(95% CI)
c
Categorical serum cotinine concentrations
Unexposed (< 0.015 ng/mL) 112 (30) 1.9 (1.0) Reference Reference
Secondhand smoker (0.015–3 ng/mL) 221 (59) 2.2 (1.0) 1.17 (1.05–1.30) 1.19 (1.05–1.35)
Active smoker (> 3 ng/mL) 43 (11) 2.3 (1.1) 1.23 (1.03–1.47) 1.27 (1.01–1.58)
Phthalates
d
Low-molecular-weight phthalates 387 1.07 (0.97–1.18) 1.06 (0.96–1.18)
High-molecular-weight phthalates 387 1.28 (1.16–1.40) 1.26 (1.15–1.39)
DEHP metabolites 387 1.24 (1.14–1.36) 1.24 (1.13–1.35)
a
Ratios are the exponentiated beta coefficients from a linear mixed model with 16-week, 26-week, and birth creatinine-
standardized BPA measurements as the outcome. Ratios represent the multiplicative difference in creatinine-standard-
ized urinary BPA concentrations from the reference category. Each predictor is run in a separate model.
b
At 16-week
visit.
c
Adjusted for maternal age, race, education, household income, and marital status.
d
Low-molecular-weight
phthalates include MBP (monobutyl phthalate), MEP (monoethyl phthalate), and MIBP (monoisobutyl phthalate). High-
molecular-weight phthalates include MBzP (monobenzyl phthalate), MEHP (mono-2-ethylhexyl phthalate), MECPP
[mono-(2-ethyl-5-carboxypentyl) phthalate], MEHHP [mono-(2-ethyl-5-hydroxylhexyl) phthalate], MEOHP [mono-(2-
ethyl-5-oxohexyl) phthalate], and MCPP (mono-3-carboxypropyl phthalate). DEHP metabolites include MECPP, MEHHP,
MEOHP, and MEHP. All phthalates concentrations are creatinine standardized.
Page 5
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examine other potential sources of BPA and
phthalate exposure.
ese results have several implications for
etiological studies of prenatal BPA exposure
and health outcomes. Because urinary BPA
concentrations varied according to the time of
sample collection and fasting time, investiga-
tors should attempt to account for the inher-
ent variability of urinary BPA concentrations.
Future studies could use several approaches to
reduce or adjust for this variability: a) stan-
dardize the timing of urine collection, b) col-
lect multiple urine samples over the course of
1 days, or c) record and adjust for the time
of day of sample collection. e low ICC for
urinary BPA concentrations during pregnancy
suggests that a single spot urine collection
has the potential to misclassify exposure.
Moreover, using mean BPA concentrations
taken over the course of pregnancy may also
result in exposure misclassification in studies
attempting to identify time-sensitive windows
of development to BPA exposure.
Studies examining the health impacts
of prenatal BPA, phthalates, or tobacco
smoke exposures may need to adjust for one
another, because these pollutants frequency
occur together and have been implicated in
the etiology of childhood health outcomes
(DiFranza et al. 2004; Engel et al. 2010;
Wakschlag et al. 2002). In addition, future
etiological studies should examine the joint
effects of BPA, phthalates, and tobacco smoke
exposure, because these common toxicants
may occur together and act synergistically on
certain health outcomes.
There are several limitations to this
study. First, our results and others demon-
strate that a single spot urine measurement
has the potential to misclassify BPA expo-
sure (Mahalingaiah et al. 2008). Second,
many of our predictor variables were mea-
sured imperfectly, and we were missing some
potentially important sources of exposure.
We did not have women’s occupations clas-
sified by an industrial hygienist, which likely
resulted in misclassification of this variable.
Furthermore, the dietary variables used in
this study were not originally designed to
assess BPA exposure, but rather pesticide and
mercury exposure. In addition, urinary BPA
concentrations likely reflect exposure over
the last day, whereas dietary questionnaire
data reflected consumption over a longer time
(weeks). ird, we did not collect informa-
tion regarding other potential sources of BPA
exposure including plastic or paper/cardboard
use, packaged food consumption, medical
devices, medications, dental treatment, or
amount and type (tap, bottled, or well) of
water consumed during pregnancy (Carwile
et al. 2009; Gehring et al. 2004).
An additional limitation is the imper-
fect correction for urine dilution using
urinary creatinine concentrations. Pregnancy-
induced changes in creatinine metabolism
and excretion may occur independently of
BPA metabolism and excretion, so the degree
of correction of urine dilution may change
throughout pregnancy. Our results suggest
that creatinine concentrations become pro-
gressively lower and more variable throughout
pregnancy. Other measures of urine dilution,
such as specific gravity, have been used and
should be compared with creatinine patterns
in pregnancy in future studies (Mahalingaiah
et al. 2008).
A single spot urine sample may misclas-
sify BPA exposure because of variability of
urinary BPA concentrations over the course
of pregnancy and day. Future studies should
standardize or adjust for the timing of urine
collection or measure BPA at multiple times
to minimize biases due to within-day and
within-woman variability of urinary BPA and
creatinine concentrations. Our data suggest
that there are numerous and potentially mod-
ifiable sources of environmental BPA expo-
sure related to canned vegetable consumption,
occupation, and other environmental expo-
sures. Additional research is needed to con-
firm these findings and determine what other
environmental sources contribute to human
BPA exposure.
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Page 7
    • "One of the limitations of this study is the short-term nature of the BPA exposure measurement. It is well established that urinary BPA concentrations vary widely throughout the day and it is difficult to estimate long-term exposure from one spot urinary measurement that reflects only recent exposure (Braun et al., 2011; Ye et al., 2011 ). However, we expect this exposure misclassification to be non-differential, biasing our results towards the null. "
    [Show abstract] [Hide abstract] ABSTRACT: Bisphenol A (BPA) is a chemical used extensively worldwide in the manufacture of plastic polymers. The environmental obesogen hypothesis suggests that early life exposure to endocrine disrupting chemicals such as BPA may increase the risk for wt gain later in childhood but few prospective epidemiological studies have investigated this relationship.
    No preview · Article · Apr 2016 · Environmental Research
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    • "Therefore, single concentrations obtained from a sufficient number of persons may adequately describe the study population's average concentration [11, 15@BULLET] even when considerable variability exists at the individual level. For example, reliability in urinary concentrations of bisphenol A (BPA), a high production volume chemical used in the manufacture of many consumer products, is rather poor (i.e., relatively low ICCs) [28, 29, 40, 48, 57, 58]. Yet, despite this variability, biomonitoring concentrations may identify activities (e.g., consumption of canned soup, handling of thermal receipt paper, consumption of water from certain plastic containers) that result in considerable increases in urinary concentrations of BPA [59][60][61][62] . "
    [Show abstract] [Hide abstract] ABSTRACT: In environmental epidemiology, use of biomonitoring (i.e., trace-level measurement of environmental chemicals or their metabolites in biospecimens) for exposure assessment has increased considerably in past decades. Although exposure biomarkers should reflect a person’s exposure to the target chemicals (or their precursors) within a specific timeframe, timing, duration, and intensity of exposures are normally unknown and likely vary within the study period. Therefore, evaluating exposure beyond a single time point may require collecting more than one biospecimen. Of note, collection and sample processing procedures will impact integrity and usefulness of biospecimens. All of the above factors are fundamental to properly interpret biomonitoring data. We will discuss the relevance of the exposure assessment study protocol design to (a) ensure that biomonitoring specimens reflect the intended exposure, (b) consider the temporal variability of concentrations of the target biomarkers, and (c) facilitate the evaluation of accuracy and comparability of biomonitoring results among studies.
    Preview · Article · Mar 2016
    • "Braun et al. (2011) "
    [Show abstract] [Hide abstract] ABSTRACT: Bisphenol A (BPA) is an endocrine and metabolic disruptor commonly employed as a color developer in thermal papers. Consequently, BPA derived from thermal papers has been considered an important source of exposure for humans, since this chemical may migrate from paper to skin upon contact. Further, due to recent restrictions on BPA use in some countries, it has been replaced by a new analogue, bisphenol S (BPS). The aim of the present study was to determine levels of BPA and BPS in 190 different thermal receipts, randomly collected from different locations in São Paulo State, Brazil, including receipts from supermarkets, general and fast-food restaurants, gas stations, bus and airplane tickets, and credit card and bank accounts. BPA and/or BPS were detected in 98% of samples at concentrations ranging from below the quantification limit to 4.3% (mg/100 mg paper). The obtained values were higher than amounts previously reported in other countries. The estimated daily intake through dermal absorption from handling of thermal receipt papers was estimated on the basis of concentrations and frequencies of handling of papers by humans in both the general population and occupationally exposed individuals. Fifth percentile, median, and 95th percentile daily intakes by the general population were 0.44, 1.42, and 2 μg/d, respectively, whereas the corresponding values for occupationally exposed population are 21.8, 71 and 101 μg/d. The potential adverse consequences of elevated occupational exposure are currently being examined.
    No preview · Article · Sep 2015 · Journal of Toxicology and Environmental Health Part A
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