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Prolonged exposure to bisphenol A from single dermal contact events Jiaying Liu, and Jonathan W. Martin Environ. Sci. Technol., Just Accepted Manuscript • DOI: 10.1021/acs.est.7b03093 • Publication Date (Web): 31 Jul 2017 Downloaded from http://pubs.acs.org on August 1, 2017
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Environmental Science & Technology
Prolonged exposure to bisphenol A from single dermal contact events
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Jiaying Liu Ɨ, Jonathan W. Martin*, Ɨ, ǂ
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Ɨ
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Alberta, Edmonton, Alberta, Canada
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ǂ
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Sweden
Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of
Department of Environmental Science and Analytical Chemistry, Stockholm University, Stockholm,
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Corresponding Author * Jonathan W. Martin; Phone: +46 072 146 2773; E-mail:
[email protected] 11 Notes The authors declare they have no competing financial interests. 12 13
Key Words
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bisphenol A, dermal exposure, dietary exposure, pharmacokinetics, metabolism
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ABBREVIATIONS: BPA
bisphenol A
BPA-d16
deuterated bisphenol A
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bisphenol-A-(diphenyl-13C12)
BPA-glucuronide
mono-β-D-glucuronide
BPS
bisphenol S
GM
geometric mean
CI
confidence interval
Cmax
maximum concentration
Tmax
sampling time of maximum concentration
P
participant
hrs
hours
LOD
limits of detection
TDI
tolerable daily Intake
EDI
estimated daily intake
MADL
maximum allowable dose level
US
United States
EPA
US Environmental Protection Agency
EFSA
European Food Safety Authority
NHANES
National Health and Nutrition Examination Survey
OEHHA
Office of Environmental Health Hazard Assessment
C12-BPA
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ABSTRACT: Bisphenol A (BPA) is an endocrine disruptor frequently detected in human biofluids. Dermal
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absorption of BPA from thermal paper receipts occurs but BPA pharmacokinetics following dermal
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exposure is not understood. To compare the pharmacokinetics of dermal and dietary BPA exposure, six
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male participants handled simulated receipts containing relevant levels of BPA (isotope-labeled BPA-d16)
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for 5 min, followed by hand-washing 2 hrs later. Urine (0-48 hrs) and serum (0-7.5 hrs) were monitored
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for free and total BPA-d16. One week later, participants returned for a dietary administration with
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monitoring as above. One participant repeated the dermal administration with extended monitoring of
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urine (9 days) and serum (2 days). After dietary exposure, urine total BPA-d16 peaked within 5 hrs and
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quickly cleared within 24 hrs. After dermal exposure, cumulative excretion increased linearly for 2 days,
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and half the participants still had detectable urinary total BPA-d16 after 1 week. The participant
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repeating the dermal exposure had detectable BPA-d16 in urine for 9 days, showed linear cumulative
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excretion over 5 days, and had detectable free BPA-d16 in serum. Proportions of free BPA-d16 in urine
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following dermal exposure (0.71% - 8.3% of total BPA-d16) were generally higher than following the
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dietary exposure (0.29% - 1.4%). Compared to dietary BPA exposure, dermal absorption of BPA leads to
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prolonged exposure and may lead to higher proportions of unconjugated BPA in systemic circulation.
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INTRODUCTION Bisphenol A (BPA) is a high production volume chemical
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used for polycarbonate plastic
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manufacturing, or in epoxy resin linings of food and beverage containers, and as a developer in thermal
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paper, such as for shopping receipts and luggage tags at airports. BPA now occurs ubiquitously in the
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environment 2 and human populations are widely exposed to low levels.3 According to national surveys
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in Canada (2012-2013), approximately 90% of the general population have detectable urinary BPA (>0.2
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ng total BPA/mL).4
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The toxicological hazard of BPA includes its activity as an endocrine disruptor.5 In low-dose animal
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studies, effects have been shown on brain function, development and behavior.6,7 Epidemiology studies
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have shown associations between gestational BPA exposure and anxious, depressive and hyperactive
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behaviors in children,8,9 but results are not consistent between studies.10 Difficulties in these population-
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level studies include representative measures of exposure, and the within-person variability of urinary
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BPA.11,12
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Diet has been regarded as the major human exposure pathway to BPA.13,14 Toxicokinetic studies in
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humans show that after oral absorption, free BPA – regarded as the toxic form of BPA – is efficiently
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metabolized by first-pass metabolism to nontoxic metabolites which are quickly eliminated through
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urine.15,16 The biological half-life of BPA following oral exposure is therefore less than 6 hrs.15,16 However,
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Stahlhut et al. found that urinary BPA concentrations did not decline rapidly with fasting time in 1,469
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participants from the 2003-2004 National Health and Nutrition Examination Survey (NHANES).17 These
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findings suggested substantial non-dietary BPA exposure pathways in the general US population, and
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the authors moreover suggested that: (i) non-food sources need to be identified, and (ii) that risk
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assessments based on assumptions of a predominant oral exposure pathway may need
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reconsideration.17
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Dermal exposure to BPA may be an important non-dietary exposure pathway in some people. High
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levels of BPA and related alternative chemicals (i.e. bisphenol S (BPS)) have been widely detected in
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paper products such as thermal paper receipts and paper currencies.
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assessment from the European Food Safety Authority (EFSA) concluded that thermal paper was the
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second most important source of BPA in all population groups above 3 years of age, contributing 7-15%
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of total average exposure.21 Data from NHANES supports the link between occupational exposure from
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thermal paper and increased urinary BPA excretion.22 Higher urinary BPA levels in cashiers was also
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observed previously,23,24 and recently the dermal contact route was estimated to contribute 52-84% of
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total BPA exposure for cashiers.25 Occupational exposure to BPA by the dermal route was also suspected
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as the cause of elevated (up to 2 orders of magnitude) urinary total BPA in thermal paper and paint
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product manufacturing.26
1,18–20
The latest exposure
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The pharmacokinetics of BPA in humans following dermal exposure are not clear. In vivo animal
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dermal absorption studies and in vitro skin penetration experiments have been used to extrapolate to
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humans, but with varying results. For example, one study concluded that dermal absorption of BPA was
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likely negligible as only 8.6% of the dose penetrated through the human skin after 24 hrs incubation,27
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while another study using a higher dose in human skin suggested that dermal BPA exposure may in fact
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be toxicologically relevant.28 Similarly, one study with human skin samples concluded that absorbed BPA
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was not biotransformed (i.e. 0.99 for urine and serum.
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Data Analysis. Data analysis was performed with Stata 12.0, and the level of significance for all of
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statistical tests was p
