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A review of dietary and non-dietary exposure to

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Food and Chemical Toxicology 50 (2012) 3725–3740

Contents lists available at SciVerse ScienceDirect

Food and Chemical Toxicology

journal homepage: www.elsevier.com/locate/foodchemtox

Review

A review of dietary and non-dietary exposure to bisphenol-A

Tinne Geens a,k, Dominique Aerts b,k, Carl Berthot c,k, Jean-Pierre Bourguignon d,k, Leo Goeyens e,k,
Philippe Lecomte f,k, Guy Maghuin-Rogister g,k, Anne-Madeleine Pironnet h,k, Luc Pussemier i,k,
Marie-Louise Scippo g,k, Joris Van Loco j,k, Adrian Covaci a,k,⇑
a
Toxicological Centre, University of Antwerp, Universiteitsplein 1, Antwerp, Belgium
b
Federal Public Service of Health, Food Chain Safety and Environment, Place Victor Horta 40/10, 1060 Brussels, Belgium
c
DG Animals, Plants and Food, FPS Health, Food Chain Safety and Environment, Eurostation, Place Victor Horta 40/10, 1060 Brussels, Belgium
d
Department of Pediatrics, University of Liège, CHU ND des Bruyères, B4030 Chénée, Belgium
e
Analytical and Environmental Chemistry, University of Brussels, Pleinlaan 2, 1050 Brussels, Belgium
f
Center for Education and Research on Macromolecules (CERM), University of Liege, B6, Sart-Tilman, Belgium
g
Department of Food Sciences, University of Liege, BatB43b, Sart Tilman, Belgium
h
Superior Health Council, Rue de l’Autonomie 4, 1070 Brussels, Belgium
i
Veterinary and Agrochemical Research Center (CODA-CERVA), Leuvensesteenweg 17, 3080 Tervuren, Belgium
j
Scientific Institute of Public Health, Department of Food, Medicines and Consumer Safety, Rue Juliette Wytsmanstraat 14, 1050 Brussels, Belgium
k
Belgian Superior Health Council, FPS Health, Food Chain Safety and Environment, Rue de l’Autonomie 4, 1070 Brussels, Belgium

a r t i c l e i n f o a b s t r a c t

Article history: Due to the large number of applications of bisphenol-A (BPA), the human exposure routes are multiple.
Received 1 April 2012 We aimed to review shortly the food and non-food sources of BPA, and to evaluate their contribution to
Accepted 28 July 2012 the human exposure. Food sources discussed here include epoxy resins, polycarbonate and other appli-
Available online 4 August 2012
cations, such as paperboard and polyvinylchloride materials. Among the non-food sources, exposures
through dust, thermal paper, dental materials, and medical devices were summarized. Based on the avail-
Keywords: able data for these exposure sources, it was concluded that the exposure to BPA from non-food sources is
Bisphenol-A
generally lower than that from exposure from food by at least one order of magnitude for most studied
Review
Human exposure
subgroups. The use of urinary concentrations from biomonitoring studies was evaluated and the back-
Food sources calculation of BPA intake seems reliable for the overall exposure assessment. In general, the total expo-
Non-food sources sure to BPA is several orders of magnitude lower than the current tolerable daily intake of 50 lg/kg bw/
Alternatives day. Finally, the paper concludes with some critical remarks and recommendations on future human
exposure studies to BPA.
Ó 2012 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3726
1.1. Properties and applications of bisphenol-A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3726
1.2. Toxicity of bisphenol-A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3727
1.3. European legislation regarding migration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3727
1.4. Aims of the review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3727
2. Food exposure to bisphenol-A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3727
2.1. Epoxy resins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3728
2.1.1. Migration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3728
2.1.2. Levels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3728
2.2. Polycarbonate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3729
2.2.1. Migration and hydrolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3729
2.2.2. Levels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3730
2.3. Other food contact applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3730

⇑ Corresponding author. Address: Toxicological Center, University of Antwerp,

Universiteitsplein 1, 2610 Wilrijk, Belgium. Tel.: +32 3 265 2498; fax: +32 3 265
2722.
E-mail address: adrian.covaci@ua.ac.be (A. Covaci).

0278-6915/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.fct.2012.07.059
 Author's personal copy

3726 T. Geens et al. / Food and Chemical Toxicology 50 (2012) 3725–3740

2.4. Intake estimation from food exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3730

3. Non-food sources to bisphenol-A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3731
3.1. Dust . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3731
3.2. Thermal paper . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3731
3.3. Other types of papers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3732
3.4. Dental materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3732
3.5. Medical devices and healthcare applications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3732
3.6. Other non-food sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3733
4. Toxicokinetics and metabolism of bisphenol-A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3733
5. Human biomonitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3733
5.1. Urinary BPA (ng/mL)  urinary output (mL/day)/body weight (kg) = ng BPA/kg/day . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3735
6. Overall estimation of exposure to bisphenol-A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3735
7. Epidemiological studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3736
8. General discussion and recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3736
Conflict of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3737
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3737
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3737

1. Introduction currently used in materials intended to come into contact with

1.1. Properties and applications of bisphenol-A
Bisphenol-A (BPA) [4,40 -dihydroxy-2,2-diphenylpropane, CAS
80-05-7] (Fig. 1A) is an industrial chemical synthesized by conden-
sation of two phenol groups and one acetone molecule. While BPA
was first synthesized in 1891, its estrogenic properties have been
hypothesized in the 1930s (Dodds and Lawson, 1938). Since 1940,
BPA was predominantly used as (1) a monomer in the manufactur-
ing of polymers such as polycarbonate, PC (Fig. 1B), epoxy resins
(Fig. 1C), polysulfone, or polyacrylate, (2) as an antioxidant and
inhibitor of end of polymerization in polyvinyl chloride plastics
(PVC) and (3) as a precursor for the synthesis of the flame retardant
tetrabromobisphenol-A (Geens et al., 2011). Polycarbonate is
food, e.g., reusable plastic bottles, feeding-bottles, plates, goblets,
cups, microwave ovenware, storage containers, etc., whereas the
epoxy resins are used for internal coating of food and beverage cans
(EFSA, 2006). However, only 3% of the produced polycarbonate, as
well as 10% of the epoxy resins, is used in materials intended to
come into contact with foodstuffs (Plastics Europe, 2007). There
are several other uses of polycarbonates, epoxy resins, polysulfone,
and polyacrylates such as sunglasses, building materials, CD-ROM,
medical devices, dental materials, etc. BPA is also used in thermal
paper (Geens et al., 2011). For a review of all applications of poly-
carbonate and epoxy resins, see ANSES (2011a).
Besides BPA, many bisphenol analogues can be obtained by con-
densation of a ketone or an aldehyde with phenols with either var-
iation in the carbonyl derivative or in the substituents on the

Fig. 1. A. Chemical structure of bisphenol-A; B. Synthesis of polycarbonate from bisphenol-A; C. Chemical structure of an epoxy resin; D. Chemical structure of bisphenol-F;
and E. Chemical structure of bisphenol-S.
 Author's personal copy
T. Geens et al. / Food and Chemical Toxicology 50 (2012) 3725–3740
aromatic ring. Although a large number of compounds can be ob-
tained by this route, many are too expensive for an industrial
application. The toxicities of most of these compounds are not
known, especially when synthesized in research laboratories. For
instance, a systematic research in SciFinder allows finding 28746
compounds inserting the OH–Ar–CH2–Ar–OH subunit. Among
them, (only) 1010 are commercially available. From these bisphe-
nols, bisphenol-F (BPF) (bis(4-hydroxyphenyl)-methane) (Fig. 1D)
is increasingly used, because of its lower viscosity and better resis-
tance against solvents than the BPA epoxy resin (Danzl et al., 2009).
Bisphenol-S (BPS) (4,4-dihydroxy-phenylsulfone) (Fig. 1E) can also
be used as a monomer in the plastic industry.
1.2. Toxicity of bisphenol-A
Since BPA showed estrogenic properties in a large number of
studies (reviewed by Chapin et al. (2008)), it is described as an
endocrine disruptor chemical (EDC). It is in particular able to bind
and activate the human estrogen receptor (the estrogenic proper-
ties of BPA were already shown in 1938 by Dodds and Lawson),
but with a capacity 1000–5000 times less than the endogenous
17-b-oestradiol (FASFC, 2009; Roy et al., 2009). BPF and BPS also
display estrogenic properties (Chen et al., 2002). Moreover, BPA
has been shown to interact with other endocrine receptors, e.g.,
thyroid hormone receptors, peroxysome proliferator-activated
receptor gamma (Diamanti-Kandarakis et al., 2009). BPA was clas-
sified as a reproductive toxic substance of category 3 as an alarm-
ing substance for the human fertility (INSERM, 2010).
The EFSA published a first risk assessment on BPA in 2006,
based on a tolerable daily intake (TDI) of 50 lg/kg body weight/
day, and concluded that human exposure through food is lower
than the TDI, even for babies and young children (EFSA, 2006). In
the light of new published data, the EFSA has concluded in 2008
and 2010 that there was no need to decrease the TDI (EFSA,
2008, 2010). However, until now, only the exposure to BPA
through food has been documented. Yet, as indicated above, BPA
can be found in a large number of non-food applications, which
necessitates a newer look at the BPA exposure routes posing health
risks.
Several scientists, including the experts from the French Agency
for Food, Environmental, and Occupational Health and Safety
(ANSES), did not agree with the use of TDI for risk assessments
on EDCs (ANSES, 2010; vom Saal and Hughes, 2005). Their opinion
is based on the effects of EDCs observed at low doses, non-mono-
tonic dose–response curves, as well as on effects occurring from
very specific windows of exposure (in particular, early in utero
exposure) (Diamanti-Kandarakis et al., 2009).
The toxicity of BPA has once more been reviewed in a recent
ANSES report (ANSES, 2011b), with a special focus on effects of
BPA at low dose, e.g. a dose below the NOAEL of 5 mg/kg body
weight/day from which the current TDI-value of 50 lg/kg body
weight/day has been derived by EFSA (2006). The French experts
have reviewed the state-of-the-art regarding effects of BPA on
the male and female reproductive system, on brain and behavior,
on metabolism and cardiovascular system, on thyroid, on the im-
mune system, on intestine, prostate and breast (ANSES, 2011b).
In general, it is not possible to conclude definitively on the effects
on humans, because of heterogeneous and sometimes poor epide-
miological data. ‘‘Suspected’’ negative effects in humans are de-
scribed on the maturation of oocytes, the cardiovascular system
and the development of diabetes. The feasibility of human epide-
miological studies, however, remains questionable for several rea-
sons. BPA cannot be isolated from the mixture of EDCs to which
humans are exposed to. There is virtually no ‘‘control’’ or unex-
posed population due to ubiquity of BPA. There could be an interval
of several decades between the fetal and early postnatal critical
3727
windows of exposure and delayed BPA effects, such as metabolic
syndrome in adulthood. Finally, due to the short half-life of BPA,
the urinary levels provide only an estimate of exposure during
the few previous days (Dekant and Völkel, 2008). In animals, pre-
natal or post-natal exposures to low doses of BPA have an effect
on different physiological systems. These systems are the male
and female reproductive systems (increase of ovarian cysts, hyper-
plasia of the endometrium, precocious puberty, and in adults, de-
crease of the sperm production), the brain (neurogenesis and
synaptogenesis), the lipid metabolism and sensitivity to insulin,
the immune system, the breast development (hyperplasia) (ANSES,
2011b).
1.3. European legislation regarding migration
Since chemical substances can be released from plastic materi-
als and articles intended to come into contact with food (Barnes,
2006), migration limits are mentioned in the European Legislation
for all permitted substances in plastic materials. For BPA, the spe-
cific migration limit (SML) is fixed to 0.6 mg/kg food since 2004
and has not been changed, except for baby bottles, for which BPA
is banned in EU since 2011. BPS has a SML of 0.05 mg/kg food
(EC, 2011a), while BPF is not allowed in plastic materials intended
to come in contact with food by European law. For plastic materials
in contact with food, SMLs have been fixed assuming that 1 kg of
food is consumed daily by a person of 60 kg for a lifetime exposure.
For the control of the migration of these chemical substances
from the material to the food, it is necessary to distinguish be-
tween materials and articles that are already in contact with food
and those which are not yet. For both groups, guidelines are given
in the Regulation (EU) N°10/2011 (EC, 2011a).
Briefly, for materials in contact with food, the migration is mea-
sured in food. The contact between the material and the food has to
be ended before the expiration date. The foodstuff has to be pre-
pared in accordance with cooking instructions on the package.
The parts of food not intended for human consumption are then re-
moved and discarded, and the remainder food is homogenized and
analyzed for the presence of the compound of interest, to check the
compliance with the SML.
For materials and articles not in contact with food, a series of
test media are used, simulating the transfer of substances from
the packaging material to food. These media should represent the
main physicochemical properties of food. When using these simu-
lants, the standardized time and temperature of the assay must, as
far as possible, reflect the potential migration of the target sub-
stance in the food (Grob et al., 2006). These simulants are then ana-
lyzed for the presence of the compound of interest, to check the
compliance with the SML.
1.4. Aims of the review
The aims of the present review were to summarize the recent
literature (mostly after 2009 and until December 2011) regarding
the food and non-food sources of BPA (with emphasis on the lat-
ter). The compiled information was further used to evaluate the
contribution of various exposure sources to the total human expo-
sure. Finally, the authors tried to identify the gaps and needs that
are required for a valuable risk assessment of BPA.
2. Food exposure to bisphenol-A
Generally, food, and especially canned food, is considered as the
predominant source of BPA. Contamination of food with BPA is
usually caused by contact with food packaging materials contain-
ing epoxy resins and PC. Epoxy resins, as well as PVC organosols
 Author's personal copy

3728 T. Geens et al. / Food and Chemical Toxicology 50 (2012) 3725–3740

Table 1
Overview of BPA in canned food samples and canned beverages.

Country Sample size Detection freq. (%) Range Refs.

Canned food (ng/g)
US 78 91 <2–730 Noonan et al. (2011)
US 97 59 <0.2–65 Schecter et al. (2010)
Canada 78 99 <0.6–534 Cao et al. (2010)
Japan 48 92 <1–842 Sajiki et al. (2007)
Korea 61 64 <3–136 Lim et al. (2009a)
Belgium 21 100 0.2–169 Geens et al. (2010)
Beverage cans (ng/mL)
Spain 11 64 <0.05–0.61 Gallart-Ayala et al. (2010)
Canada 69 100 0.03–4.5 Cao et al. (2009a)
Belgium 45 91 <0.02–8.1 Geens et al. (2010)
Portugal 30 70 <0.01–4.7 Cunha et al. (2011)

are often used as internal coatings of cans to prevent direct contact
between the metal can walls and the food or beverage, and to pro-
tect the cans from rusting and corrosion (Cao et al., 2011; Goodson
et al., 2002). These protective coatings are also used on metal lids
for foods in glass jars (Cao et al., 2011). Due to an incomplete poly-
merization process, residues of BPA monomer in PC containers and
coatings can migrate into foods, especially during storage and pro-
cessing at elevated temperatures (Cao et al., 2011; Geens et al.,
2010; Noonan et al., 2011).
2.1. Epoxy resins
2.1.1. Migration
The influence of damage, storage conditions and heating on the
migration of BPA was studied by Goodson et al. (2004). Empty
epoxy phenolic coated cans were filled with four foods and 10%
ethanol as food simulant. Filled cans of each food type or simulant
were sealed and processed using usual conditions. Cans were
stored at 5, 20 or 30 °C and analyzed at different time intervals
(up to 9 months). Half of the cans were dented in order to evaluate
the effect of damage on the migration. Between 80–100% of free
BPA already present as free monomer in the coating had migrated
into the food during sterilization. Extended storage at various tem-
peratures or damaging of the can did not change the migrated BPA
levels (Goodson et al., 2004).
The effect of heat treatment on the migration of BPA was ob-
served by Munguia-Lopez et al. (2002, 2005) and Munguia-Lopez
and Soto-Valdez (2001). Most of the BPA migrated during heat
treatment (121 °C and 90 min) using an aqueous food simulant, a
fatty food simulant, jalapeño peppers or tuna fish (Munguia-Lopez
and Soto-Valdez, 2001; Munguia-Lopez et al., 2005). For jalapeño
peppers, which are more acidic than tuna, sterilization for 9 min
at 100 °C had a minimal effect on the migration of BPA, both for
the aqueous food stimulant and the acid food simulant. Due to
the milder heat processing conditions for jalapeño peppers
compared to tuna, part of the residual BPA remained on the coating
after processing. Afterwards, BPA increased during storage time,
especially during the first 40 days (Munguia-Lopez and Soto-
Valdez, 2001; Munguia-Lopez et al., 2002). Kang and Kondo
(2003) reported that the temperature has more influence on the
migration of BPA from an epoxy can coating in water than the heat-
ing time.
2.1.2. Levels
The dominant contribution of canned food to the overall expo-
sure to BPA was confirmed in several intervention studies. In a
study of Carwile et al. (2011), the urine of 75 volunteers who con-
sumed one serving of canned soup during five days showed a spec-
tacular increase of 1200% in urinary BPA concentrations compared
to urine concentrations following the consumption of fresh food
during five days. Braun et al. (2011a) observed higher BPA concen-
trations in urine of pregnant women who consumed at least once a
day canned vegetables compared to those who did not consume
canned vegetables. In a dietary intervention study where volun-
teers were subjected to a 3-day ‘‘fresh food’’ diet that was not
canned or packaged in plastic, Rudel et al. (2011) observed a 66%
decrease in urinary BPA concentration compared to the concentra-
tions prior to the intervention.
Several studies worldwide determined BPA in canned food,
including US (Noonan et al., 2011; Schecter et al., 2010), Canada
(Cao et al., 2010, 2011), Japan (Sajiki et al., 2007), Korea (Lim
et al., 2009a), New Zealand (Thomson and Grounds, 2005), UK
(Goodson et al., 2002) and Belgium (Geens et al., 2010). The sample
size, detection frequency and concentration range are summarized
in Table 1.
In all studies, large variations in BPA concentrations were found
between different products of the same food type, but also be-
tween different lots of the same product. Noonan et al. (2011) ob-
served a 100-fold difference (2.6–310 ng/g) between the minimal
and maximal BPA values in peas, while green beans had a 30-fold
difference (22–730 ng/g) between brands. Geens et al. (2010) ob-
served also a large variation (1.2–82 ng/g) between five brands of
corn. While some studies reported tuna fish to have the highest
contamination of BPA (Cao et al., 2010; Lim et al., 2009a), in other
studies, tuna samples had the lowest concentrations of BPA (Noo-
nan et al., 2011). Such variation is probably due to the different
proprietary composition of the coatings from can manufacturers
and to the different can styles or coating choices for various prod-
ucts used by the food producers (Noonan et al., 2011). Unfortu-
nately, these differences have been less investigated and are not
subject of any regulation. In contrast, the lot-to-lot variability for
samples of the same food type and brand was smaller than the var-
iability between and within foods (Noonan et al., 2011). In food
where both a solid portion and liquid supernatant are present,
BPA intends to partition into the solid part (Geens et al., 2010; Noo-
nan et al., 2011). Yet, the BPA concentration in the solid part
seemed to be dependent on the type of food. While for corn (Yos-
hida et al., 2001), green beans and peas (Noonan et al., 2011), BPA
was partitioned in the solid part of the food, BPA remained in the
aqueous solution for peeled oranges (Yoshida et al., 2001). It is
not clear whether the migration of BPA into the solid portion could
be explained by the absorption to fibers, by the fat content of the
food or by other mechanisms (Yoshida et al., 2001).
Similar to food cans, BPA can also migrate from beverage cans.
The most relevant studies are summarized in Table 1. In contrast to
canned food samples, BPA concentrations in canned beverages
showed a more narrow range. For the Canadian and the Belgian
study, respectively 85% and 75% of the samples had concentrations
below 1 ng/mL (Cao et al., 2009a; Geens et al., 2010). The lower
concentrations found in beverages can possibly be explained by
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T. Geens et al. / Food and Chemical Toxicology 50 (2012) 3725–3740
the differences in the can type, can coating and sterilization condi-
tions between food and beverages (Geens et al., 2010). Besides BPA,
Cunha et al. (2011) detected BPB in 50% of the canned beverages
(range 0.07–0.16 ng/mL). Gallart-Ayala et al. (2010)) could not de-
tect BPB, Bisphenol E or BPS in any soft drinks, but they could de-
tect BPF in two samples (0.14 and 0.22 ng/mL).
Next to the use of epoxy resins as protective layer of food and
beverage cans, epoxy resins can also be used as internal coating
on metal lids for food in glass jars, a source scarcely investigated
until now. Whilst the contact between the lid and the food is rare
when compared to contact between food and can, such contact can
sometimes occur. It is caused by transportation of the cans, by
shaking, as well as by accidental storage in a non-vertical position
(Cao et al., 2009b). Therefore, Cao et al. (2009b) determined BPA in
99 baby food products of seven Canadian brands in glass jars with
metal lids. BPA was detected in 85 samples (86%), from which 69
samples (70%) had levels of less than 1 ng/g with an overall average
concentration of 1.1 ng/g.
Cao et al. (2011) investigated 154 food composite samples from
the 2008 total diet study in Quebec City, Canada. BPA was detected
in 55 of the 154 food samples (36%) tested. High concentrations of
BPA were found mostly in the composite canned foods, with the
highest BPA level being observed in canned fish (106 ng/g).
BPA was also detected in some foods that are nor canned, nor
packaged in jars, such as yeast, baking powder, cheese, bread, cere-
als, and fast foods. The source of BPA in these food items was sug-
gested to be the packaging paper, especially plastic packaging film
in PVC, or BPA could be introduced during the production process if
equipments or containers with epoxy coating or plastic parts have
been used. BPA contamination of fast food could be due to the
wrapping paper or BPA may already have been present in the
ingredients used to prepare the fast food. BPA intakes from 19
out of 55 samples in which BPA was detected, accounted for more
than 95% of the total dietary estimated intake in Canada, and most
of the 19 samples were either canned or in jars. The remaining 36
samples in which BPA was detected, contributed with only 5% to
the estimated dietary intake. Therefore, the intake of BPA from
non-canned foods was estimated to be low (Cao et al., 2011).
2.2. Polycarbonate
2.2.1. Migration and hydrolysis
On January 28, 2011 the European Commission (EC) published a
Directive that PC may not be used any longer for baby bottles (EC,
2011b). Additionally the EC issued the regulation No. 321/2011
(EC, 2011c), indicating that baby bottles made of PC may not be
produced any more from the 1st of May 2011 and not be put on
the market from the 1st of June 2011. Although similar bans on
the production, import and sale of PC baby bottles have been intro-
duced in Canada and several US states, exposure through PC can
Table 2
Migration of BPA from polycarbonate baby bottles. BPA has a specific migration limit of 600 lg/kg (EC, 2011a).
Reference Highest BPA
concentration (lg/L)
De Coensel et al. (2009) 0.30
Ehlert et al. (2008) 0.73
Le et al. (2008) 1.33
7.67
Kubwabo et al. (2009) 6.5
Maragou et al. (2008) 14.3
Nam et al. (2010) 18.5
Biedermann-Brem and Grob, 2009 137
Biedermann-Brem et al. (2008) 500
Cao and Corriveau (2008b) 521
3729
still be of relevant in other countries and by the use of ‘‘old’’ PC
baby bottles or other PC food contact applications.
BPA can leach from PC into liquids through two different pro-
cesses: diffusion of residual BPA present in PC after manufacturing
and hydrolysis/aminolysis of the polymer (Aschberger et al., 2010).
Experiments using official simulants usually report the migration
of BPA which is, even under rather drastic conditions (such as 1 h
at 100 °C), typically in the range of 0.1–1 lg/L (Biedermann-Brem
and Grob, 2009). For a usual migration behavior, a decrease is ob-
served after continued use. The low migration from PC baby bottles
into food simulants was confirmed in several recent studies (Bie-
dermann-Brem et al., 2008; Santillana et al., 2011; Simoneau
et al., 2011). Most of the baby bottles showed migration below
the detection limit of 0.1 lg/kg (Simoneau et al., 2011) or
<0.4 lg/L from new baby bottles and after 30 washing cycles (Bie-
dermann-Brem et al., 2008).
Increased migration of BPA from PC baby bottles was observed
for higher temperatures and longer testing periods (Biedermann-
Brem and Grob, 2009; De Coensel et al., 2009; Kubwabo et al.,
2009; Le et al., 2008; Lim et al., 2009b; Nam et al., 2010). An in-
crease in the BPA migration rate up to 55-fold during exposure of
the PC to boiling water (100 °C) compared to water at 20 °C was
observed (Le et al., 2008). Microwave heating did not seem to have
an effect, and migration was mainly temperature dependent (Ehl-
ert et al., 2008; De Coensel et al., 2009).
Contrary to the usual migration behavior, where a decrease in
migration or a constant migration was observed after repeated
use of the PC bottles, several studies reported an increase in the
BPA migration over time, due to hydrolysis of the PC (Brede et al.,
2003). Biedermann-Brem and Grob (2009) revealed that the higher
concentrations can be due to aging that increases the wettability of
the bottle wall, which in turn promotes the adherence of water to
the bottle wall. Drying in the dish washing machine causes dis-
solved salts to reconcentrate on the bottle wall and to be baked onto
the PC at elevated temperature. They may promote the degradation
of the polymer and the release of BPA, especially when alkali chem-
icals are deposited, such as washing solutions (Biedermann-Brem
and Grob, 2009). Rinsing of bottles before the drying step could
overcome this ‘‘baking’’ and, thus, the release of high BPA concen-
trations. However, preparing a drink according to the usual recom-
mendations results usually in a BPA release <0.5 lg/L (Biedermann-
Brem and Grob, 2009). Similarly, aminolysis of PC was observed
after contact with two biogenic amines (1,4-diaminobutane and tri-
methylamine) (Maia et al., 2010) or after contact with alkaline
detergent solutions (Maia et al., 2009).
The highest migration or release of BPA from PC bottles was
observed under conditions which are not likely to occur under nor-
mal use, i.e. at elevated temperature or contact time (Table 2). De
Coensel et al. (2009) reported only very low migration levels of
BPA (6–13 ng/L) when the bottles are used under normal conditions
Relevant conditions
60 s and 1000 W (65 °C)
3 cycles of 100 °C in microwave oven (3 min)
7 days at room temperature 24 h at 100 °C
Migration in water (24 h at 60 °C)
20 cycles of cleaning-sterilization-filling with boiling water and left at room
temperature for 45 min
100 times for 30 min in steam bath at 95 °C
Previously boiled tap water (pH 9.5) in microwave for 10 min Release of BPA
A slanted position of the bottle in the dishwasher, hindering the detergent solution to
run off and rinsing before drying
Heating water at 70 °C for 6 days
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3730 T. Geens et al. / Food and Chemical Toxicology 50 (2012) 3725–3740

(20 s at 1000 W in the microwave oven at 37 °C). During normal Table 3

use, the released BPA quantities are negligible (maximum 2 ng Estimated intake of BPA in children and adults.

per feeding) and far below the TDI value. Age category Estimation through dietary
exposure (lg/kg bw/day)
2.2.2. Levels Children
The effect of migration of BPA from PC drinking bottles was EFSA (2006) Infants (3–12 month) 0.2–13
illustrated in an intervention study where volunteers were re- Children 5.3
Health Canada (2008) 1–4 years 0.26–1.98
quested to consume all cold beverages from PC drinking bottles 5–11 years 0.15–1.28
during one week. An increase of 69% in urinary BPA concentrations Chapin et al. (2008) Infants-bottle fed 1–11
was observed after one week compared with urinary levels ob- Infants-breast fed 0.2–1
tained after a wash-out period of one week, where no use of PC- Children (6–12 m) 1.7–13
Children (2–6 years) 0.04–14.7
bottles was allowed (Carwile et al., 2009).
FDA (2009) 0–12 m 0.3–0.6
In Canada, Cao and Corriveau (2008a) could not detect BPA in 51 12–24 m 0.5–1.1
non-PC bottled water products (detection limit 0.5 ng/mL). How- >2 years 0.1–0.3
ever, BPA was detected in 4 out of 5 bottled water in PC products ANSES (2010) Infants (<36 m) 0.1–0.5
(<0.5–1.4 ng/mL). In a 5-week experiment, levels of 8.8 and Children (3–17 years) 0.2–0.6
WHO (2010) Infants 0–6 m 0.01–4.5
6.5 ng/mL were measured in two bottles. Therefore the authors
Infants 6–36 m 0.01–3.0
warn for higher BPA levels that could be detected in some PC bot- Children > 3 years 0.2–1.9
tled water products due to the accidental or careless exposure to
Adults
heat (e.g. sun) for extended periods of time during storage and EFSA (2006) Adults 1.5
transportation (Cao and Corriveau, 2008a). In a Greek study (Amir- Health Canada (2008) 12–19 years 0.09–0.73
idou and Voutsa, 2011), BPA was determined in water from five >20 years 0.07–0.60
Chapin et al. (2008) Adults 0.008–1.5
PET-bottles with a median concentration of 4.6 ng/L. Water from
FDA (2009) >2 years 0.1–0.3
one PC bottle contained 112 ng/L which increased to 170 ng/L after ANSES (2010) Adults 0.1–0.3
30 days of sun exposure. The maximum daily intake through bot- WHO (2010) Adults 0.4–4.2
tled water, assuming a daily intake of 2 L water was estimated to
be merely 0.006 lg/kg bw/day.
PC is used also for water pipes and epoxy-phenolic resins are in the EU today, however PVC materials which were produced prior
widely used as a surface-coating on residential drinking water to this action may still be in use.
storage tanks (Bae et al., 2002). Li et al. (2010) detected BPA in
tap water from six different drinking water plants in Guangzhou, 2.4. Intake estimation from food exposure
China in concentrations between 15 and 317 ng/L. Daily mean in-
take of BPA of adults was estimated to be 148 ng/day from drinking The estimated intake through food by different national and
2 L of tap water. Yet, more data are needed to quantify the possible international agencies is summarized in Table 3. These estimations
dietary exposure to BPA via drinking water (EFSA, 2006). are sometimes based on highest observed concentrations or migra-
tion values or are derived using 95th percentile estimates of con-
2.3. Other food contact applications sumption. The highest estimated BPA dietary exposures were for
0–6 months of age infants who were exclusively fed on canned li-
BPA is rarely measured in non-canned foods, thus, the contribu- quid infant formula using PC bottles. In this case, sources of BPA
tion from the non-canned foods to the overall dietary intake of BPA exposure include migration from both the formula packaging and
is not well known (Cao et al., 2011). Geens et al. (2010) determined from the PC bottle (WHO, 2010). However, in all studies, even
BPA in 16 solid food samples packaged in glass, plastic, paper and the worst case, estimates stay below the current TDI.
laminated paperboard/polyethylene carton (Tetra Pak). BPA could Mean exposures for infants fed with infant formula using PC
be detected in all food samples in a concentration range of 0.1– bottles were 2.0–2.4 lg/kg bw per day, with 95th percentile expo-
1.28 ng/g with an average concentration of 0.46 ng/g. This mean sures ranging from 2.7 to 4.5 lg/kg bw per day (WHO, 2010). In-
concentration is about 100 times lower than the average concen- fants who were either fed with formula from non-PC bottles or
tration in similar food types, packaged in cans which were exam- exclusively breastfed had substantially lower estimated mean
ined in the same study. BPA could not be detected above the BPA exposures (0.01 lg/kg bw per day from powdered formula,
quantification limit of 0.02 ng/mL in five beverages packaged in 0.5 lg/kg bw per day from canned liquid formula and 0.3 lg/kg
PET and Tetra Pak (Geens et al., 2010). Also Sajiki et al. (2007) bw per day from breast milk), compared to those exclusively fed
found considerably lower concentrations of BPA in 15 out of 23 on infant formula using PC bottles. Once solid foods are introduced
food samples (range <1–14 ng/g) packaged in plastic and in 4 out (at 6–36 months), exposure to BPA decreases relative to body
of 16 food samples (<0.2–1 ng/g) packaged in paper, compared weight.
with the food samples packaged in cans. For children above 3 years, the highest mean BPA exposure was
No BPA was observed to migrate from EcoCare™ lined alumin- estimated to be 0.7 lg/kg bw per day, with a maximum up to
ium, stainless steel, or Tritan™ plastic water bottles during an 1.9 lg/kg bw per day (Table 3). Depending on the extent of pack-
incubation period of 120 h (detection limit 0.05 ng/mL). In con- aged food (canned) in the diet, adult BPA exposures were compara-
trast, detectable amount of BPA were leached from PC bottles ble to those for children above 3 years: a highest mean exposure of
and epoxy-lined aluminum bottles (Cooper et al., 2011). 1.4 lg/kg bw per day, with a maximum exposure up to 4.2 lg/
BPA was found to be present in commercial PVC cling films and kg bw per day (Table 3). It was assumed that all exposure to BPA
plastic sheeting bags available on the market in Spain and migra- from the diet was in the form of unconjugated BPA. These calcu-
tion studies suggested it would migrate into food (Lopez-Cervantes lated international dietary exposure estimates (WHO, 2010) are
and Paseiro-Losada, 2003). Yet, the former application of BPA in the consistent, but slightly higher than those obtained using data re-
PVC polymerisation process by some EU manufacturers appeared ported from comparable national surveys.
to have ceased (EFSA, 2006). Therefore, based on this information, In Canada, dietary intake estimates of BPA by different age-sex
no BPA exposure from food contact uses of PVC should be expected groups were made based on the concentrations found in the food
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T. Geens et al. / Food and Chemical Toxicology 50 (2012) 3725–3740
composites combined with data of the 24-h diet recall from the
Nutrition Canada Survey (Cao et al., 2011). Dietary intakes of BPA
were low for all age–sex groups, with 0.17–0.33 lg/kg bw/day for
infants, 0.082–0.23 lg/kg bw/day for children aged from 1 to
19 years, and 0.052–0.081 lg/kg bw/day for adults. Where Cao
et al. (2011) included both canned and non-canned food in their
estimation, other studies made intake estimations only based on
canned food and only for adults. For example, Thomson and
Grounds (2005) estimated an intake of 0.008 lg/kg bw/day in
New Zealand, Geens et al. (2010) found 0.015 lg/kg bw/day in Bel-
gium, while Lim et al. (2009a) estimated an intake of 0.030 lg/
kg bw/day in Korea. Mariscal-Arcas et al. (2009) included, next to
canned food, also migration from polycarbonate tableware and
estimated an intake of 0.030 lg/kg bw/day.
Overall, intake of BPA from food is well below the current TDI of
50 lg/kg bw/day. However, more knowledge is necessary on the ef-
fect of food processing, preparation and cooking procedures on BPA
levels in the final cooked foods. Since PC tools and containers with
epoxy coatings may be used during food preparation for cooking,
BPA could be introduced into the final cooked foods due to migra-
tion from PC and coatings (Cao et al., 2011).
3. Non-food sources to bisphenol-A
3.1. Dust
Because of the low vapor pressure of BPA and, therefore, its low
concentrations in air, inhalation of BPA from air is unlikely to be an
important exposure source (Dekant and Völkel, 2008).
Ingestion of house dust has been demonstrated to be an impor-
tant exposure pathway to several contaminants in young children
due to their more frequent hand-to-mouth contact and larger in-
take of dust compared to adults (Jones-Otazo et al., 2005; Calafat
et al., 2008). Due to the wide use of BPA in a variety of indoor appli-
cations and consumer products, such as epoxy-based floorings,
adhesives, paints, electronic equipments, and printed circuit
boards, volatilization and/or leaching of BPA from these products
are a source of contamination of indoor dust (Loganathan and Kan-
nan, 2011). Consequently, BPA was detected in indoor dust with a
high detection frequency and ranged widely up to 10,000 ng/g
dust (Geens et al., 2009). Median concentrations of BPA in various
studies ranged between 422 and 1460 ng/g in US (Völkel et al.,
2008; Geens et al., 2009; Loganathan and Kannan, 2011).
Higher concentrations were observed in laboratories (Logana-
than and Kannan, 2011) and offices (Geens et al., 2009) most prob-
ably due to the use of more electric and electronic equipment and
furniture than in homes. Contrary, lower concentrations were ob-
served in dust samples from daycare centers in US (Rudel et al.,
2003; Wilson et al., 2007). Toddlers have a more frequent
hand-to-mouth contact and will therefore have a higher dust in-
take. Although the amount of dust daily ingested is uncertain,
the intake of BPA from dust ingestion is low and was estimated
Fig. 2. Structure of thermal paper (from Lassen et al., 2011).
3731
to be less than 0.006 lg/kg bw/day for toddlers and less than
0.0005 lg/kg bw/day for adults (Geens et al., 2009; Loganathan
and Kannan, 2011). The contribution of dust to the total intake of
BPA is therefore probably less than 1–5%.
3.2. Thermal paper
BPA is used as an additive in thermal paper made for printers
relying on the thermal transfer technology, whereby BPA is used
as a color developer. In these papers, one side is coated with a pow-
dery layer of BPA (Lassen et al., 2011). Under heat or pressure, BPA
reacts with the thermal paper dye to produce a color-developing
complex (Fig. 2). This technique is mainly used in lightweight
printing devices, such as cash registers or credit card terminals.
Many people come in contact with thermal paper on a daily ba-
sis. The presence of BPA in thermal paper may contribute to the
overall exposure by oral intake (direct contact of unwashed hands
with food or mouth) or by dermal exposure. Moreover, thermal pa-
per is also a major source of contamination of recycled paper with
BPA (Takahashi et al., 2002; Zalko et al., 2011). Braun et al. (2011a)
already reported the higher levels of urinary BPA of cashiers, which
might have a higher skin contact with BPA-containing thermal pa-
per compared to the general population. Worldwide, BPA was de-
tected in thermal paper (Denmark, Sweden, Switzerland, US)
with a detection frequency between 44% and 100%. BPA concentra-
tions in the thermal paper were up to 2.3% (Biedermann et al.,
2010; EWG, 2010; Lassen et al., 2011; Liao and Kannan, 2011a;
Mendum et al., 2011; Östberg and Noaksson, 2010) (Table 4). Liao
and Kannan (2011a) could not detect BPA in all seven thermal pa-
pers from Japan, most probably due to the phase-out of BPA in
thermal paper in Japan in 2001.
The amount of BPA transferred to the skin after holding such a
paper for 5 s was between 0.2 and 6 lg BPA with an average of
1.1 lg per finger (Biedermann et al., 2010). If the fingers were
wet or very greasy, the transferred amount was about 10 times
higher. Repeated contact with fresh recorder paper did not give a
significant increase in BPA on the skin, indicating equilibrium be-
tween the BPA concentration in the paper and on the surface layer
of the skin. Biedermann et al. (2010) could not conclude whether
BPA passed through the skin, but found that BPA can enter the skin
to such a depth that it can no longer be washed off. For normal
skin, a potential exposure of 71 lg/day was estimated when touch-
ing the most contaminated paper frequently during a working day
of 10 h (Biedermann et al., 2010). Mielke et al. (2011) predicted
that dermal exposure can have a relevant contribution to the total
BPA exposure.
Based on the worst case dermal exposure of 71 lg/day (0.97 lg/
kg bw/day) determined by Biedermann et al. (2010), and on the ex-
tent of dermal absorption recently published, (10% (EU, 2008), 13%
(Mørck et al., 2010), 46% (Zalko et al., 2011) and 60% (Biedermann
et al., 2010)), dermal exposure can result in an uptake between
7.1 lg/day (0.1 lg/kg bw/day) and 42.6 lg/day (0.58 lg/kg bw/
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3732 T. Geens et al. / Food and Chemical Toxicology 50 (2012) 3725–3740

Table 4
Overview of BPA in thermal paper.

Country Sample size Detection freq. (%) % (g BPA/100 g paper) Refs.

Denmark 12 65 n.d–1.7 Lassen et al. (2011)
Sweden 16 100 0.6–2.3 Östberg and Noaksson (2010)
Switzerland 13 85 <5.105–1.7 Biedermann et al. (2010)
US 36 44 0.8–2.8 EWG (2010)
US, Boston 10 80 <0.09–1.7 Mendum et al. (2011)
US, Japan, Korea, Vietnam 103 94 <1.107–1.4 Liao and Kannan (2011a)

day). Similarly, a Danish study reported a realistic worst case sce- it might be present as an impurity from the synthesis process (Fle-
nario which resulted in a daily uptake of 240 lg BPA (Lassen et al., isch et al., 2010; Fung et al., 2000; Nathanson et al., 1997; Van
2011). In this scenario, it is assumed that the receipts are touched Landuyt et al., 2011). BPA can also leach into the saliva as a result
with humid fingers and that 50% of the quantity left on the skin is of bis-DMA hydrolysis through esterases present in the saliva (re-
absorbed (Lassen et al., 2011). However, the actual exposure of the viewed by Van Landuyt et al., 2011).
general consumer will mostly be lower. Several in vivo studies measured BPA in saliva after sealant
placement. Salivary BPA levels decreased over time; the highest
exposures were measured immediately after sealant placement.
3.3. Other types of papers
BPA exposure after sealant placement is most likely an acute event,
yet none of the studies could detect BPA 3 h after sealant place-
Thermal paper can also be the primary cause of the contamina-
ment. Possibly, analytical methods used in these studies were
tion of paper currencies. Paper currencies from 21 countries were
not sensitive enough to detect extremely low doses of BPA that
analyzed for BPA (Liao and Kannan, 2011b). BPA was found in all pa-
chronically leach from the resin over longer periods of time. Hence,
per currencies at concentrations ranging up to 82.7 lg/g. The con-
chronic low-dose BPA exposure after dental sealant placement
tamination of the paper currencies can probably be explained by
cannot be ruled out (Fleisch et al., 2010).
frequent contact with thermal paper in a wallet. Because the BPA
The relevance of the released amounts of BPA from dental mate-
used in thermal paper is not covalently bound, it can be easily trans-
rials in vitro has recently been reviewed in a meta-analysis done by
ferred from thermal receipt papers to other objects, including paper
Van Landuyt et al. (2011). It was computed that one full crown res-
currencies. BPA may be also present also in the production process
toration of a molar may release 13 lg BPA in the average case sce-
of currency paper. The estimated daily intake of BPA through der-
nario or 30 mg BPA in the worst case scenario, both after 24 h. The
mal absorption from handling paper currencies was on the order
average BPA release (0.2 lg/kg body weight/day for a person
of a few nano grams per day (Liao and Kannan, 2011b).
weighting 60 kg) is 250-fold lower than the TDI of 50 lg/kg body
It has been estimated that approximately 30% of thermal papers
weight/day, but 10-fold higher than the TDI in the worst case sce-
enter recycling streams of municipal wastepaper. Recycling of
nario. This indicates that the 24-h release of BPA from dental mate-
thermal paper can introduce BPA into the paper production cycle
rials is relevant in patients with multiple or large restorations and
(Liao and Kannan, 2011a). Vinggaard et al. (2000) showed that,
that resin-based dental materials may represent a relevant source
while virgin paper contained no or negligible amounts of BPA, lev-
of BPA in such patients (Van Landuyt et al., 2011). Sealants pro-
els in the recycled paper ranged from 0.6 to 24 lg BPA/g of kitchen
duced by different manufacturers released markedly different
roll. Similarly, a Japanese study examined paperboard and papers
amounts of BPA (Vandenberg et al., 2007).
used for food packaging. In the virgin paper and paperboard, con-
Von Goetz et al. (2010) estimated the chronic exposure after
centrations between (0.034–0.36 lg/g) were detected, while the
dental surgery to be 215 ng BPA/day. This estimation was based
concentrations in recycled paper and paperboard were >10-fold
on the measurement of 0.3 ng/mL in the saliva of one out of 21
higher (range 0.19–26 lg/g) (Ozaki et al., 2004). More than 80%
individuals at 120 h after surgery. It probably represents a worst-
of others papers, including flyers, tickets, newspapers, toilet paper,
case scenario for chronic exposure, since concentrations in saliva
contained BPA in concentrations ranging up to 14.4 lg/g. Thus, BPA
will decrease further over time and only one individual had still
concentrations in ‘‘other’’ papers were 3–4 orders of magnitude
measurable concentrations after 120 h.
lower than in thermal paper, most probably due to the recycling
of thermal paper (Liao and Kannan, 2011a). The exposure to BPA
from other papers will have an insignificant contribution to the
3.5. Medical devices and healthcare applications
overall exposure. Liao and Kannan (2011a) made an assessment
through dermal exposure of BPA from thermal and ‘‘other’’ paper.
A small fraction of the BPA-based polymers polycarbonate and
The median dermal exposure to BPA of the general population
polysulfone is used in medical and healthcare applications such
was 17.4 ng/day, while this was 1303 ng/day for the occupationally
as PC eye lenses, tube connections, blood oxygenators, inhaler
exposed population. Thermal paper contributed for more than 98%
housing, and newborn incubators, as well as polysulfone surgical
to this value. Liao and Kannan (2011a) calculated that for an over-
trays, nebulizers, and humidifiers (Geens et al., 2011). BPA can also
all exposure to BPA of 1 lg/kg bw/day, paper could contribute 1.6–
leach into a drug formulation which most likely occurs with liquid
51% in an occupationally exposed population.
and suspension formulations that are packaged in PC container-
closures or metal canisters with epoxy lining (FDA, 2009).
3.4. Dental materials PVC, which may also contain BPA, is used in the manufacturing
of medical products, such as those found in the neonatal intensive
Dental composite resins consist of a mixture of co-monomers care units, including bags containing intravenous fluids and total
and are most commonly based on bisphenol-A glycidyl methacry- parenteral nutrition and tubing associated with their administra-
late (bis-GMA). In addition to bis-GMA, these resins contain other tion; nasogastric and enteral feeding tubes; and umbilical
monomers to modify the properties, e.g. bisphenol-A dimethacry- catheters. In a study of Calafat et al. (2009), BPA was analysed in
late (bis-DMA). Although BPA is not used itself in composite resins, urine from 42 low-birth-weight infants in neonatal intensive care
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T. Geens et al. / Food and Chemical Toxicology 50 (2012) 3725–3740
units using a large number of PVC-containing devices, such as
mechanical and high-frequency ventilation, surgery, and cardiac
catherization. Median concentrations of BPA in these premature in-
fants were one order of magnitude higher than the median concen-
tration and almost twice the 95th percentile of the general
population (children 6–11years who were examined as part of
the NHANES 2003–2004) (Calafat et al., 2009).
Hemodialysis patients can be exposed to substantial amounts of
BPA due to the use of PC as casing and the hollow-fibers’ hemodi-
alysis membrane often made of polysulfone. Moreover, the re-
leased BPA is directly introduced into the blood circulation.
Although not an exposure source for the general population,
hemodialysis may be an important contributor for this specific
group (Geens et al., 2011; Haishima et al., 2001; Yamasaki et al.,
2001). Almost no data exist to quantify the dose of BPA that treated
patients receive; further research is therefore highly necessary
(FDA, 2009).
3.6. Other non-food sources
In a Danish study, the migration from the shield and ring of
baby dummies was examined. These parts can be made of PC,
although it has been largely replaced by polypropylene and co-
polyester. Even when the shield and ring contained PC, migration
of BPA into sweat and saliva was low and the calculated exposure
to BPA in dummies was far below the BPA exposure from baby bot-
tles (Lassen et al., 2011).
4. Toxicokinetics and metabolism of bisphenol-A
The toxicokinetics of BPA has been studied in rodents, non-hu-
man primate and humans (Doerge et al., 2010a,b; Völkel et al.,
2002, 2005). After oral administration, BPA undergoes a rapid first
pass metabolism in the intestine and liver, being completely ab-
sorbed from the gastrointestinal tract. BPA is not extensively
metabolized via Phase I reactions, but it is rapidly conjugated with
glucuronic acid (Phase II metabolism) to the non-active BPA-glucu-
ronide in the gut wall and liver. Minor amounts of BPA might also
react with sulfate to form BPA-sulfate. The formation of BPA conju-
gates is considered a detoxification process (Matthews et al., 2001;
Snyder et al., 2000) and only the free BPA forms display estrogenic
activity (Matthews et al., 2001). The BPA conjugates formed in the
liver are delivered to the blood in humans to reach the kidney,
being further excreted in the urine with terminal half-lives of less
than 6 h (Völkel et al., 2002, 2005). The applied doses were com-
pletely recovered in urine; hence, BPA exposure can be estimated
from urinary levels (Völkel et al., 2002). BPA ingested by inhalation
or dermal contact does not undergo first pass effect and will there-
fore be eliminated at a slower rate.
In adult rhesus monkeys, the concentration–time profile after
oral administration of BPA was remarkably similar to humans, gi-
ven a similar dose (Doerge et al., 2010b). Minimal pharmacokinetic
differences were observed between neonatal and adult monkeys
for the free form of BPA, which was present in less than 1% of
the total circulating concentration of BPA (Doerge et al., 2010b).
In rodents, BPA-glucuronide is subject to enterohepatic recircula-
tion, which prolongs elimination processes, thereby increasing
internal exposures to BPA, and leads to extensive fecal excretion
(Pottenger et al., 2000). The absence of enterohepatic circulation
of BPA-glucuronide in humans is most likely due to a higher
threshold for biliary elimination as compared to rats.
Several tissues, including human liver and kidney, contain b-
glucuronidase in membranes of lysosomes and the endoplasmic
reticulum (Sperker et al., 1997). It has been suggested that b-glucu-
ronidase activity in tissues, especially placenta, could reverse the
3733
detoxification of BPA at the tissue level (Ginsberg and Rice,
2009). The experimental evidence to support this hypothesis is lar-
gely indirect and inconsistent with the rapid elimination of agly-
cone BPA from the circulation in adult non-human primates and
humans (Völkel et al., 2002). Also viable human skin explants effi-
ciently absorbs and metabolizes BPA. About 46% of the applied
dose of BPA was absorbed and largely transferred into BPA-glucu-
ronide and BPA-sulfate (Zalko et al., 2011).
5. Human biomonitoring
As a non-persistent chemical with an elimination half-life of a
few hours, the BPA concentrations in blood are lower than those
in urine and decrease quickly after the exposure (Needham and
Sexton, 2000). As a result, BPA will be non-detectable in a larger
proportion of blood samples with the current analytical technology
(WHO, 2010). Moreover, it is difficult to rule out contamination
with trace levels of free BPA during sample collection, storage
and analysis because of the ubiquitous presence of BPA in the envi-
ronment (WHO, 2010; Markham et al., 2010; Völkel et al., 2008).
Even detectable concentrations do not thus necessarily reflect
BPA exposures.
Since BPA is rapidly and almost completely excreted as BPA-con-
jugates, urine is the matrix of choice for biomonitoring. Long-term
daily intake of BPA leads to steady-state BPA concentrations in the
ng/mL range in human samples (Welshons et al., 2006). Urinary
concentrations of total (free plus conjugated) BPA have often been
used to evaluate exposure to BPA from all sources (Vandenberg
et al., 2010). Several biomonitoring studies have been conducted
in North America, Europe and Asia, revealing the worldwide expo-
sure to BPA. The most important studies are summarized in Table 5.
A study documenting measurable urinary BPA levels in Mexican
women provides preliminary evidence that pregnant women who
delivered prematurely (<37 weeks gestation) had higher urinary
concentrations of BPA compared to women delivering after
37 weeks (Cantonwine et al., 2010). The impact of gestational ver-
sus childhood BPA exposures is unclear. In a recent US study, ges-
tational BPA exposure affected behavioral and emotional
regulation domains at 3 years, especially among girls. These results
suggested that gestational BPA exposure might be associated with
anxious, depressive, and hyperactive behaviors related to impaired
behavioral regulation at 3 years (Braun et al., 2011b).
Two recent large-scale studies which included 2514 and 5476
participants were performed in the USA and Canada, respectively.
Exposure to BPA was ubiquitous with a detection frequency of
more than 90% in both studies (Calafat et al., 2008; Bushnik
et al., 2010). Also in seven Asian countries, BPA was detected in
94% of the samples (Zhang et al., 2011). In the US study, highest
urinary concentrations were detected in adolescents (12–19 years)
followed by children (6–11 years) and adults (>19 years). After
adjusting BPA levels for creatinine, children had the highest BPA
concentrations, followed by adolescents and adults (Calafat et al.,
2008). Also in the Canadian study (Bushnik et al., 2010), creatinine
adjusted BPA levels were higher in the youngest age category (6–
11years) than for the other age categories. In the GerES IV study
in Germany, children in the age category 3–5years had higher con-
centrations than the 6–8years; 9–11years; and 12–14years age
category (Becker et al., 2009). Vandenberg et al. (2010) also con-
cluded that there is an indication that young children are submit-
ted to the highest exposure risk.
For practical reasons, biomonitoring studies with urine samples
generally collect single spot urine samples instead of 24 h urine
samples. Because of BPA’s short elimination half-life, spot urine
samples primarily reflect the exposure that occurred within a rel-
atively short period before urine collection (Koch and Calafat,
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3734 T. Geens et al. / Food and Chemical Toxicology 50 (2012) 3725–3740

Table 5
Overview of the most recent worldwide biomonitoring studies in urine.

Country Population Concentrations Exposure Det. Freq. (%) Refs.

US 2514 (P6–P60 years) GM 2.6 ng/mL (2.6 lg/g cr) GM 0.047 lg/kg bw/day 93 Calafat et al.
314 (6–11 years) GM 3.6 ng/mL (4.3 lg/g cr) GM 0.065 lg/kg bw/day (2008) Lakind and
713 (12–19 years) GM 3.7 ng/mL (2.8 lg/g cr) GM 0.071 lg/kg bw/day Naiman (2008)
950 (20–59 years) GM 2.6 ng/mL (2.4 lg/g cr) GM 0.053 lg/kg bw/day (20–
537 (P60 years) GM 1.9 ng/mL (2.3 lg/g cr) 39 years)
GM 0.038 lg/kg bw/day (40–
59 years)
GM 0.034 lg/kg bw/day
US 394 adults GM 1.33 ng/mL (1.36 lg/g cr) GM 0.023 lg/kg bw/daya 95 Calafat et al.
(2005)
Canada 5476 6–79 years GM 1.16 ng/mL (1.40 lg/g cr) 91 Bushnik et al.
6–11 years GM 1.30 ng/mL (2.00 lg/g cr) GM 0.025 lg/kg bw/day 93 (2010)
12–19 years GM 1.50 ng/mL (1.31 lg/g cr) GM 0.031 lg/kg bw/day 94
20–39 years GM 1.33 ng/mL (1.49 lg/g cr) GM 0.026 lg/kg bw/day 91
40–59 years GM 1.04 ng/mL (1.33 lg/g cr) GM 0.020 lg/kg bw/day
60–79 years GM 0.90 ng/mL (1.26 lg/g cr) GM 0.017 lg/kg bw/day 88
88
Germany 599 (3–14 years) GM 2.66 ng/mL median 2.74 ng/mL GM 0.060 lg/kg bw/day 99 Becker et al.
137 (3–5 years) GM 3.55 ng/mL median 3.53 ng/mL 99 (2009)
145 (6–8 years) GM 2.72 ng/mL median 2.81 ng/mL 99
149 (9–11 years) GM 2.22 ng/mL median 2.13 ng/mL 99
168 (12–14 years) GM 2.42 ng/mL median 2.60 ng/mL 98
Germany 147 <0.3–9.3 ng/mL Median 0.030 lg/kg bw/day Völkel et al. (2008)
Belgium 193 0.1–53.4 ng/mL (0.18–32.4 lg/g cr) GM 0.040 lg/kg bw/day 99 Milieu en
14–16 years GM 2.22 ng/mL (1.66 lg/g cr) Gezondheid
(2010)
Italy 715 (20–74 years) GM 3.59 ng/mL GM 0.063 lg/kg bw/daya Galloway et al.
111 (20–40 years) GM 4.31 ng/mL median 4.4 ng/mL GM 0.075 lg/kg bw/daya (2010)
157 (41–65 years) GM 3.95 ng/mL median 3.7 ng/mL GM 0.069 lg/kg bw/daya
452 (66–74 years) GM 3.32 ng/mL median 3.2 ng/mL GM 0.058 lg/kg bw/daya
Korea 516 Mean 2.74 ng/mL, median 0.64 ng/mL Mean 0.055 lg/kg bw/dayb 76 Hong et al. (2009)
China 419 males GM 1.41 ng/mL (0.72 lg/g cr) GM 0.032 lg/kg bw/dayc 58 He et al. (2009)
503 females GM 0.58 ng/mL (0.23 lg/g cr) GM 0.010 lg/kg bw/dayd 44
China 287 GM 3.0 ng/mL (2.75 lg/g cr)0.41– GM 0.060 lg/kg bw/daya 100 Li et al. (in press)
3–24 years 198.05 lg/g cr
China 116 GM 1.10 ng/mL (1.03 lg/g cr) 90 Zhang et al. (2011)
Vietnam 30 GM 1.42 ng/mL (1.27 lg/g cr) 100 Zhang et al. (2011)
Malaysia 29 GM 1.00 ng/mL (1.93 lg/g cr) 97 Zhang et al. (2011)
India 21 GM 1.59 ng/mL (2.51 lg/g cr) 100 Zhang et al. (2011)
Kuwait 32 GM 1.24 ng/mL (1.09 lg/g cr) 81 Zhang et al. (2011)
Japan 36 GM 0.84 ng/mL (0.67 lg/g cr) 100 Zhang et al. (2011)
Korea 32 GM 2.00 ng/mL (2.53 lg/g cr) 97 Zhang et al. (2011)
All Asian countries Children Median 0.039 lg/kg bw/day Zhang et al. (2011)
Adults median 0.037 lg/kg bw/day
US 404 pregnant women Median 1.3 ng/mL < 0.36–35.2 ng/mL Median 0.027 lg/kg bw/daye 91 Wolff et al. (2008)
The Netherlands 100 pregnant women GM 1.5 ng/mL (1.7 lg/g cr), median GM 0.024 lg/kg bw/daye 82 Ye et al. (2008)
1.2 ng/mL (1.6 lg/g cr), range < 0.26– median 0.019 lg/kg bw/daye
46 ng/mL (0.1–22.7 lg/g cr)
Spain 120 pregnant women Median 2.2 ng/mL Median 0.035 lg/kg bw/daye 91 Casas et al. (2011)
Mexico 60 pregnant women GM 1.95 ng/mL, 0.41 – 7.47 ng/mL GM 0.034 lg/kg bw/daya 80 Cantonwine et al.
(2010)
Germany 91 samples from 47 <0.45–17.85 ng/mL 42 Völkel et al. (2011)
infants (1–5 months)
US 81 (23–64 months) GM 4.8 ng/mL (6.6 lg/g cr) Median 0.114 lg/kg bw/day 100 Morgan et al.
0.4–211 ng/mL (0.5–334 lg/g cr) (2011)
Spain 30 (boys 4 years) Median 4.2 ng/mL 97 Casas et al. (2011)
US 90 (girls 6–8 years) GM 2.0 ng/mL (3.0 lg/g cr) GM 0.033 lg/kg bw/dayf 94.4 Wolff et al. (2007)
median 1.8 ng/mL median 0.030 lg/kg bw/dayf
<0.3–54.3 ng/mL
US 195 samples from 35 GM 3.4 ng/mL (3.4 lg/g cr) GM 0.057 lg/kg bw/day 95 Teitelbaum et al.
children (6–10 years) median 3.6 ng/mL (3.5 lg/g cr) median 0.060 lg/kg bw/day (2008)
<0.36–40 ng/mL (0.2–36.3 lg/g cr)
a
Assuming 1.4 L urine (Lakind and Naiman, 2008) and 80 kg bw (EPA Exposure Factors Handbook 2011).
b
Assuming 1.4 L urine (Lakind and Naiman, 2008) and 70 kg bw (Hong et al., 2009).
c
Assuming 1.6 L urine (Lakind and Naiman, 2008) and 70 kg bw (Hong et al., 2009).
d
Assuming 1.6 L urine (Lakind and Naiman, 2008) and 70 kg bw (Hong et al., 2009).
e
Assuming 1.2 L urine (Lakind and Naiman, 2008) and 75 kg bw (EPA Exposure Factors Handbook 2011).
f
Assuming 0.6 L urine and 36 kg bw (Lakind and Naiman, 2008).

2009). However, when the population investigated is sufficiently Assuming steady-state excretion, the daily intake of BPA corre-
large, the spot sampling approach may provide sufficient statistical sponds with the excretion of BPA within 24 h (Lakind and Naiman,
power to categorize the average population exposure to BPA 2008). For estimating the daily BPA intake, the urinary concentra-
(WHO, 2010). tions of total BPA (free and conjugated after the hydrolysis of the
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T. Geens et al. / Food and Chemical Toxicology 50 (2012) 3725–3740 3735

conjugates) (ng/mL) are multiplied with 24 h urinary output (mL)
to get the daily excretion of BPA in ng/day. Since excretion of in-
gested BPA into urine is essentially complete in 24 h (Völkel
et al., 2002, 2005) this was assumed to be equal to the daily intake.
This estimated intake can be adjusted for body weight to obtain an
exposure expressed in ng/kg bw/day (Lakind and Naiman, 2008).
5.1. Urinary BPA (ng/mL)  urinary output (mL/day)/body weight
(kg) = ng BPA/kg/day
Instead of adjusting for urinary output, BPA concentrations can
also be adjusted for daily creatinine excretion. However, many fac-
tors contribute to the daily variability in creatinine output such as
diurnal variation, changes in the rate of glomerular filtration, body
mass, age, gender, health status, and external factors such as diet,
exercise, and drug use. Since the variation in the range of creati-
nine concentration in the urine may be over 1000%, while the var-
iation in daily urinary volume is up to 300% (Boeniger et al., 1993),
correction for urinary output is generally preferred over creatinine
excretion (Lakind and Naiman, 2008). However, the urine volume
is also related to several factors such as liquid intake, physical
exercise, and individual health and lifestyle factors (WHO, 2010).
Next to the use of generic values to describe typical urinary output
specified for age and gender, also generic values for body weight
have to be used when individual values are not available.
Daily intake calculations based on biomonitoring data allow the
comparison of individual (or group) exposures with doses that tox-
icological studies have determined to be harmful. Although these
dose calculations are performed using certain assumptions (e.g.
daily urine volume or creatinine excretion, uniform metabolism),
they reflect real exposures, where all possible exposure sources
are included (Needham et al., 2007). These urinary data (Table 5)
show that estimated median exposures are in the range of 0.01–
0.05 lg/kg body weight (bw) per day for adults and somewhat
higher (0.02–0.12 lg/kg bw per day) for children. The 95th percen-
tile exposure estimates are 0.27 lg/kg bw per day for the general
population and higher for infants (0.45–1.61 lg/kg bw per day)
and 3- to 5-year-old children (0.78 lg/kg bw per day) (WHO, 2010).
6. Overall estimation of exposure to bisphenol-A
Based on the available data from the previous chapters, it be-
comes clear that the exposure to BPA from non-food sources is
generally lower than the exposure from food by at least one order
of magnitude for most age subgroups studied. An overview of the
estimated intake through different exposure pathways based on
a median and worst case intake scenario is given in Table 6 for dif-
ferent studies. In a median exposure scenario, food was estimated
to contribute for more than 90% to the overall BPA-exposure for all
age groups of non-occupationally exposed individuals. BPA con-
centrations in food from food surveys and BPA migration from food
contact materials were considered in this assessment. Exposure
through dust ingestion, dental surgery and dermal absorption from
thermal paper remained below 5% in normal situations, for tod-
dlers, children, and adults (Table 6). Some additional potential
sources of exposure (unpackaged food and medical devices) have
been identified, but non-food exposure to BPA is poorly
characterized.
A comparison between the intake assessments based on expo-
sure from food and non-food source and biomonitoring values

Table 6
Overview of the estimated intake of BPA through multiple exposure pathways based on a median intake scenario.

Source Country Population Daily intake of BPA Contribution to median Refs.

exposure scenario
Children
Total Food Toddlers 1088–4992 ng/day >90% Von Goetz et al.
(2010)
Total Food USA Children 18 months– 1700–2700 ng/day (median) 99% Wilson et al. (2007)
5 years
Dust Eastern US Toddlers 42.2–435 ng/day (median – 95th <1% Loganathan and
percentile) Kannan (2011)
Dust Belgium Toddlers 73–975 ng/day (median – 95th <5% Geens et al. (2009)
percentile)
Inhalation (dust-air) USA Children 7.8–14 ng/day <1% Wilson et al. (2007)
(18 months–5 yeras)
Dental Surgery Children (>6y) 215 ng/day <5% Von Goetz et al.
(2010)
Adults
Total Food Adults 1560–10453 ng/day >90% von Goetz et al.
(2010)
Canned food New-Zealand Adults 570 ng/day (average)–6900 (99th Thomson and
percentile) Grounds (2005)
Canned food and Belgium Adults 1050 ng/day (average)–6050 ng/day >90% Geens et al. (2010)
beverages (95th percentile)
Dust Eastern USA Adults 8.44–109 ng/day (median – 95th <1% Loganathan and
percentile) Kannan (2011)
Dust Belgium Adults 29–244 ng/day (median – 95th <5% Geens et al. (2009)
percentile)
Thermal paper USA-Japan-Korea- General population 17.4–541 ng/day (median – 95th <5% Liao and Kannan
Vietnam Occupational percentile) (2011a)
exposed 1303 – 40590 ng/day (median – 95th
percentile)
Paper Currencies Worldwide General population 0.0001–1.41 ng/day (median) <1% Liao and Kannan
Occupational 0.0007–14.1 ng/day (median) (2011b)
exposed
Paper other than USA General population 0.1 ng/day <1% Liao and Kannan
thermal paper (2011a)
Dental surgery Adults 215 ng/day <5% Von Goetz et al.
(2010)

3736
120
100
BPA exposure (ng/kg bw per day)
80
60
40
20
0 Several characteristics of BPA deserve special attention and
biomonitoring canned food
Fig. 3. Comparison between BPA exposure calculated from biomonitoring data and
BPA exposure from canned food and non-food sources. Error bars represent
standard deviations.
indicates that in general it is possible to rely on the biomonitoring
data to assess overall human exposure to BPA. Fig. 3 cumulates BPA
exposure calculated from canned food/drinks, as mean/median/GM
values taken from WHO (2010) and background documents where-
in and from the specific national studies (see Chapter 2, WHO,
2010). Non-food sources include exposure from dust, thermal pa-
per, medical devices and dental materials (see Chapter 3, WHO,
2010). BPA cumulative exposure was calculated based on biomon-
itoring data (see Chapter 6, WHO, 2010).
7. Epidemiological studies
The majority of epidemiological studies used cross-sectional de-
signs with a single measurement of urinary BPA. Cross-sectional
studies have a limited interpretability, especially for outcomes that
have a long latency period (e.g. cardiovascular disease, diabetes).
Moreover the use of single urine samples is another limitation gi-
ven the short half-life of BPA. The association between BPA expo-
sure and end-points such as cancer, reproductive outcomes,
cardiovascular disease and diabetes, pubertal development out-
comes and growth and neurodevelopment outcomes are summa-
rized in a report of a Joint FAO/WHO expert meeting (WHO, 2010).
Three epidemiological studies revealed the association between
higher urinary concentrations of BPA and lower semen quality,
however in two of these studies, this correlation was not signifi-
cant. No evidence was found for the association between the BPA
concentrations in urine and an altered age of pubertal onset in
girls. A prospective study of Braun et al. (2009) suggested that pre-
natal BPA exposures, especially during early pregnancy, may be
associated with the later development of externalizing behaviours,
such as aggression and hyperactivity, and this, particularly in girls.
However, replication of this study with serial measurements of uri-
nary BPA is necessary.
Based on the cross-sectional analysis of urinary BPA concentra-
tions from the US-NHANES, an association was reported between
BPA-exposure and self-reported diagnosis of pre-existing cardio-
vascular disease (Lang et al., 2008; Melzer et al., in press) and dia-
betes (Melzer et al., 2010). Also here, confirmation with
prospective studies with serial measurements of BPA is necessary
and this during the relevant windows of exposure, years or even
decades before the development of cardiovascular disease, diabe-
tes and reproductive abnormalities. The question however remains
as to whether human epidemiological studies will enable to link
BPA exposure and long term effects, despite ubiquity, short half life
and mixture effects of BPA.
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T. Geens et al. / Food and Chemical Toxicology 50 (2012) 3725–3740
8. General discussion and recommendations
The above chapters provide a detailed overview of the principal
sources for human exposure to BPA and their contribution to the
overall exposure. The major human route of exposure to BPA has
been shown by several assessments to be the dietary pathway.
However, other exposures, e.g. dermal exposure including from
thermal or recycled papers, dental materials and other medical de-
vices, need to be more thoroughly characterized. Exposure through
air and dust inhalation is considered negligible. These tentatively
postulated ways of exposure have to be confirmed by biomonitor-
ing data obtained from urine samples, the most suitable matrix to
improve our knowledge on absorption, distribution, metabolism
and excretion of BPA.
non-food make its risk assessment particularly challenging. Firstly, BPA is
ubiquitous because it is manufactured in large amounts and used
in a large variety of applications. Hence, BPA can be found above
the detection limits in urine in the majority of the people moni-
tored worldwide (WHO, 2010). In addition, the exposure routes
are multiple. On the other hand, BPA is readily metabolized so that
there is a continuous competition between absorption and elimi-
nation within the human body. Determining a causal link between
BPA exposure and negative health effects under such dynamic con-
ditions is a major challenge for the future.
Epidemiological studies are difficult to interpret due to the fol-
lowing reasons: (1) humans are exposed to numerous and varied
endocrine disruptors, it is thus difficult to identify the specific ef-
fects of BPA; BPA has the ability to interact with human estrogen
receptors of both a, b, and c subtypes, and in vitro experiments
have revealed significant estrogen and androgen activity of BPA.
In addition, thyroid hormone receptors, PPAR-gamma receptors
and GPR30 receptors could be involved; (2) Endocrine disrupters’
impact on sexual development, reproduction potency, health
(especially cancers of sexual organs but also cardiovascular dis-
eases and diabetes) depends upon time windows of exposure (in
utero, newborn babies, adolescents, adults, menopaused women,
. . .). Early exposure is more likely to account for effects due to vul-
nerability of mechanisms during early set up of homeostasis of
processes like control of reproduction and energy balance (Bour-
guigon and Parent, 2010).
Some precautions must be taken when designing biomonitoring
campaigns or protocols for epidemiological research. The following
points deserve particular attention for such studies:
 Attention is required to avoid external contamination with BPA
during sampling and analysis, particularly when measuring free
BPA. The nature and potential contribution of BPA sources dur-
ing sampling and analysis of biological specimens is needed. A
detailed description of the sample collection protocols, includ-
ing sampling location and procedures, sample handling and
storage conditions, should be included in all biomonitoring
studies. To monitor for potential external contamination, labo-
ratory, as well as field blanks, are required.
 The selection of several target populations throughout life in
biomonitoring studies: (i) adults, teenagers, infants, babies, pre-
mature newborn babies; (ii) male or female; (iii) pregnant
women; (iv) fertile or non-fertile men or women; (v) ethnical
group; (vi) identify geographical differences; (vii) different body
mass index.
 Because of BPA’s short elimination half-life, strategies to
address the large variability in BPA concentrations of spot urine
samples need to be developed to adequately categorize expo-
sure as appropriate to the end-point of interest. When the pop-
ulation investigated is sufficiently large (e.g. nation-wide), the
 Author's personal copy
T. Geens et al. / Food and Chemical Toxicology 50 (2012) 3725–3740
spot sampling approach may provide enough statistical power
to categorize the average population exposure to BPA. For other
purposes, biomonitoring data would be strengthened with the
collection of multiple spot urine samples, particularly in studies
aimed at evaluating the potential impact of exposure to BPA on
human health. Furthermore, the study design should consider
the impact of time of day of sampling (e.g. in relation to con-
sumption of food) and time of last urination as important expo-
sure contributors to provide the best approach for BPA exposure
assessment.
 Focus on all exposure routes: (i) occupational exposure (plastic
industry); (ii) foodstuffs in contact with BPA containing materi-
als; (iii) other oral contact materials than food (dummies, toys);
(iv) dust in the (indoor) environment; (v) dermal contact (ther-
mal paper); (vi) medical devices
 Link between ‘‘exposure window’’ and ‘‘multiple effects’’: (i)
exposure in utero can have effects delayed until the adult period
or even on the following generations; (ii) levels of BPA in human
body can be highly variable with time and repeated biomonitor-
ing can help to control this variability; (iii) it is still unclear
whether BPA concentrations in maternal biological specimens
are adequate surrogates for fetal and infant exposures.
 Confounding factors and bias: (i) adjustments needed according
to age, -food habits, smoking habits, etc.; (ii) effects of other
potential endocrine disrupting compounds and contaminants
(ideally a large panel of chemicals should be monitored); (iii)
unmeasured factors may confound potential BPA-outcome asso-
ciations and bias effect estimates from epidemiological studies.
This concern may be overstated in cases when the confounding
factor is not associated with BPA exposure or the outcome.
 To avoid some of these pitfalls, it is recommended to pay atten-
tion to the amount and quality of information that could be
obtained, e.g., through a specific and detailed questionnaire on
diet, kitchen utensils and other implements, housing, occupa-
tional exposure, hobbies, etc. In addition, in order to refine the
exposure assessment and to improve the risk assessment, the
following points should be considered:
 When considering all the exposure routes, more information is
needed on the bioavailability of BPA. Therefore more research
work is needed on the absorption after dermal contact and dust
inhalation.
 Since a lot of contact materials are able to release BPA, it is also
important to rely on experimental procedures for an accurate
and sensitive control of the quality of packaging material and
kitchen utensils. It is, indeed, known that temperature, nature
of the simulant and aging of the material can all affect the
amount of released BPA (Nam et al., 2010). Standardized proce-
dures adapted to this kind of contaminants and packaging
materials should be developed not only for pre-market control
of kitchen implements but also for refining the prediction of
exposure.
Several additional issues highly relevant for future research
have been identified and need to be better addressed:
 Surveys of BPA concentrations in infant formula and in toddler
food, especially if such food is packed in metal cans
 Studies on BPA migration from paper packaging to food, espe-
cially if recycled paper is used
 More data on BPA concentrations in unpackaged foods have to
be gathered, together with data on the consumption patterns
for materials and products containing BPA
 It would certainly be more helpful, than simply examining BPA
exposure, to try to correlate epidemiological studies with con-
tamination of consumed food and drinks established using
in vitro methods (target cells equipped with reporter genes,
3737
receptor assays) of measurements of estrogenic activity in order
to consider the whole oral exposure to endocrine disruptors.
 There are several biomonitoring studies which provide scien-
tific indications of the gestational BPA exposure (Cantonwine
et al., 2010; Braun et al., 2011b). It is advisable for this group
of vulnerable people (e.g. pregnant women) to employ the pre-
cautionary principle and to make efforts to reduce the exposure
to certain consumer products which are known to contain BPA-
based polymers. It is yet unclear at the moment what the ben-
efits of such reductions are. Since BPA is a potential endocrine
disruptor, the exposure of the fetus to endocrine disrupting
chemicals is of high concern and should be carefully evaluated
and minimized.
In addition, the risk assessment is made very difficult because
BPA is a potential endocrine disruptor. Therefore the risk identifi-
cation and risk characterization processes are not straightforward.
Indeed, numerous molecular targets can be involved and the deter-
mination of a toxic threshold is not always possible. Furthermore,
the toxicological tests are not yet fully validated nor worldwide ac-
cepted as it is the case for in vitro and in vivo tests used to charac-
terize carcinogenic/mutagenic compounds. This critical point has
to be solved in order to convince public authorities and industrial
companies of the risks of endocrine disruptors for the public
health, the future of the human population and the environment.
Therefore, as in the case of carcinogenic agents, epidemiological
studies on a large scale may be necessary to obtain more evidence
for deleterious effects.
Another area of concern in the effects of EDCs in general and of
BPA in particular is the possible transgenerational mode of action
due to alterations of the epigenome during exposure in early life
(Bernal and Jirtle, 2010). Such mechanisms are challenging the epi-
demiological studies and reinforce the question as to whether pre-
venting measures should be proposed in pregnant women and
young children, following a precautionary principle.
Finally, it is important to be aware that BPA is not the only
chemical of concern. There are many alternatives to BPA for which
the toxicological properties are not known. Therefore, it could be
advisable to recommend the use of multi-contaminant analysis
methods, on the one hand, so that a large panel of potential endo-
crine disrupting compounds could be monitored in the same time,
and also the use of biological screening methods, on the other
hand, in order to be able to detect the presence of still unknown
chemicals with endocrine disrupting potential.
Conflict of Interest
The authors declare that there are no conflicts of interest.
Acknowledgments
AC and TG acknowledge Funds for Scientific Research (FWO)
and University of Antwerp for financial support. The authors thank
the Belgian Superior Health Council for initiating the study and for
the financial contribution.
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