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 Lige, CHU ND des Bruyres, B4030 Chne, 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 lAutonomie 4, 1070 Brussels, Belgium i Veterinary and Agrochemical Research Center (CODA-CERVA), Leuvensesteenweg 17, 3080 Tervuren, Belgium j Scientic 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 lAutonomie 4, 1070 Brussels, Belgium a r t i c l e i n f o Article history: Received 1 April 2012 Accepted 28 July 2012 Available online 4 August 2012 Keywords: Bisphenol-A Review Human exposure Food sources Non-food sources Alternatives a b s t r a c t Due to the large number of applications of bisphenol-A (BPA), the human exposure routes are multiple. We aimed to review shortly the food and non-food sources of BPA, and to evaluate their contribution to the human exposure. Food sources discussed here include epoxy resins, polycarbonate and other appli- 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- able data for these exposure sources, it was concluded that the exposure to BPA from non-food sources is generally lower than that from exposure from food by at least one order of magnitude for most studied subgroups. The use of urinary concentrations from biomonitoring studies was evaluated and the back- calculation of BPA intake seems reliable for the overall exposure assessment. In general, the total expo- sure to BPA is several orders of magnitude lower than the current tolerable daily intake of 50 lg/kg bw/ day. Finally, the paper concludes with some critical remarks and recommendations on future human exposure studies to BPA. 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 0278-6915/$ - see front matter 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.fct.2012.07.059
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). Food and Chemical Toxicology 50 (2012) 37253740 Contents lists available at SciVerse ScienceDirect Food and Chemical Toxicology j our nal homepage: www. el sevi er . com/ l ocat e/ f oodchemt ox 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 1.1. Properties and applications of bisphenol-A Bisphenol-A (BPA) [4,4 0 -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 rst 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 ame retardant tetrabromobisphenol-A (Geens et al., 2011). Polycarbonate is currently used in materials intended to come into contact with 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. 3726 T. Geens et al. / Food and Chemical Toxicology 50 (2012) 37253740 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 nding 28746 compounds inserting the OHArCH 2 ArOH 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 10005000 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- sied as a reproductive toxic substance of category 3 as an alarm- ing substance for the human fertility (INSERM, 2010). The EFSA published a rst 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 doseresponse curves, as well as on effects occurring from very specic 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 denitively 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 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 Vlkel, 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- cic migration limit (SML) is xed 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 xed 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) N10/2011 (EC, 2011a). Briey, 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, reect 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 T. Geens et al. / Food and Chemical Toxicology 50 (2012) 37253740 3727 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 inuence of damage, storage conditions and heating on the migration of BPA was studied by Goodson et al. (2004). Empty epoxy phenolic coated cans were lled 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 80100% 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, jalapeo peppers or tuna sh (Munguia-Lopez and Soto-Valdez, 2001; Munguia-Lopez et al., 2005). For jalapeo 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 jalapeo peppers compared to tuna, part of the residual BPA remained on the coating after processing. Afterwards, BPA increased during storage time, especially during the rst 40 days (Munguia-Lopez and Soto- Valdez, 2001; Munguia-Lopez et al., 2002). Kang and Kondo (2003) reported that the temperature has more inuence on the migration of BPA froman 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 conrmed 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 ve days showed a spec- tacular increase of 1200% in urinary BPA concentrations compared to urine concentrations following the consumption of fresh food during ve 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 (2.6310 ng/g) between the minimal and maximal BPA values in peas, while green beans had a 30-fold difference (22730 ng/g) between brands. Geens et al. (2010) ob- served also a large variation (1.282 ng/g) between ve brands of corn. While some studies reported tuna sh 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 bers, 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 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 <2730 Noonan et al. (2011) US 97 59 <0.265 Schecter et al. (2010) Canada 78 99 <0.6534 Cao et al. (2010) Japan 48 92 <1842 Sajiki et al. (2007) Korea 61 64 <3136 Lim et al. (2009a) Belgium 21 100 0.2169 Geens et al. (2010) Beverage cans (ng/mL) Spain 11 64 <0.050.61 Gallart-Ayala et al. (2010) Canada 69 100 0.034.5 Cao et al. (2009a) Belgium 45 91 <0.028.1 Geens et al. (2010) Portugal 30 70 <0.014.7 Cunha et al. (2011) 3728 T. Geens et al. / Food and Chemical Toxicology 50 (2012) 37253740 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 0.070.16 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 sh (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 lm 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 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 ofcial 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 0.11 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 conrmed 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 (613 ng/L) when the bottles are used under normal conditions Table 2 Migration of BPA from polycarbonate baby bottles. BPA has a specic migration limit of 600 lg/kg (EC, 2011a). Reference Highest BPA concentration (lg/L) Relevant conditions De Coensel et al. (2009) 0.30 60 s and 1000 W (65 C) Ehlert et al. (2008) 0.73 3 cycles of 100 C in microwave oven (3 min) Le et al. (2008) 1.33 7.67 7 days at room temperature 24 h at 100 C Kubwabo et al. (2009) 6.5 Migration in water (24 h at 60 C) Maragou et al. (2008) 14.3 20 cycles of cleaning-sterilization-lling with boiling water and left at room temperature for 45 min Nam et al. (2010) 18.5 100 times for 30 min in steam bath at 95 C Biedermann-Brem and Grob, 2009 137 Previously boiled tap water (pH 9.5) in microwave for 10 min Release of BPA Biedermann-Brem et al. (2008) 500 A slanted position of the bottle in the dishwasher, hindering the detergent solution to run off and rinsing before drying Cao and Corriveau (2008b) 521 Heating water at 70 C for 6 days T. Geens et al. / Food and Chemical Toxicology 50 (2012) 37253740 3729 (20 s at 1000 W in the microwave oven at 37 C). During normal use, the released BPA quantities are negligible (maximum 2 ng per feeding) and far below the TDI value. 2.2.2. Levels The effect of migration of BPA from PC drinking bottles was illustrated in an intervention study where volunteers were re- quested to consume all cold beverages from PC drinking bottles during one week. An increase of 69% in urinary BPA concentrations was observed after one week compared with urinary levels ob- tained after a wash-out period of one week, where no use of PC- bottles was allowed (Carwile et al., 2009). In Canada, Cao and Corriveau (2008a) could not detect BPA in 51 non-PC bottled water products (detection limit 0.5 ng/mL). How- ever, BPA was detected in 4 out of 5 bottled water in PC products (<0.51.4 ng/mL). In a 5-week experiment, levels of 8.8 and 6.5 ng/mL were measured in two bottles. Therefore the authors warn for higher BPA levels that could be detected in some PC bot- tled water products due to the accidental or careless exposure to heat (e.g. sun) for extended periods of time during storage and transportation (Cao and Corriveau, 2008a). In a Greek study (Amir- idou and Voutsa, 2011), BPA was determined in water from ve PET-bottles with a median concentration of 4.6 ng/L. Water from one PC bottle contained 112 ng/L which increased to 170 ng/L after 30 days of sun exposure. The maximum daily intake through bot- 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 widely used as a surface-coating on residential drinking water storage tanks (Bae et al., 2002). Li et al. (2010) detected BPA in tap water from six different drinking water plants in Guangzhou, 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 2 L of tap water. Yet, more data are needed to quantify the possible dietary exposure to BPA via drinking water (EFSA, 2006). 2.3. Other food contact applications BPA is rarely measured in non-canned foods, thus, the contribu- tion from the non-canned foods to the overall dietary intake of BPA is not well known (Cao et al., 2011). Geens et al. (2010) determined BPA in 16 solid food samples packaged in glass, plastic, paper and laminated paperboard/polyethylene carton (Tetra Pak). BPA could be detected in all food samples in a concentration range of 0.1 1.28 ng/g with an average concentration of 0.46 ng/g. This mean concentration is about 100 times lower than the average concen- tration in similar food types, packaged in cans which were exam- ined in the same study. BPA could not be detected above the quantication limit of 0.02 ng/mL in ve beverages packaged in PET and Tetra Pak (Geens et al., 2010). Also Sajiki et al. (2007) found considerably lower concentrations of BPA in 15 out of 23 food samples (range <114 ng/g) packaged in plastic and in 4 out of 16 food samples (<0.21 ng/g) packaged in paper, compared with the food samples packaged in cans. No BPA was observed to migrate from EcoCare lined alumin- ium, stainless steel, or Tritan plastic water bottles during an incubation period of 120 h (detection limit 0.05 ng/mL). In con- trast, detectable amount of BPA were leached from PC bottles and epoxy-lined aluminum bottles (Cooper et al., 2011). BPA was found to be present in commercial PVC cling lms and plastic sheeting bags available on the market in Spain and migra- tion studies suggested it would migrate into food (Lopez-Cervantes and Paseiro-Losada, 2003). Yet, the former application of BPA in the PVC polymerisation process by some EU manufacturers appeared to have ceased (EFSA, 2006). Therefore, based on this information, no BPA exposure from food contact uses of PVC should be expected in the EU today, however PVC materials which were produced prior to this action may still be in use. 2.4. Intake estimation from food exposure The estimated intake through food by different national and international agencies is summarized in Table 3. These estimations are sometimes based on highest observed concentrations or migra- tion values or are derived using 95th percentile estimates of con- sumption. The highest estimated BPA dietary exposures were for 06 months of age infants who were exclusively fed on canned li- quid infant formula using PC bottles. In this case, sources of BPA exposure include migration from both the formula packaging and from the PC bottle (WHO, 2010). However, in all studies, even the worst case, estimates stay below the current TDI. Mean exposures for infants fed with infant formula using PC bottles were 2.02.4 lg/kgbwper day, with 95th percentile expo- sures ranging from 2.7 to 4.5 lg/kgbwper day (WHO, 2010). In- fants who were either fed with formula from non-PC bottles or exclusively breastfed had substantially lower estimated mean BPA exposures (0.01 lg/kgbwper day from powdered formula, 0.5 lg/kgbwper day from canned liquid formula and 0.3 lg/kg bw per day from breast milk), compared to those exclusively fed on infant formula using PC bottles. Once solid foods are introduced (at 636 months), exposure to BPA decreases relative to body weight. For children above 3 years, the highest mean BPA exposure was estimated to be 0.7 lg/kgbwper day, with a maximum up to 1.9 lg/kgbwper day (Table 3). Depending on the extent of pack- aged food (canned) in the diet, adult BPA exposures were compara- ble to those for children above 3 years: a highest mean exposure of 1.4 lg/kg bw per day, with a maximum exposure up to 4.2 lg/ kgbwper day (Table 3). It was assumed that all exposure to BPA from the diet was in the form of unconjugated BPA. These calcu- lated international dietary exposure estimates (WHO, 2010) are consistent, but slightly higher than those obtained using data re- ported from comparable national surveys. In Canada, dietary intake estimates of BPA by different age-sex groups were made based on the concentrations found in the food Table 3 Estimated intake of BPA in children and adults. Age category Estimation through dietary exposure (lg/kg bw/day) Children EFSA (2006) Infants (312 month) Children 0.213 5.3 Health Canada (2008) 14 years 511 years 0.261.98 0.151.28 Chapin et al. (2008) Infants-bottle fed Infants-breast fed Children (612 m) Children (26 years) 111 0.21 1.713 0.0414.7 FDA (2009) 012 m 1224 m >2 years 0.30.6 0.51.1 0.10.3 ANSES (2010) Infants (<36 m) Children (317 years) 0.10.5 0.20.6 WHO (2010) Infants 06 m Infants 636 m Children > 3 years 0.014.5 0.013.0 0.21.9 Adults EFSA (2006) Adults 1.5 Health Canada (2008) 1219 years >20 years 0.090.73 0.070.60 Chapin et al. (2008) Adults 0.0081.5 FDA (2009) >2 years 0.10.3 ANSES (2010) Adults 0.10.3 WHO (2010) Adults 0.44.2 3730 T. Geens et al. / Food and Chemical Toxicology 50 (2012) 37253740 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 agesex groups, with 0.170.33 lg/kgbw/day for infants, 0.0820.23 lg/kgbw/day for children aged from 1 to 19 years, and 0.0520.081 lg/kgbw/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/kgbw/day in New Zealand, Geens et al. (2010) found 0.015 lg/kgbw/day in Bel- gium, while Lim et al. (2009a) estimated an intake of 0.030 lg/ kgbw/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/kgbw/day. Overall, intake of BPA from food is well below the current TDI of 50 lg/kgbw/day. However, more knowledge is necessary on the ef- fect of food processing, preparation and cooking procedures on BPA levels in the nal cooked foods. Since PC tools and containers with epoxy coatings may be used during food preparation for cooking, BPA could be introduced into the nal 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 Vlkel, 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 oorings, 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 (Vlkel et al., 2008; Geens et al., 2009; Loganathan and Kannan, 2011). Higher concentrations were observed in laboratories (Logana- than and Kannan, 2011) and ofces (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 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 15%. 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; stberg 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 nger (Biedermann et al., 2010). If the ngers were wet or very greasy, the transferred amount was about 10 times higher. Repeated contact with fresh recorder paper did not give a signicant 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/ kgbw/day) determined by Biedermann et al. (2010), and on the ex- tent of dermal absorption recently published, (10% (EU, 2008), 13% (Mrck 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/kgbw/day) and 42.6 lg/day (0.58 lg/kgbw/ Fig. 2. Structure of thermal paper (from Lassen et al., 2011). T. Geens et al. / Food and Chemical Toxicology 50 (2012) 37253740 3731 day). Similarly, a Danish study reported a realistic worst case sce- nario which resulted in a daily uptake of 240 lg BPA (Lassen et al., 2011). In this scenario, it is assumed that the receipts are touched with humid ngers and that 50% of the quantity left on the skin is absorbed (Lassen et al., 2011). However, the actual exposure of the general consumer will mostly be lower. 3.3. Other types of papers Thermal paper can also be the primary cause of the contamina- tion of paper currencies. Paper currencies from 21 countries were analyzed for BPA(Liao and Kannan, 2011b). BPAwas found in all pa- per currencies at concentrations ranging up to 82.7 lg/g. The con- tamination of the paper currencies can probably be explained by frequent contact with thermal paper in a wallet. Because the BPA used in thermal paper is not covalently bound, it can be easily trans- ferred fromthermal receipt papers to other objects, including paper currencies. BPA may be also present also in the production process of currency paper. The estimated daily intake of BPA through der- mal absorption from handling paper currencies was on the order of a few nano grams per day (Liao and Kannan, 2011b). It has been estimated that approximately 30% of thermal papers enter recycling streams of municipal wastepaper. Recycling of thermal paper can introduce BPA into the paper production cycle (Liao and Kannan, 2011a). Vinggaard et al. (2000) showed that, while virgin paper contained no or negligible amounts of BPA, lev- els in the recycled paper ranged from 0.6 to 24 lg BPA/g of kitchen roll. Similarly, a Japanese study examined paperboard and papers used for food packaging. In the virgin paper and paperboard, con- centrations between (0.0340.36 lg/g) were detected, while the concentrations in recycled paper and paperboard were >10-fold higher (range 0.1926 lg/g) (Ozaki et al., 2004). More than 80% of others papers, including yers, tickets, newspapers, toilet paper, contained BPA in concentrations ranging up to 14.4 lg/g. Thus, BPA concentrations in other papers were 34 orders of magnitude 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 insignicant contribution to the overall exposure. Liao and Kannan (2011a) made an assessment through dermal exposure of BPA from thermal and other paper. The median dermal exposure to BPA of the general population was 17.4 ng/day, while this was 1303 ng/day for the occupationally exposed population. Thermal paper contributed for more than 98% to this value. Liao and Kannan (2011a) calculated that for an over- all exposure to BPA of 1 lg/kg bw/day, paper could contribute 1.6 51% in an occupationally exposed population. 3.4. Dental materials Dental composite resins consist of a mixture of co-monomers and are most commonly based on bisphenol-A glycidyl methacry- late (bis-GMA). In addition to bis-GMA, these resins contain other monomers to modify the properties, e.g. bisphenol-A dimethacry- late (bis-DMA). Although BPA is not used itself in composite resins, it might be present as an impurity from the synthesis process (Fle- isch et al., 2010; Fung et al., 2000; Nathanson et al., 1997; Van Landuyt et al., 2011). BPA can also leach into the saliva as a result of bis-DMA hydrolysis through esterases present in the saliva (re- viewed by Van Landuyt et al., 2011). 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. BPA exposure after sealant placement is most likely an acute event, yet none of the studies could detect BPA 3 h after sealant place- ment. Possibly, analytical methods used in these studies were not sensitive enough to detect extremely low doses of BPA that chronically leach from the resin over longer periods of time. Hence, chronic low-dose BPA exposure after dental sealant placement cannot be ruled out (Fleisch et al., 2010). The relevance of the released amounts of BPA from dental mate- rials in vitro has recently been reviewed in a meta-analysis done by Van Landuyt et al. (2011). It was computed that one full crown res- toration of a molar may release 13 lg BPA in the average case sce- nario or 30 mg BPA in the worst case scenario, both after 24 h. The average BPA release (0.2 lg/kg body weight/day for a person weighting 60 kg) is 250-fold lower than the TDI of 50 lg/kg body weight/day, but 10-fold higher than the TDI in the worst case sce- nario. This indicates that the 24-h release of BPA from dental mate- rials is relevant in patients with multiple or large restorations and that resin-based dental materials may represent a relevant source of BPA in such patients (Van Landuyt et al., 2011). Sealants pro- duced by different manufacturers released markedly different amounts of BPA (Vandenberg et al., 2007). Von Goetz et al. (2010) estimated the chronic exposure after dental surgery to be 215 ng BPA/day. This estimation was based on the measurement of 0.3 ng/mL in the saliva of one out of 21 individuals at 120 h after surgery. It probably represents a worst- case scenario for chronic exposure, since concentrations in saliva will decrease further over time and only one individual had still measurable concentrations after 120 h. 3.5. Medical devices and healthcare applications A small fraction of the BPA-based polymers polycarbonate and polysulfone is used in medical and healthcare applications such as PC eye lenses, tube connections, blood oxygenators, inhaler housing, and newborn incubators, as well as polysulfone surgical trays, nebulizers, and humidiers (Geens et al., 2011). BPA can also leach into a drug formulation which most likely occurs with liquid and suspension formulations that are packaged in PC container- closures or metal canisters with epoxy lining (FDA, 2009). PVC, which may also contain BPA, is used in the manufacturing of medical products, such as those found in the neonatal intensive care units, including bags containing intravenous uids and total parenteral nutrition and tubing associated with their administra- tion; nasogastric and enteral feeding tubes; and umbilical catheters. In a study of Calafat et al. (2009), BPA was analysed in urine from 42 low-birth-weight infants in neonatal intensive care Table 4 Overview of BPA in thermal paper. Country Sample size Detection freq. (%) % (g BPA/100 g paper) Refs. Denmark 12 65 n.d1.7 Lassen et al. (2011) Sweden 16 100 0.62.3 stberg and Noaksson (2010) Switzerland 13 85 <5.10 5 1.7 Biedermann et al. (2010) US 36 44 0.82.8 EWG (2010) US, Boston 10 80 <0.091.7 Mendum et al. (2011) US, Japan, Korea, Vietnam 103 94 <1.10 7 1.4 Liao and Kannan (2011a) 3732 T. Geens et al. / Food and Chemical Toxicology 50 (2012) 37253740 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 611years who were examined as part of the NHANES 20032004) (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-bers 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 specic 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; Vlkel et al., 2002, 2005). After oral administration, BPA undergoes a rapid rst 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 detoxication 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 (Vlkel et al., 2002, 2005). The applied doses were com- pletely recovered in urine; hence, BPA exposure can be estimated from urinary levels (Vlkel et al., 2002). BPA ingested by inhalation or dermal contact does not undergo rst pass effect and will there- fore be eliminated at a slower rate. In adult rhesus monkeys, the concentrationtime prole 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 detoxication 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 (Vlkel et al., 2002). Also viable human skin explants ef- 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 difcult 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; Vlkel et al., 2008). Even detectable concentrations do not thus necessarily reect 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 (1219 years) followed by children (611 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 35years had higher con- centrations than the 68years; 911years; and 1214years 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 BPAs short elimination half-life, spot urine samples primarily reect the exposure that occurred within a rel- atively short period before urine collection (Koch and Calafat, T. Geens et al. / Food and Chemical Toxicology 50 (2012) 37253740 3733 2009). However, when the population investigated is sufciently large, the spot sampling approach may provide sufcient statistical power to categorize the average population exposure to BPA (WHO, 2010). Assuming steady-state excretion, the daily intake of BPA corre- sponds with the excretion of BPA within 24 h (Lakind and Naiman, 2008). For estimating the daily BPA intake, the urinary concentra- tions of total BPA (free and conjugated after the hydrolysis of the Table 5 Overview of the most recent worldwide biomonitoring studies in urine. Country Population Concentrations Exposure Det. Freq. (%) Refs. US 2514 (P6P60 years) 314 (611 years) 713 (1219 years) 950 (2059 years) 537 (P60 years) GM 2.6 ng/mL (2.6 lg/g cr) GM 3.6 ng/mL (4.3 lg/g cr) GM 3.7 ng/mL (2.8 lg/g cr) GM 2.6 ng/mL (2.4 lg/g cr) GM 1.9 ng/mL (2.3 lg/g cr) GM 0.047 lg/kg bw/day GM 0.065 lg/kg bw/day GM 0.071 lg/kg bw/day GM 0.053 lg/kg bw/day (20 39 years) GM 0.038 lg/kg bw/day (40 59 years) GM 0.034 lg/kg bw/day 93 Calafat et al. (2008) Lakind and Naiman (2008) US 394 adults GM 1.33 ng/mL (1.36 lg/g cr) GM 0.023 lg/kg bw/day a 95 Calafat et al. (2005) Canada 5476 679 years 611 years 1219 years 2039 years 4059 years 6079 years GM 1.16 ng/mL (1.40 lg/g cr) GM 1.30 ng/mL (2.00 lg/g cr) GM 1.50 ng/mL (1.31 lg/g cr) GM 1.33 ng/mL (1.49 lg/g cr) GM 1.04 ng/mL (1.33 lg/g cr) GM 0.90 ng/mL (1.26 lg/g cr) GM 0.025 lg/kg bw/day GM 0.031 lg/kg bw/day GM 0.026 lg/kg bw/day GM 0.020 lg/kg bw/day GM 0.017 lg/kg bw/day 91 93 94 91 88 88 Bushnik et al. (2010) Germany 599 (314 years) 137 (35 years) 145 (68 years) 149 (911 years) 168 (1214 years) GM 2.66 ng/mL median 2.74 ng/mL GM 3.55 ng/mL median 3.53 ng/mL GM 2.72 ng/mL median 2.81 ng/mL GM 2.22 ng/mL median 2.13 ng/mL GM 2.42 ng/mL median 2.60 ng/mL GM 0.060 lg/kg bw/day 99 99 99 99 98 Becker et al. (2009) Germany 147 <0.39.3 ng/mL Median 0.030 lg/kg bw/day Vlkel et al. (2008) Belgium 193 1416 years 0.153.4 ng/mL (0.1832.4 lg/g cr) GM 2.22 ng/mL (1.66 lg/g cr) GM 0.040 lg/kg bw/day 99 Milieu en Gezondheid (2010) Italy 715 (2074 years) 111 (2040 years) 157 (4165 years) 452 (6674 years) GM 3.59 ng/mL GM 4.31 ng/mL median 4.4 ng/mL GM 3.95 ng/mL median 3.7 ng/mL GM 3.32 ng/mL median 3.2 ng/mL GM 0.063 lg/kg bw/day a GM 0.075 lg/kg bw/day a GM 0.069 lg/kg bw/day a GM 0.058 lg/kg bw/day a Galloway et al. (2010) Korea 516 Mean 2.74 ng/mL, median 0.64 ng/mL Mean 0.055 lg/kg bw/day b 76 Hong et al. (2009) China 419 males 503 females GM 1.41 ng/mL (0.72 lg/g cr) GM 0.58 ng/mL (0.23 lg/g cr) GM 0.032 lg/kg bw/day c GM 0.010 lg/kg bw/day d 58 44 He et al. (2009) China 287 324 years GM 3.0 ng/mL (2.75 lg/g cr)0.41 198.05 lg/g cr GM 0.060 lg/kg bw/day a 100 Li et al. (in press) 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 Adults Median 0.039 lg/kg bw/day median 0.037 lg/kg bw/day Zhang et al. (2011) US 404 pregnant women Median 1.3 ng/mL < 0.3635.2 ng/mL Median 0.027 lg/kg bw/day e 91 Wolff et al. (2008) The Netherlands 100 pregnant women GM 1.5 ng/mL (1.7 lg/g cr), median 1.2 ng/mL (1.6 lg/g cr), range < 0.26 46 ng/mL (0.122.7 lg/g cr) GM 0.024 lg/kg bw/day e median 0.019 lg/kg bw/day e 82 Ye et al. (2008) Spain 120 pregnant women Median 2.2 ng/mL Median 0.035 lg/kg bw/day e 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/day a 80 Cantonwine et al. (2010) Germany 91 samples from 47 infants (15 months) <0.4517.85 ng/mL 42 Vlkel et al. (2011) US 81 (2364 months) GM 4.8 ng/mL (6.6 lg/g cr) 0.4211 ng/mL (0.5334 lg/g cr) Median 0.114 lg/kg bw/day 100 Morgan et al. (2011) Spain 30 (boys 4 years) Median 4.2 ng/mL 97 Casas et al. (2011) US 90 (girls 68 years) GM 2.0 ng/mL (3.0 lg/g cr) median 1.8 ng/mL <0.354.3 ng/mL GM 0.033 lg/kg bw/day f median 0.030 lg/kg bw/day f 94.4 Wolff et al. (2007) US 195 samples from 35 children (610 years) GM 3.4 ng/mL (3.4 lg/g cr) median 3.6 ng/mL (3.5 lg/g cr) <0.3640 ng/mL (0.236.3 lg/g cr) GM 0.057 lg/kg bw/day median 0.060 lg/kg bw/day 95 Teitelbaum et al. (2008) 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). 3734 T. Geens et al. / Food and Chemical Toxicology 50 (2012) 37253740 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 (Vlkel 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 ltration, 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 specied 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 reect 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 (0.020.12 lg/kgbwper day) for children. The 95th percen- tile exposure estimates are 0.27 lg/kgbwper day for the general population and higher for infants (0.451.61 lg/kgbwper day) and 3- to 5-year-old children (0.78 lg/kgbwper 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 identied, 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 exposure scenario Refs. Children Total Food Toddlers 10884992 ng/day >90% Von Goetz et al. (2010) Total Food USA Children 18 months 5 years 17002700 ng/day (median) 99% Wilson et al. (2007) Dust Eastern US Toddlers 42.2435 ng/day (median 95th percentile) <1% Loganathan and Kannan (2011) Dust Belgium Toddlers 73975 ng/day (median 95th percentile) <5% Geens et al. (2009) Inhalation (dust-air) USA Children (18 months5 yeras) 7.814 ng/day <1% Wilson et al. (2007) Dental Surgery Children (>6y) 215 ng/day <5% Von Goetz et al. (2010) Adults Total Food Adults 156010453 ng/day >90% von Goetz et al. (2010) Canned food New-Zealand Adults 570 ng/day (average)6900 (99th percentile) Thomson and Grounds (2005) Canned food and beverages Belgium Adults 1050 ng/day (average)6050 ng/day (95th percentile) >90% Geens et al. (2010) Dust Eastern USA Adults 8.44109 ng/day (median 95th percentile) <1% Loganathan and Kannan (2011) Dust Belgium Adults 29244 ng/day (median 95th percentile) <5% Geens et al. (2009) Thermal paper USA-Japan-Korea- Vietnam General population Occupational exposed 17.4541 ng/day (median 95th percentile) 1303 40590 ng/day (median 95th percentile) <5% Liao and Kannan (2011a) Paper Currencies Worldwide General population Occupational exposed 0.00011.41 ng/day (median) 0.000714.1 ng/day (median) <1% Liao and Kannan (2011b) Paper other than thermal paper USA General population 0.1 ng/day <1% Liao and Kannan (2011a) Dental surgery Adults 215 ng/day <5% Von Goetz et al. (2010) T. Geens et al. / Food and Chemical Toxicology 50 (2012) 37253740 3735 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 fromcanned food/drinks, as mean/median/GM values taken from WHO (2010) and background documents where- in and from the specic 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 signi- 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, conrmation 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. 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 conrmed by biomonitor- ing data obtained from urine samples, the most suitable matrix to improve our knowledge on absorption, distribution, metabolism and excretion of BPA. Several characteristics of BPA deserve special attention and 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 difcult to interpret due to the fol- lowing reasons: (1) humans are exposed to numerous and varied endocrine disruptors, it is thus difcult to identify the specic 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 signicant 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 eld 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 BPAs 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 sufciently large (e.g. nation-wide), the 0 20 40 60 80 100 120 biomonitoring canned food non-food B P A
e x p o s u r e
( n g / k g
b w
p e r
d a y ) 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. 3736 T. Geens et al. / Food and Chemical Toxicology 50 (2012) 37253740 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 specic and detailed questionnaire on diet, kitchen utensils and other implements, housing, occupa- tional exposure, hobbies, etc. In addition, in order to rene 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 rening the prediction of exposure. Several additional issues highly relevant for future research have been identied 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, 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- tic 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- ets 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 difcult because BPA is a potential endocrine disruptor. Therefore the risk identi- 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. Conict of Interest The authors declare that there are no conicts of interest. Acknowledgments AC and TG acknowledge Funds for Scientic Research (FWO) and University of Antwerp for nancial support. 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