Bisphenol A Release: Survey of the Composition of Dental Composite Resins
Elisabeth Dursun1, *, Hélène Fron-Chabouis2, Jean-Pierre Attal2, Anne Raskin3
1 Unité de Recherche en Biomatériaux, Innovations et Interfaces - EA 4462,
Faculté de Chirurgie Dentaire, Université Paris Descartes, Paris,
Groupe Hospitalier Mondor-Chenevier, Créteil,
2 Unité de Recherche en Biomatériaux, Innovations et Interfaces - EA 4462,
Faculté de Chirurgie Dentaire, Université Paris Descartes, Paris,
Hôpital Charles Foix, Ivry-sur-Seine,
3 UMR 7268 ADES, EFS, CNRS
Faculté d’Odontologie, Université d'Aix-Marseille, Marseille,
Pôle d’Odontologie, UF des soins spécifiques, APHM, Hôpital de la Timone, Marseille,
Bisphenol A (BPA) is an endocrine disruptor with potential toxicity. Composite resins may not contain pure BPA, but its derivatives are widely used. Several studies found doses of BPA or its derivatives in saliva or urine of patients after composite resin placement.
The aims of this study were to establish an exhaustive list of composite resins marketed in Europe and their composition, and to assess the extent of BPA derivatives used.
A research on manufacturers' websites was performed to reference all composite resins marketed in Europe, then their composition was determined from both material safety data sheets and a standardized questionnaire sent to manufacturers. Manufacturers had to indicate whether their product contained the monomers listed, add other monomers if necessary, or indicate “not disclosed”.
160 composite resins were identified from 31 manufacturers and 23 manufacturers (74.2%) responded to the survey. From the survey and websites, the composition of 130 composite resins (81.2%) was: 112 (86.2%) based on BPA derivatives, 97 (74.7%) on bis-GMA, 17 (13.1%) without monomer derived from BPA (UDMA, sometimes with TEGDMA) and 6 (4.6%) with UDMA (only);
1 (0.8%) did not contain a BPA derivative or UDMA or TEGDMA. Pure BPA was never reported.
This work has established a list of 18 composite resins that contain no BPA derivative. Manufacturers should be required to report the exact composition of their products as it often remains unclear or incomplete.
Keywords: Biocompatibility, Bisphenol A, Composite resin, Monomer.
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Bisphenol A Release: Survey of the Composition of Dental Composite Resins
Bisphenol A (BPA) is an organic compound used in the industrial production of polycarbonates and epoxy resins [1European Food Safety Authority. Opinion of the scientific panel on food additives, flavourings, processing aids and materials in contact with food (AFC) related to 2,2-bis(4-hydroxyphenyl)propane. EFSA J 2006; 428: 1-75.]. However, BPA is an endocrine disruptor, with potential toxicity in vitro [2Wetherill YB, Akingbemi BT, Kanno J, et al. In vitro molecular mechanisms of bisphenol A action. Reprod Toxicol 2007; 24(2): 178-98. [http://dx.doi.org/10.1016/j.reprotox.2007.05.010] [PMID: 17628395] ] and in vivo [3Richter CA, Birnbaum LS, Farabollini F, et al. In vivo effects of bisphenol A in laboratory rodent studies. Reprod Toxicol 2007; 24(2): 199-224. [http://dx.doi.org/10.1016/j.reprotox.2007.06.004] [PMID: 17683900] ]. Among other effects, it can cause changes in the structure of the unborn child’s mammary glands - promoting further tumor development - and has effects on the brain and behavior, the female reproductive system, and metabolism and obesity [4Agence nationale de sécurité sanitaire. Évaluation des risques du bisphénol A (BPA) pour la santé humaine. Rapport d’expertise collective 2013; 1-298.
Available at: https://www.anses.fr/en/system/files/CHIM2009sa0331Ra-0.pdf]. Infants, young children and pregnant or lactating women are the most sensitive [5Shelby MD. NTP-CERHR monograph on the potential human reproductive and developmental effects of bisphenol A. NTP CERHR MON 2008; 22(22): v- vii-ix, 1-64 passim. [PMID: 19407859] ]. Thus, the manufacturing of baby bottles containing BPA has been banned by the European Union since 2011. From January 1, 2015, France has banned BPA in all food packaging. In its latest comprehensive re-evaluation of BPA exposure and toxicity, the European Food Safety Authorities has concluded no risks at actual exposure levels [6Scientific Opinion on the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs: Part I – Exposure assessment. EFSA J 2015; 13: 3978. [http://dx.doi.org/10.2903/j.efsa.2015.3978] ]. However, a lower Tolerable Daily Intake (TDI) has been set at 4µg/kg bw/day (ie 12.5 times less than the last TDI). Besides, its possible “low-dose effect” [7International Food Safety Authorities Network. Bisphenol A – Current state of knowledge and future actions by WHO and FAO. Information Note no 5 2009.
Available at: http://www.who.int/foodsafety/publications/fs_management/No_05_Bisphenol_A_Nov09_en.pdf-9Rhomberg LR, Goodman JE. Low-dose effects and nonmonotonic dose-responses of endocrine disrupting chemicals: has the case been made? Regul Toxicol Pharmacol 2012; 64(1): 130-3. [http://dx.doi.org/10.1016/j.yrtph.2012.06.015] [PMID: 22750031] ], defined as “any biological changes occurring in the range of typical human exposures, or biological changes that occur at doses below those used in traditional toxicology studies” was suspected.
Pure BPA is not a component of dental composite resins. However, derivatives of BPA - from pure BPA - are widely used: bisphenol A diglycidyl methacrylate (bis-GMA) especially, but also bisphenol A dimethacrylate (bis-DMA), polycarbonate-modified bis-GMA (PC bis-GMA), ethoxylated bisphenol A glycol dimethacrylate (bis-EMA) and 2,2-bis[(4-methacryloxy polyethoxy)phenyl]propane (bis-MPEPP).
Several studies have investigated the levels of BPA and its derivatives in the saliva or urine after polymerization of a restoration made of a composite resin containing at least one of these monomers. The results vary: some studies in vitro [10American Dental Association Council on Scientific Affairs. Determination of bisphenol a released from resin-based composite dental restoratives. J Am Dent Assoc 2014; 145(7): 763-5. [http://dx.doi.org/10.14219/jada.2014.42] [PMID: 24982285] ] and in vivo [11Kingman A, Hyman J, Masten SA, et al. Bisphenol A and other compounds in human saliva and urine associated with the placement of composite restorations. J Am Dent Assoc 2012; 143(12): 1292-302. [http://dx.doi.org/10.14219/jada.archive.2012.0090] [PMID: 23204083] ] have detected some levels (in very low doses) and others do not detect any [12Lewis JB, Rueggeberg FA, Lapp CA, Ergle JW, Schuster GS. Identification and characterization of estrogen-like components in commercial resin-based dental restorative materials. Clin Oral Investig 1999; 3(3): 107-13. [http://dx.doi.org/10.1007/s007840050087] [PMID: 10803120] ]. This BPA elution would result from impurities in the synthesis of resins or their degradation [13Van Landuyt KL, Nawrot T, Geebelen B, et al. How much do resin-based dental materials release? A meta-analytical approach. Dent Mater 2011; 27(8): 723-47. [http://dx.doi.org/10.1016/j.dental.2011.05.001] [PMID: 21664675] ]. These variations can be explained by the different susceptibility of BPA derivatives to hydrolysis by salivary esterases. Bis-GMA does not undergo this reaction, because its chemical structure with stable ether bonds prevents hydrolysis. However, bis-DMA hydrolyzes at its ester bonds, releasing an amount of BPA that is not negligible. These differences could also be related to the detection technique [14Fleisch AF, Sheffield PE, Chinn C, Edelstein BL, Landrigan PJ. Bisphenol A and related compounds in dental materials. Pediatrics 2010; 126(4): 760-8. [http://dx.doi.org/10.1542/peds.2009-2693] [PMID: 20819896] ]. Furthermore, a recent study showed absorption of BPA by the sublingual area in dogs, allowing its direct entry into the bloodstream, by passing the digestive system and liver and multiplying its bioavailability by a factor of 80 [15Gayrard V, Lacroix MZ, Collet SH, et al. High bioavailability of bisphenol A from sublingual exposure. Environ Health Perspect 2013; 121(8): 951-6. [PMID: 23761051] ].
Yet, the exact composition of the composite resins on the market and the potential composite resins without BPA derivatives are not known. No study has sought to identify all monomers contained in the marketed composite resins.
The objectives of this study were first, to provide an exhaustive list of the composite resins sold in Europe and detail their composition and second, to estimate the number of composite resins using BPA or BPA derivatives (bis-GMA, bis-DMA, bis-EMA, bis-MPEPP, PC bis-GMA) in their manufacturing.
MATERIALS AND METHODOLOGY
To reference all composite resins sold in Europe, a search was conducted of the manufacturers' websites. Next, the composition of the composite resins was searched on the materials’ safety data sheet (MSDS) and using a standardized questionnaire sent to manufacturers. This questionnaire listed 13 monomers found in the MSDS and in the various studies of these materials; the manufacturer had to indicate, for each product, if the material contained these monomers or not, or else write “not disclosed” (ND). The manufacturer could also add monomers to the proposed list (Table 1). Manufacturers were contacted by email and/or telephone and the details were transmitted by email; they had 4 months to answer and an extra 2 months after a reminder email. When the manufacturer had not answered or the information was not available (MSDS, internet), the result was noted as “ND”. All results were recorded and analyzed by using Microsoft Excel 2008, v12.3.6.
Table 1 List of the surveyed monomers (found in materials’ safety data sheet and various studies of these resin composites and proposed to manufacturers) that resin composites can contain.
A total of 160 composite resins were identified from 31 companies (Table 2); 23 companies (74.2%) responded to the survey, with complete responses for 119/135 composite resins they marketed (88%). For the 8 manufacturers who did not respond (25.8%), the search of the internet and especially the MSDS provided responses for 11 of the 25 composite resins marketed (44%).
Table 2 List of the 160 composite resins marketed in Europe by 31 manufacturers and type of response (R) from the manufacturer (1: response; 2: partial response; 0: no response).
In total, 12 monomers were found in these 130 (119+11) composite resins; pure BPA was never reported. Table 3 reports their frequency of use.
Table 3 List of the 12 monomers contained in the surveyed composite resins (CR) and their frequency of use (among the 130 CR whose composition was established).
Table 4 List of the composite resins that contain no bis-GMA, no BPA-derivative (with UDMA), or neither BPA-derivative nor UDMA.
Among the 130 composite resins: 112 (86.2%) contained BPA derivatives, 97 (74.7%) bis-GMA and 43 (33.1%) bis-GMA and urethane dimethacrylate (UDMA); 17 (13.1%) contained no monomer derived from BPA (UDMA, sometimes with TEGDMA) and 6 (4,6%) with UDMA (only); 1 (0.8%) did not contain a BPA derivative or UDMA or TEGDMA (Table 4). 18 (13.8%) composite resins without any BPA derivative were identified. Among the 33 composite resins (25.4%) that did not contain bis-GMA, 24 (18.5%) did not contain bis-EMA and 18 (13.8%) did not contain bis-MPEPP. A single composite resin contained bis-DMA.
The adverse estrogenic effects of BPA are well established, which explains the new regulations banning this molecule, especially in food containers [4Agence nationale de sécurité sanitaire. Évaluation des risques du bisphénol A (BPA) pour la santé humaine. Rapport d’expertise collective 2013; 1-298.
Available at: https://www.anses.fr/en/system/files/CHIM2009sa0331Ra-0.pdf]. The elution of BPA sometimes detected after the making of a composite resin restoration remains far below toxic levels and at a certain time after placement, unpolymerized monomers would be completely absorbed into saliva, posing little risk of chronic low-dose BPA exposure, so some authors still encourage the use of molecules made from BPA [14Fleisch AF, Sheffield PE, Chinn C, Edelstein BL, Landrigan PJ. Bisphenol A and related compounds in dental materials. Pediatrics 2010; 126(4): 760-8. [http://dx.doi.org/10.1542/peds.2009-2693] [PMID: 20819896] , 16Chen L, Suh BI. Bisphenol A in dental materials: a review. JSM Dent 2013; 1: 1004.].
However, two factors seem to follow the recommendations against BPA content in composite resins. The first is related to the 2008 results of Bellinger et al. [17Bellinger DC, Trachtenberg F, Zhang A, Tavares M, Daniel D, McKinlay S. Dental amalgam and psychosocial status: the New England Children’s Amalgam Trial. J Dent Res 2008; 87(5): 470-4. [http://dx.doi.org/10.1177/154405910808700504] [PMID: 18434579] ], who demonstrated that in children 6 to 10 years’ old, the presence of composite resins was associated with a psychosocial behavior that was worse than with amalgams. These results were confirmed and clarified by Maserejian et al. in 2012 [18Maserejian NN, Trachtenberg FL, Hauser R, et al. Dental composite restorations and psychosocial function in children. Pediatrics 2012; 130(2): e328-38. [http://dx.doi.org/10.1542/peds.2011-3374] [PMID: 22802599] ], who indicated that the psychosocial behavior was worse for children with bis-GMA than UDMA composite resin restorations. Fortunately, the last studies of this team are more reassuring concerning sealants and fluid composite resin [19Maserejian NN, Shrader P, Trachtenberg FL, Hauser R, Bellinger DC, Tavares M. Dental sealants and flowable composite restorations and psychosocial, neuropsychological, and physical development in children. Pediatr Dent 2014; 36(1): 68-75. [PMID: 24717713] ] and concerning the renal function of the children [20Trachtenberg FL, Shrader P, Barregard L, Maserejian NN. Dental composite materials and renal function in children. Br Dent J 2014; 216(2): E4. [http://dx.doi.org/10.1038/sj.bdj.2014.36] [PMID: 24457893] ] or their immunity markers [21Maserejian NN, Shrader P, Brown OA, et al. Dental sealants and composite restorations and longitudinal changes in immune function markers in children. Int J Paediatr Dent 2014; 24(3): 215-25. [http://dx.doi.org/10.1111/ipd.12064] [PMID: 24033362] ]. Recently, Maserejian et al. [22Maserejian NN, Trachtenberg FL, Wheaton OB, et al. Changes in urinary bisphenol A concentrations associated with placement of dental composite restorations in children and adolescents. J Am Dent Assoc 2016; 147(8): 620-30. [http://dx.doi.org/10.1016/j.adaj.2016.02.020] [PMID: 27083778] ] in 2016 showed that placement of bis-GMA-based restorations in children and adolescents may temporarily increase BPA concentration in urine, but no longer detectable 14 days or 6 months after treatment. Second, BPA may have greater effects at low than high doses. Wozniack et al. [23Wozniak AL, Bulayeva NN, Watson CS. Xenoestrogens at picomolar to nanomolar concentrations trigger membrane estrogen receptor-alpha-mediated Ca2+ fluxes and prolactin release in GH3/B6 pituitary tumor cells. Environ Health Perspect 2005; 113(4): 431-9. [http://dx.doi.org/10.1289/ehp.7505] [PMID: 15811834] ] registered effects at doses of 1 pmol. The American National Toxicology Program [24Chapin RE, Adams J, Boekelheide K, et al. NTP-CERHR expert panel report on the reproductive and developmental toxicity of bisphenol A. Birth Defects Res B Dev Reprod Toxicol 2008; 83(3): 157-395. [http://dx.doi.org/10.1002/bdrb.20147] [PMID: 18613034] ] states that these low-dose effects can occur from 0.23 mg/L. This theory remains controversial [25Teeguarden JG, Hanson-Drury S. A systematic review of Bisphenol A “low dose” studies in the context of human exposure: a case for establishing standards for reporting “low-dose” effects of chemicals. Food Chem Toxicol 2013; 62: 935-48. [http://dx.doi.org/10.1016/j.fct.2013.07.007] [PMID: 23867546] ]. However, the European Food Safety Authority decided last year recently to divide by 10 the maximum daily dose allowed (or 5 mg/kg/day).
Moreover, exposure to BPA during gestation could induce increased spontaneous abortion, abnormal gestation time, reduced birth weight, increased male genital abnormalities, childhood obesity, but also altered behavior, disrupted neurodevelopment in children and increased asthma risk [26Rochester JR. Bisphenol A and human health: a review of the literature. Reprod Toxicol 2013; 42: 132-55. [http://dx.doi.org/10.1016/j.reprotox.2013.08.008] [PMID: 23994667] ]. Because of these potential adverse developmental effects after prenatal exposure to BPA, it would be cautious to limit exposure to unpolymerized dental resin materials during pregnancy. Thus, it could be relevant to select composite resins that do not contain these derivatives for at-risk populations, such pregnant women [27Braun JM, Yolton K, Dietrich KN, et al. Prenatal bisphenol A exposure and early childhood behavior. Environ Health Perspect 2009; 117(12): 1945-52. [http://dx.doi.org/10.1289/ehp.0900979] [PMID: 20049216] ] and as children [28Roen EL, Wang Y, Calafat AM, et al. Bisphenol A exposure and behavioral problems among inner city children at 7-9 years of age. Environ Res 2015; 142: 739-45. [http://dx.doi.org/10.1016/j.envres.2015.01.014] [PMID: 25724466] ].
Moreover, patients may ask about the possible bis-GMA content of composite resins. Whatever the opinion of the practitioner, he or she must know the composition of the composite resins used. In this study, 160 composite resins currently marketed by 31 manufacturers in Europe were identified. The composition of 130 (marketed by 23 manufacturers) was established: 112 (86.2%) contain BPA derivatives. Although we had a good response rate (74.2%), we could not obtain the composition of all the products because of strategic reasons, lack of reliable representatives or trade secrets.
In total, 25.8% of the manufacturers did not agree to communicate the composition of their composite resins. They are not required to indicate the exact composition of the materials, which should be required as for drugs. MSDS forms indicate the product’s composition only partially, often mentioning only the family of the molecules.
However, we should be cautioned against choosing one of the 18 composite resins without BPA derivatives: the latter contain other monomers that are not necessarily more biocompatible. Indeed, BPA is not the only potentially toxic monomer in composite resins; others may be toxic [29Goldberg M. In vitro and in vivo studies on the toxicity of dental resin components: a review. Clin Oral Investig 2008; 12(1): 1-8. [http://dx.doi.org/10.1007/s00784-007-0162-8] [PMID: 18040729] ]. In particular, the structure of TEGDMA and HEMA can be degraded by salivary esterases and result in liposoluble metabolites that could accumulate in fatty tissues [30Seiss M, Track N, Hickel R, Reichl FX. In vitro stability of methylmethacrylic acid, TEGDMA and HEMA exposed to esterases. Dent Mater 2009; 25(8): 1044-9. [http://dx.doi.org/10.1016/j.dental.2009.03.005] [PMID: 19361853] ]. Even UDMA, deemed less risky, may present some cytotoxicity beyond a certain concentration [31Wataha JC, Hanks CT, Strawn SE, Fat JC. Cytotoxicity of components of resins and other dental restorative materials. J Oral Rehabil 1994; 21(4): 453-62. [http://dx.doi.org/10.1111/j.1365-2842.1994.tb01159.x] [PMID: 7965356] ]. Whatever the composite resin, a certain rate of unpolymerized monomers is released, which is associated with their characteristics, the degree of polymerization and the release medium [32Ferracane JL. Elution of leachable components from composites. J Oral Rehabil 1994; 21(4): 441-52. [http://dx.doi.org/10.1111/j.1365-2842.1994.tb01158.x] [PMID: 7965355] ].
Indirect and CAD-CAM composite restorations maximize the conversion rate and thus minimize the release. Certain procedures reduce exposure to free monomers due to direct composite restorations: rubber dam use, prolonged curing (up to double the recommended time) or a second curing step after covering the restoration with glycerin. In addition, these free monomers are mostly present on the surface of the material, where the exposure to oxygen inhibits polymerization. Hence, Rueggeberg et al. [33Rueggeberg FA, Dlugokinski M, Ergle JW. Minimizing patients’ exposure to uncured components in a dental sealant. J Am Dent Assoc 1999; 130(12): 1751-7. [http://dx.doi.org/10.14219/jada.archive.1999.0132] [PMID: 10599178] ] and Komurcuoglu et al. [34Komurcuoglu E, Olmez S, Vural N. Evaluation of residual monomer elimination methods in three different fissure sealants in vitro. J Oral Rehabil 2005; 32(2): 116-21. [http://dx.doi.org/10.1111/j.1365-2842.2004.01405.x] [PMID: 15641977] ] showed that brushing the restoration’s surface with pumice allowed for removal of the inhibition layer and eliminated more than 90% of the residual monomers. Applying a dry or wet cotton roll and, to a lesser extent, water/air spray also enables their withdrawal up to 70%. Sasaki et al. [35Sasaki N, Okuda K, Kato T, et al. Salivary bisphenol-A levels detected by ELISA after restoration with composite resin. J Mater Sci Mater Med 2005; 16(4): 297-300. [http://dx.doi.org/10.1007/s10856-005-0627-8] [PMID: 15803273] ] showed that gargling with warm water for 30 sec after placement of the composite resin may reduce salivary levels of BPA.
Finally, using alternative materials without resin would be ideal; some high-viscosity glass ionomers or inorganic biomaterials, carbomers (albeit with lower mechanical and aesthetic properties) or ceramic (for extended restorations) may be considered.
This study has established a list of 18 BPA derivative-free products that can be used on a daily basis by the general practitioner. The respective long-term effects on human health of the different monomers remain unclear and deserve to be the subject of cohort studies.
Manufacturers should be required to report the exact composition of their products, as is required in the pharmaceutical industry, so that practitioners are able to communicate it to patients and to meet the traceability requirements.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of interest.
European Food Safety Authority. Opinion of the scientific panel on food additives, flavourings, processing aids and materials in contact with food (AFC) related to 2,2-bis(4-hydroxyphenyl)propane. EFSA J 2006; 428: 1-75.
vom Saal FS, Akingbemi BT, Belcher SM, et al. Chapel Hill bisphenol A expert panel consensus statement: integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure. Reprod Toxicol 2007; 24(2): 131-8. [http://dx.doi.org/10.1016/j.reprotox.2007.07.005] [PMID: 17768031]
American Dental Association Council on Scientific Affairs. Determination of bisphenol a released from resin-based composite dental restoratives. J Am Dent Assoc 2014; 145(7): 763-5. [http://dx.doi.org/10.14219/jada.2014.42] [PMID: 24982285]
Maserejian NN, Shrader P, Brown OA, et al. Dental sealants and composite restorations and longitudinal changes in immune function markers in children. Int J Paediatr Dent 2014; 24(3): 215-25. [http://dx.doi.org/10.1111/ipd.12064] [PMID: 24033362]
Maserejian NN, Trachtenberg FL, Wheaton OB, et al. Changes in urinary bisphenol A concentrations associated with placement of dental composite restorations in children and adolescents. J Am Dent Assoc 2016; 147(8): 620-30. [http://dx.doi.org/10.1016/j.adaj.2016.02.020] [PMID: 27083778]
Wozniak AL, Bulayeva NN, Watson CS. Xenoestrogens at picomolar to nanomolar concentrations trigger membrane estrogen receptor-alpha-mediated Ca2+ fluxes and prolactin release in GH3/B6 pituitary tumor cells. Environ Health Perspect 2005; 113(4): 431-9. [http://dx.doi.org/10.1289/ehp.7505] [PMID: 15811834]
Chapin RE, Adams J, Boekelheide K, et al. NTP-CERHR expert panel report on the reproductive and developmental toxicity of bisphenol A. Birth Defects Res B Dev Reprod Toxicol 2008; 83(3): 157-395. [http://dx.doi.org/10.1002/bdrb.20147] [PMID: 18613034]
Teeguarden JG, Hanson-Drury S. A systematic review of Bisphenol A “low dose” studies in the context of human exposure: a case for establishing standards for reporting “low-dose” effects of chemicals. Food Chem Toxicol 2013; 62: 935-48. [http://dx.doi.org/10.1016/j.fct.2013.07.007] [PMID: 23867546]