Endocrine Disruption Potentials of Bisphenol A Alternatives - Are Bisphenol A Alternatives Safe from Endocrine Disruption?

Ji, Kyunghee;Choi, Kyungho

  • Received : 2013.02.07
  • Accepted : 2013.02.22
  • Published : 2013.02.28


Objectives: Although a great body of knowledge is available on the toxicity of bisphenol A (BPA), little is known about that of BPA alternatives, such as bisphenol analogues (BPs) or $Tritan^{TM}$ copolyesters. This review provides a summary of the available information on the toxicity of BPs and three components of $Tritan^{TM}$, with a special focus on endocrine disruption. Methods: We collected from the literature a battery of in vitro and in vivo assay data developed to assess endocrine disruption of four BPs (bisphenol AF, B, F, and S) and three major components of $Tritan^{TM}$ ((di-methylterephthalate (DMT), 1,4-cyclohexanedimethanol (CHDM), and 2,2,4,4-tetramethyl-1,3-cyclobutanediol (TMCD)). Results: Several alternative compounds were identified as possessing comparable or even greater endocrinedisrupting effects than BPA in in vitro and in vivo studies. Conclusions: Potential endocrine disruption of BPA alternatives requires further studies on health consequences in experimental animals and in humans following longer term exposure.


bisphenols;endocrine disruption;Tritan


  1. Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM, et al. Endocrine- disrupting chemicals: an Endocrine society scientific statement. Endocrine Reviews. 2009; 30: 293-342.
  2. Liao C, Liu F, Alomirah H, Loi VD, Mohd MA, Moon HB, et al. Bisphenol S in urine from the United States and seven Asian countries: occurrence and human exposures. Environ Sci Technol. 2012b; 46: 6860-6866.
  3. Goodman JE, Witorsch RJ, McConnell EE, Sipes IG, Slayton TM, Yu CJ, et al. Weight-of-evidence evaluation of reproductive and developmental effects of low doses of bisphenol A. Crit Rev Toxicol. 2009; 39: 1-75.
  4. Zhang X, Chang H, Wiseman S, He Y, Higley E, Jones P, et al. Bisphenol A disrupts steroidogenesis in human H295R cells. Toxicol Sci. 2011; 121: 320-327.
  5. Vandenberg LN, Chahoud I, Heindel JJ, Padmanabhan V, Paumgartten FJR, Schoenfelder G. Urinary, circulating, and tissue biomonitoring studies indicate widespread exposure to bisphenol A. Environ Health Perspect. 2010; 118: 1055-1070.
  6. Volkel W, Colnot T, Csanady GA, Filsner JG, Dekant W. Metabolism and kinetics of bisphenol A in humans at low doses following oral administration. Chem Res Toxicol 2002; 15: 1281-1287.
  7. Volkel W, Bittner N, Dekant W. Quantitation of bisphenol A and bisphenol A glucuronide in biological samples by high performance liquid chromatography- tandem mass spectrometry. Drug Metab Dispos 2005; 33: 1748-1757.
  8. European Commission. 2011. Commission directive 2011/8/EU of 28 January 2011 on the restriction of use of Bisphenol A in plastic infant feeding bottles. Available: [accessed 4 February 2013].
  9. Osimitz TG, Eldridge ML, Sloter E, Welsh W, Ai N, Sayler GS, et al. Lack of androgenicity and estrogenicity of the three monomers used in Eastman’s TritanTM copolyesters. Food Chem Toxicol. 2012; 50: 2196-2205.
  10. Danzl E, Sei K, Soda S, Ike M, Fujita M. Biodegradation of bisphenol A, bisphenol F and bisphenol S in seawater. Int J Environ Res Public Health. 2009; 6: 1472-1484.
  11. Akahori Y, Nakai M, Yamasaki K, Takatsuki M, Shimohigashi Y, Ohtaki M. Relationship between the results of in vitro receptor binding assay to human estrogen receptor alpha and in vivo uterotrophic assay: comparative study with 65 selected chemicals. Toxicol In Vitro. 2008; 22: 225-231.
  12. Li Y, Burns KA, Arao Y, Luh CJ, Korach KS. Differential estrogenic actions of endocrine-disrupting chemicals bisphenol A, bisphenol AF, and zearalenone through estrogen receptor $\alpha$ and $\beta$ in vitro. Environ Health Perspect. 2012; 120: 1029- 1035.
  13. Matsushima A, Liu X, Okada H, Shimohigashi M, Shimohigashi Y. Bisphenol AF is a full agonist for the estrogen receptor $ER\alpha$ but a highly specific antagonist for ERa. Environ Health Perspect. 2010; 118: 1267-1272.
  14. Perez P, Pulgar R, Olea-Serrano F, Villalobos M, Rivas A, Metzler M, et al. The estrogenicity of bisphenol A-related diphenylalkanes with various substituents at the central carbon and the hydroxyl groups. Environ Health Perspect. 1998; 106: 167-174.
  15. Stout MD. 2008. NTP research concept: Bisphenol AF. Available: BPAF_Concept_final-100608_508.pdf [accessed 4 February 2013].
  16. Yoshihara S, Mizutare T, Makishima M, Suzuki N, Fujimoto N, Igarashi K, et al. Potent estrogenic metabolites of bisphenol A and bisphenol B formed by rat liver S9 fraction: their structures and estrogenic potency. Toxicol Sci. 2004; 78: 50-59.
  17. Fromme H, Küchler T, Otto T, Pilz K, Müller J, Wenzel A. Occurrence of phthalates and bisphenol A and F in the environment. Water Res. 2002; 36: 1429-1438.
  18. Kuruto-Niwa R, Nozawa R, Miyakoshi T, Shiozawa T, Terao Y. Estrogenic activity of alkylphenols, bisphenol S, and their chlorinated derivatives using a GFP expression system. Environ Toxicol Pharmacol. 2005; 19: 121-130.
  19. Simoneau C, Valzacchi S, Morkunas V, Van den Eede L. Comparison of migration from polyethersulphone and polycarbonate baby bottles. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2011; 28: 1763-1768.
  20. Watanabe M, Fukazawa H, Shiraishi F, Shiraishi H, Shiozawa T, Terao T. Analysis and estrogenic activity of bisphenol A and other chemicals released from waste paper by pulping. J Environ Chem. 2004; 14: 65.
  21. Ball GL, McLellan CJ, Bhat VS. Toxicological review and oral risk assessment of terephthalic acid (TPA) and its esters: a category approach. Crit Rev Toxicol. 2012; 42: 28-67.
  22. US EPA. 2010. Office of Pollution Prevention and Toxics. ChemRTK 1990 HPV challenge program chemicals list. Available: [accessed 4 February 2013].
  23. OECD. 2009. The 2007 OECD list of high production volume chemicals. ENV/JM/MONO(2009)40. OECD. Paris, France 23 October 2009. Available: cote=env/jm/mono(2009)40&doclanguage= en [accessed 4 February 2013].
  24. Liao C, Liu F, Guo Y, Moon HB, Nakata H, Wu Q, et al. Occurrence of eight bisphenol analogues in indoor dust from the United States and several Asian countries: Implications for human exposure. Environ Sci Technol. 2012d; 46: 9138-9145.
  25. Cobellis L, Colacurci N, Trabucco E, Carpentiero C, Grumetto L. Measurement of bisphenol A and bisphenol B levels in human blood sera from healthy and endometriotic women. Biomed Chromatogr. 2009; 23: 1186-1190.
  26. Cunha SC, Fernandes JO. Quantification of free and total bisphenol A and bisphenol B in human urine by dispersive liquid-liquid microextraction (DLLME) and heart-cutting multidimensional gas chromatography-mass spectrometry (MD-GC/MS). Talanta. 2010; 83: 117-125.
  27. Grumetto L, Montesano D, Seccia S, Albrizio S, Barbato F. Determination of bisphenol A and bisphenol B residues in canned peeled tomatoes by reversed-phase liquid chromatography. J Agric Food Chem. 2008; 56: 10633-10637.
  28. Gallart-Ayala H, Moyano E, Galceran M.T. Analysis of bisphenols in soft drinks by on-line solid phase extraction fast liquid chromatography-tandem mass spectrometry. Anal Chim Acta. 2011; 683: 227-233.
  29. Liao C, Kannan K. Widespread occurrence of bisphenol A in paper and paper products: Implications for human exposure. Environ Sci Technol. 2011; 45: 9372-9379.
  30. Liao C, Liu F, Kannan K. Bisphenol S, a new bisphenol analogue, in paper products and currency and its association with bisphenol a residues. Environ Sci Technol. 2012a; 46: 6515-6522.
  31. Liao C, Liu F, Moon HB, Yamashita N, Yun S, Kannan K. Bisphenol analogues in sediments from industrialized areas in the United States, Japan, and Korea: spatial and temporal distributions. Environ Sci Technol. 2012c; 46: 11558-11565.
  32. Vinas P, Campillo N, Martinez-Castillo N, Hernandez- Cordoba M. Comparison of two derivatizationbased methods for solid-phase microextraction-gas chromatography-mass spectrometric determination of bisphenol A, bisphenol S and bisphenol migrated from food cans. Anal Bioanal Chem. 2010; 397: 115-125.
  33. Chen MY, Ike M, Fujita M. Acute toxicity, mutagenicity, and estrogenicity of bisphenol-A and other bisphenols. Environ Toxicol. 2002; 17: 80-86.
  34. Kitamura S, Suzuki T, Sanoh S, Kohta R, Jinno N, Sugihara K, et al. Comparative study of the endocrine- disrupting activity of bisphenol A and 19 related compounds. Toxicol Sci. 2005; 84: 249-
  35. Blair RM, Fang H, Branham WS, Hass BS, Dial SL, Moland CL, Tong W, Shi L, Perkins R, Sheehan D.M. The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands. Toxicol Sci. 2000; 54: 138-153.
  36. Grignard E, Lapenna S, Bremer S. Weak estrognic transcriptional activities of bisphenol A and bisphenol S. Toxicol In Vitro. 2012; 26: 727-731.
  37. Bermudez DS, Gray Jr LE, Wilson VS. Modeling the interaction of binary and ternary mixtures of estradiol with bisphenol A and bisphenol AF in an in vitro estrogen-mediated transcriptional activation assay (T47D-KBluc). Toxicol Sci. 2010; 116: 477-487.
  38. Yamasaki K, Takeyoshi M, Sawaki M, Imatanaka N, Shinoda K, Takatsuki M. Immature rat uterotrophic assay of 18 chemicals and Hershberger assay of 30 chemicals. Toxicology. 2003; 183: 93-115.
  39. Feng Y, Yin J, Jiao Z, Shi J, Li M, Shao B. Bisphenol AF may cause testosterone reduction by directly affecting testis function in adult male rats. Toxicol Lett. 2012; 211: 201-209.
  40. Hashimoto Y, Moriguchi Y, Oshima H, Kawaguchi M, Miyazaki K, Nakamura M. Measurement of estrogenic activity of chemicals for the development of new dental polymers. Toxicol In Vitro. 2001; 15:
  41. Rivas A, Lacroix M, Olea-Serrano F, Laïos I, Leclercq G, Olea N. Estrogenic effect of a series of bisphenol analogues on gene and protein expression in MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2002; 82: 45-53.
  42. Yamasaki K, Takeyoshi M, Yakabe Y, Sawaki M, Imatanaka N, Takatsuki M. Comparison of reporter gene assay and immature rat uterotrophic assay of twenty-three chemicals. Toxicology. 2002; 170: 21-30.
  43. Hashimoto Y, Nakamura M. Estrogenic activity of dental materials and bisphenol-A related chemicals in vitro. Dent Mater J. 2000; 19: 245.
  44. Zhang HC, Chen LY, Liu SS, Yin DQ. Jointed estrogenic activities of bisphenol A and three of its analogs. Huan Jing Ke Xue. 2009; 30: 260-265.
  45. Stroheker T, Picard K, Lhuguenot JC, Canivenc- Lavier MC, Chagnon MC. Steroid activities comparison of natural and food wrap compounds in human breast cancer cell lines. Food Chem Toxicol. 2004; 42: 887-897.
  46. Cabaton N, Dumont C, Severin I, Perdu E, Zalko D, Cherkaoui-Malki M, et al. Genotoxic and endocrine activities of bis(hydroxyphenyl)methane (bisphenol F) and its derivatives in the HepG2 cell line. Toxicology 2009; 255: 15-24.
  47. Satoh K, Ohyama K, Aoki N, Iida M, Nagai F. Study on anti-androgenic effects of bisphenol A diglycidyl ether (BADGE), bisphenol F diglycidyl ether (BFDGE) and their derivatives using stably transfected with human androgen receptor, AREcoScreen. Food Chem Toxicol. 2004; 42: 983-993.
  48. Gallegos Saliner A, Amat L, Carbo-Dorca R, Schultz TW, Cronin MT. Molecular quantum similarity analysis of estrogenic activity. J Chem Inf Comput Sci. 2003; 43: 1166-1176.
  49. Yang C, Yaniger S, Jordan VC, Klein D, Bittner G. Most plastic products release estrogenic chemicals: a potential health problem that can be solved. Environ Health Perspect. 2011; 119: 989-996.
  50. US FDA. 2011. Inventory of Effective Food Contact Substance (FCS) Notifications: FCN No. 1041. Available: scripts/fcn/fcnDetailNavigation.cfm?rpt=fcsListing &id=1041 [accessed 4 February 2013].
  51. European Commission. 2011. Commission Regulation (EU) No. 10/2011 of 14 January 2011 on Plastic Materials and Articles Intended to Come into Contact with Food Text with EEA Relevance. Available: [accessed 4 February 2013].
  52. Ike M, Chen MY, Danzl E, Sei K, Fujita M. Biodegradation of a variety of bisphenols under aerobic and anaerobic conditions. Water Sci Technol. 2006; 53: 153-159.

Cited by

  1. Bioaccumulation and biomagnification of emerging bisphenol analogues in aquatic organisms from Taihu Lake, China vol.598, 2017,