Abstract
Although some regulatory agencies have claimed that consumer exposures to tetrabromobisphenol A (TBBPA) are not likely to cause adverse health effects in humans or the environment, the safety of tetrabromobisphenol A (TBBPA) has been questioned. Here, we summarize the literature concerning in vivo and in vitro neurotoxicity of TBBPA over the past decades. Most laboratory rodent studies reported that gavage administration of TBBPA at doses below 1000 mg/kg/day generally exerted no or limited effects on neuropathology and locomotor behaviors, but increased anxiety and auditory impairments were observed in several studies. In fish and amphibians, waterborne exposure to TBBPA was generally reported to disrupt neurodevelopment and lead to neurobehavioral alterations. Moreover, in vitro studies support the observations that TBBPA could exert neurotoxic effects in vertebrates. Thus, we suggest that TBBPA could have adverse effects on the nervous system in vertebrates. Given rapid excretion and low availability of TBBPA in laboratory rodents following single gavage administration, we speculate that single-daily gavage could result in an underestimation of the neurotoxic effects of TBBPA in rodents. Thus, we propose to employ multiple-daily administration routes (such as dermal, inhalation, and drinking water), to further assess the neurotoxic effects of TBBPA in mammals.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
References
Bajard L, Melymuk L, Blaha L (2019) Prioritization of hazards of novel flame retardants using the mechanistic toxicology information from ToxCast and Adverse Outcome Pathways. Environ Sci Eur 31. https://doi.org/10.1186/s12302-019-0195-z
Cariou R, Antignac JP, Zalko D, Berrebi A, Cravedi JP, Maume D, Marchand P, Monteau F, Riu A, Andre F, Le Bizec B (2008) Exposure assessment of French women and their newborns to tetrabromobisphenol-A: occurrence measurements in maternal adipose tissue, serum, breast milk and cord serum. Chemosphere. 73:1036–1041. https://doi.org/10.1016/j.chemosphere.2008.07.084
Chen JF, Tanguay RL, Simonich M, Nie SF, Zhao YX, Li LL, Bai CL, Dong QX, Huang CJ, Lin KF (2016) TBBPA chronic exposure produces sex-specific neurobehavioral and social interaction changes in adult zebrafish. Neurotoxicol Teratol 56:9–15. https://doi.org/10.1016/j.ntt.2016.05.008
Cope RB, Kacew S, Dourson M (2015) A reproductive, developmental and neurobehavioral study following oral exposure of tetrabromobisphenol A on Sprague-Dawley rats. Toxicology. 329:49–59. https://doi.org/10.1016/j.tox.2014.12.013
EC (2008) COMMISSION RECOMMENDATION of 30 May 2008 on risk reduction measures for the substances sodium chromate, sodium dichromate and 2,2’,6,6’tetrabromo-4,4’-isopropylidenediphenol (tetrabromobisphenol A). Off J Eur Union. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A32008H0454&qid=1623824950752. Accessed 16 Apr 2021
ECB, (2006). European Union Risk Assessment Report—2,20,6,60-tetrabromo-4,40-isopropylidenediphenol (Tetrabromobisphenol-A or TBBP-A) (CAS: 79-94-7) Part-human Health, II-human Health., in: Bureau E C (Ed.).
EFSA (2011) Scientific opinion on tetrabromobisphenol A (TBBPA) and its derivatives in food. EFSA J 9:2477
Fini JB, Le Mevel S, Palmier K, Darras VM, Punzon I, Richardson SJ, Clerget-Froidevaux MS, Demeneix BA (2012) Thyroid hormone signaling in the Xenopus laevis embryo is functional and susceptible to endocrine disruption. Endocrinology. 153:5068–5081. https://doi.org/10.1210/en.2012-1463
Gu YX, Liang XX, Yin NY, Yang Y, Wan B, Guo LH, Faiola F (2019) New insights into mechanism of bisphenol analogue neurotoxicity: implications of inhibition of O-GlcNAcase activity in PC12 cells. Arch Toxicol 93:2661–2671. https://doi.org/10.1007/s00204-019-02525-3
Guyot R, Chatonnet F, Gillet B, Hughes S, Flamant F (2014) Toxicogenomic analysis of the ability of brominated flame retardants TBBPA and BDE-209 to disrupt thyroid hormone signaling in neural cells. Toxicology. 325:125–132. https://doi.org/10.1016/j.tox.2014.08.007
Hakk H, Letcher R (2003) Metabolism in the toxicokinetics and fate of brominated flame retardants—a review. Environ Int 29:801–828. https://doi.org/10.1016/S0160-4120(03)00109-0
Hamers T, Kamstra JH, Sonneveld E, Murk AJ, Kester MHA, Andersson PL, Legler J, Brouwer A (2006) In vitro profiling of the endocrine-disrupting potency of brominated flame retardants. Toxicol Sci 92:157–173. https://doi.org/10.1093/toxsci/kfj187
Hendriks HS, van Kleef RGDM, van den Berg M, Westerink RHS (2012) Multiple novel modes of action involved in the in vitro neurotoxic effects of tetrabromobisphenol-A. Toxicol Sci 128:235–246. https://doi.org/10.1093/toxsci/kfs136
Hendriks HS, Koolen LA, Dingemans MM, Viberg H, Lee I, Leonards PE, Ramakers GM, Westerink RH (2015) Effects of neonatal exposure to the flame retardant tetrabromobisphenol-A, aluminum diethylphosphinate or zinc stannate on long-term potentiation and synaptic protein levels in mice. Arch Toxicol 89:2345–2354. https://doi.org/10.1007/s00204-014-1366-8
Ho KL, Yuen KK, Yau MS, Murphy MB, Wan Y, Fong BM, Tam S, Giesy JP, Leung KS, Lam MH (2017) Glucuronide and sulfate conjugates of tetrabromobisphenol A (TBBPA): chemical synthesis and correlation between their urinary levels and plasma TBBPA content in voluntary human donors. Environ Int 98:46–53. https://doi.org/10.1016/j.envint.2016.09.018
Iakovleva I, Begum A, Brannstrom K, Wijsekera A, Nilsson L, Zhang J, Andersson PL, Sauer-Eriksson AE, Olofsson A (2016) Tetrabromobisphenol A is an efficient stabilizer of the transthyretin tetramer. PLoS One 11:e0153529. https://doi.org/10.1371/journal.pone.0153529
IARC (2018) IARC monographs on the evaluation of carcinogenic risks to humans. Some industrial chemicals. Volume 115. http://publications.iarc.fr/_publications/media/download/5407/6d629d6018d1032e3f3f2d61581b5bacab5f5525.pdf. Accessed 5 Mar 2021
International, W, 2002. Determination of water solubility of tetrabromobisphenol-A, in: Ltd. W I (Ed.).
Jarema KA, Hunter DL, Shaffer RM, Behl M, Padilla S (2015) Acute and developmental behavioral effects of flame retardants and related chemicals in zebrafish. Neurotoxicol Teratol 52:194–209. https://doi.org/10.1016/j.ntt.2015.08.010
Kacew S, Hayes AW (2020) Absence of neurotoxicity and lack of neurobehavioral consequences due to exposure to tetrabromobisphenol A (TBBPA) exposure in humans, animals and zebrafish. Arch Toxicol 94:59–66. https://doi.org/10.1007/s00204-019-02627-y
Kang MJ, Kim JH, Shin S, Choi JH, Lee SK, Kim HS, Kim ND, Kang GW, Jeong HG, Kang W, Chun YJ, Jeong TC (2009) Nephrotoxic potential and toxicokinetics of tetrabromobisphenol A in rat for risk assessment. J Toxicol Environ Health A 72:1439–1445. https://doi.org/10.1080/15287390903212907
Kim UJ, Oh JE (2014) Tetrabromobisphenol A and hexabromocyclododecane flame retardants in infant-mother paired serum samples, and their relationships with thyroid hormones and environmental factors. Environ Pollut 184:193–200. https://doi.org/10.1016/j.envpol.2013.08.034
Kim B, Colon E, Chawla S, Vandenberg LN, Suvorov A (2015) Endocrine disruptors alter social behaviors and indirectly influence social hierarchies via changes in body weight. Environ Health 14:64. https://doi.org/10.1186/s12940-015-0051-6
Kim AH, Chun HJ, Lee S, Kim HS, Lee J (2017) High dose tetrabromobisphenol A impairs hippocampal neurogenesis and memory retention. Food Chem Toxicol 106:223–231. https://doi.org/10.1016/j.fct.2017.05.053
Kitamura S, Kato T, Iida M, Jinno N, Suzuki T, Ohta S, Fujimoto N, Hanada H, Kashiwagi K, Kashiwagi A (2005) Anti-thyroid hormonal activity of tetrabromobisphenol A, a flame retardant, and related compounds: affinity to the mammalian thyroid hormone receptor, and effect on tadpole metamorphosis. Life Sci 76:1589–1601. https://doi.org/10.1016/j.lfs.2004.08.030
Klose J, Tigges J, Masjosthusmann S, Schmuck K, Bendt F, Hubenthal U, Petzsch P, Kohrer K, Koch K, Fritsche E (2020) TBBPA targets converging key events of human oligodendrocyte development resulting in two novel AOPs. ALTEX. https://doi.org/10.14573/altex.2007201
Knudsen GA, Hughes MF, McIntosh KL, Sanders JM, Birnbaum LS (2015) Estimation of tetrabromobisphenol A (TBBPA) percutaneous uptake in humans using the parallelogram method. Toxicol Appl Pharmacol 289:323–329. https://doi.org/10.1016/j.taap.2015.09.012
Knudsen GA, Hall SM, Richards AC, Birnbaum LS (2018) TBBPA disposition and kinetics in pregnant and nursing Wistar Han IGS rats. Chemosphere. 192:5–13. https://doi.org/10.1016/j.chemosphere.2017.10.122
Li AJ, Zhuang TF, Shi W, Liang Y, Liao CY, Song MY, Jiang GB (2020) Serum concentration of bisphenol analogues in pregnant women in China. Sci Total Environ 707:136100. https://doi.org/10.1016/j.scitotenv.2019.136100
Liang SJ, Liang SX, Zhou H, Yin NY, Faiola F (2019a) Typical halogenated flame retardants affect human neural stem cell gene expression during proliferation and differentiation via glycogen synthase kinase 3 beta and T3 signaling. Ecotoxicol Environ Saf 183:109498. https://doi.org/10.1016/j.ecoenv.2019.109498
Liang SX, Liang SJ, Yin NY, Hu BW, Faiola F (2019b) Toxicogenomic analyses of the effects of BDE-47/209, TBBPA/S and TCBPA on early neural development with a human embryonic stem cell in vitro differentiation system. Toxicol Appl Pharmacol 379:114685. https://doi.org/10.1016/j.taap.2019.114685
Lilienthal H, Verwer CM, van der Ven LT, Piersma AH, Vos JG (2008) Exposure to tetrabromobisphenol A (TBBPA) in Wistar rats: neurobehavioral effects in offspring from a one-generation reproduction study. Toxicology. 246:45–54. https://doi.org/10.1016/j.tox.2008.01.007
Nakajima A, Saigusa D, Tetsu N, Yamakuni T, Tomioka Y, Hishinuma T (2009) Neurobehavioral effects of tetrabromobisphenol A, a brominated flame retardant, in mice. Toxicol Lett 189:78–83. https://doi.org/10.1016/j.toxlet.2009.05.003
Noyes PD, Haggard DE, Gonnerman GD, Tanguay RL (2015) Advanced morphological-behavioral test platform reveals neurodevelopmental defects in embryonic zebrafish exposed to comprehensive suite of halogenated and organophosphate flame retardants. Toxicol Sci 145:177–195. https://doi.org/10.1093/toxsci/kfv044
NTP (2014) NTP technical report on the toxicology studies of tetrabromobisphenol A (CASRN 79-94-7) in F344/NTac rats and B6C3F1/N mice and toxicology and carcinogenesis studies of tetrabromobisphenol A in Wistar Han [Crl:WI(Han)] rats and B6C3F1/N mice (gavage studies), in: Services N T P P H S U S D o H a H (Ed.). https://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr587_508.pdf. Accessed 12 May 2021
Osimitz TG, Droege W, Hayes AW (2016) Subchronic toxicology of tetrabromobisphenol A in rats. Hum Exp Toxicol 35:1214–1226. https://doi.org/10.1177/0960327115627684
Park C, Kim SJ, Lee WK, Moon SK, Kwak S, Choe SK, Park R (2016) Tetrabromobisphenol-A induces apoptotic death of auditory cells and hearing loss. Biochem Biophys Res Commun 478:1667–1673. https://doi.org/10.1016/j.bbrc.2016.09.001
Per Eriksson EJ, Fredriksson A (2001) Brominated flame retardants: a novel class of developmental neurotoxicants in our environment? Environ Health Perspect 109:903–908. https://doi.org/10.1289/ehp.01109903
Rock KD, Gillera SEA, Devarasetty P, Horman B, Knudsen G, Birnbaum LS, Fenton SE, Patisaul HB (2019) Sex-specific behavioral effects following developmental exposure to tetrabromobisphenol A (TBBPA) in Wistar rats. Neurotoxicology. 75:136–147. https://doi.org/10.1016/j.neuro.2019.09.003
Saegusa Y, Fujimoto H, Woo G-H, Inoue K, Takahashi M, Mitsumori K, Hirose M, Nishikawa A, Shibutani M (2009) Developmental toxicity of brominated flame retardants, tetrabromobisphenol A and 1,2,5,6,9,10-hexabromocyclododecane, in rat offspring after maternal exposure from mid-gestation through lactation. Reprod Toxicol 28:456–467. https://doi.org/10.1016/j.reprotox.2009.06.011
Schauer UM, Volkel W, Dekant W (2006) Toxicokinetics of tetrabromobisphenol a in humans and rats after oral administration. Toxicol Sci 91:49–58. https://doi.org/10.1093/toxsci/kfj132
Shi ZX, Jiao Y, Hu Y, Sun ZW, Zhou XQ, Feng JF, Li JG, Wu YN (2013) Levels of tetrabromobisphenol A, hexabromocyclododecanes and polybrominated diphenyl ethers in human milk from the general population in Beijing, China. Sci Total Environ 452-453:10–18. https://doi.org/10.1016/j.scitotenv.2013.02.038
Siracusa JS, Yin L, Measel E, Liang S, Yu X (2018) Effects of bisphenol A and its analogs on reproductive health: a mini review. Reprod Toxicol 79:96–123. https://doi.org/10.1016/j.reprotox.2018.06.005
Slotkin TA, Skavicus S, Stapleton HM, Seidler FJ (2017) Brominated and organophosphate flame retardants target different neurodevelopmental stages, characterized with embryonic neural stem cells and neuronotypic PC12 cells. Toxicology. 390:32–42. https://doi.org/10.1016/j.tox.2017.08.009
Szychowski KA, Wojtowicz AK (2013) Components of plastic disrupt the function of the nervous system. Postepy Hig Med Dosw 20(67):499–506. https://doi.org/10.5604/17322693.1051001
Szychowski KA, Wojtowicz AK (2016) TBBPA causes neurotoxic and the apoptotic responses in cultured mouse hippocampal neurons in vitro. Pharmacol Rep 68:20–26. https://doi.org/10.1016/j.pharep.2015.06.005
Van der Ven LTM, Van de Kuil T, Verhoef A, Verwer CM, Lilienthal H, Leonards PEG, Schauer UMD, Cantón RF, Litens S, De Jong FH, Visser TJ, Dekant W, Stern N, Håkansson H, Slob W, Van den Berg M, Vos JG, Piersma AH (2008) Endocrine effects of tetrabromobisphenol-A (TBBPA) in Wistar rats as tested in a one-generation reproduction study and a subacute toxicity study. Toxicology 245:76–89. https://doi.org/10.1016/j.tox.2007.12.009
Veldhoen N, Boggs A, Walzak K, Helbing CC (2006) Exposure to tetrabromobisphenol-A alters TH-associated gene expression and tadpole metamorphosis in the Pacific tree frog Pseudacris regilla. Aquat Toxicol 78:292–302. https://doi.org/10.1016/j.aquatox.2006.04.002
Viberg H, Eriksson P (2011) Differences in neonatal neurotoxicity of brominated flame retardants, PBDE 99 and TBBPA, in mice. Toxicology. 289:59–65. https://doi.org/10.1016/j.tox.2011.07.010
Ye GZ, Chen YJ, Wang H-o, Ye T, Lin Y, Huang QS, Chi YL, Dong SJ (2016) Metabolomics approach reveals metabolic disorders and potential biomarkers associated with the developmental toxicity of tetrabromobisphenol A and tetrachlorobisphenol A. Sci Rep 6:35257. https://doi.org/10.1038/srep35257
Yin NY, Liang SJ, Liang SX, Yang RJ, Hu BW, Qin ZF, Liu AF, Faiola F (2018) TBBPA and its alternatives disturb the early stages of neural development by interfering with the NOTCH and WNT pathways. Environ Sci Technol 52:5459–5468. https://doi.org/10.1021/acs.est.8b00414
Yu YJ, Yu ZL, Chen HB, Han YJ, Xiang MD, Chen XC, Ma RX, Wang ZD (2019) Tetrabromobisphenol A: disposition, kinetics and toxicity in animals and humans. Environ Pollut 253:909–917. https://doi.org/10.1016/j.envpol.2019.07.067
Zhang YF, Xu W, Lou QQ, Li YY, Zhao YX, Wei WJ, Qin ZF, Wang HL, Li JZ (2014) Tetrabromobisphenol A disrupts vertebrate development via thyroid hormone signaling pathway in a developmental stage-dependent manner. Environ Sci Technol 48:8227–8234. https://doi.org/10.1021/es502366g
Zhou H, Yin N, Faiola F (2020) Tetrabromobisphenol A (TBBPA): a controversial environmental pollutant. J Environ Sci 97:54–66. https://doi.org/10.1016/j.jes.2020.04.039
Zhu BR, Zhao G, Yang LH, Zhou BS (2018) Tetrabromobisphenol A caused neurodevelopmental toxicity via disrupting thyroid hormones in zebrafish larvae. Chemosphere. 197:353–361. https://doi.org/10.1016/j.chemosphere.2018.01.080
Zhu B, Han J, Lei L, Hua J, Zuo Y, Zhou B (2021) Effects of SiO2 nanoparticles on the uptake of tetrabromobisphenol A and its impact on the thyroid endocrine system in zebrafish larvae. Ecotoxicol Environ Saf 209:111845. https://doi.org/10.1016/j.ecoenv.2020.111845
Acknowledgements
The reviews and editors are appreciated for comments and suggestions to improve the paper.
Funding
This work was supported by the National Natural Science Foundation of China (21876196) and the National Key Research and Development Program of China (2018YFA0901103).
Author information
Authors and Affiliations
Contributions
Z.Q. had the idea for the article, M.D. performed the literature search and data analysis, Y.L. and M.Z. gave meaningful suggestions for the article. All authors drafted and/or critically revised the work.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Conflict of interest
The authors declare no competing interests.
Additional information
Responsible Editor: Ludek Blaha
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Dong, M., Li, Y., Zhu, M. et al. Tetrabromobisphenol A: a neurotoxicant or not?. Environ Sci Pollut Res 28, 54466–54476 (2021). https://doi.org/10.1007/s11356-021-15166-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11356-021-15166-w