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Mammalian toxicology and human exposures to the flame retardant 2,2′,6,6′-tetrabromo-4,4′-isopropylidenediphenol (TBBPA): implications for risk assessment

Abstract

The compound 2,2′,6,6′-Tetrabromo-4,4′-isopropylidenediphenol (tetrabromobisphenol A, TBBPA) is used as a reactive and additive flame retardant. This review evaluates the mammalian toxicology of TBBPA and summarizes recent human exposure and risk assessments. TBBPA has a low potential for systemic or reproductive toxicity, and no-observed-adverse-effect-levels were greater than 1,000 mg/kg body weight (bw)/day in a 90-day oral toxicity study, a developmental toxicity study and a two-generation reproductive and developmental toxicity study. Some interactions of TBBPA with hormone-mediated pathways were noted in vitro; however, when studied in vivo, TBBPA did not produce adverse effects that might be considered to be related to disturbances in the endocrine system. Therefore, in accordance with internationally accepted definitions, TBBPA should not be considered an “endocrine disruptor.” Furthermore, TBBPA is rapidly excreted in mammals and therefore does not have a potential for bioaccumulation. Measured concentrations of TBBPA in house dust, human diet and human serum samples are very low. Daily intakes of TBBPA in humans were estimated to not exceed a few ng/kg bw/day. Due to the low exposures and the low potential for toxicity, margins of exposures for TBBPA in the human population were between 6 × 104 (infants) to 6 × 107 (adults). Exposures of the general population are also well below the derived-no-effect-levels derived for endpoints of potential concern in REACH.

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Fig. 1

Abbreviations

ADME:

Absorption, distribution, metabolism, and excretion

AR:

Androgen receptor

BMD:

Benchmark dose

Bw:

Body weight

DHPN:

N-nitroso bis(2-hydroxypropyl)amine

DMBA:

7,12-Dimethylbenz(a)anthracene

DNEL:

Derived-no-effect-level

ECHA:

European chemicals agency

ER:

Estrogen receptor

EU:

European Union

GD:

Gestational day

GLP:

Good laboratory practice

LOAEL:

Lowest-observed-adverse-effect-level

LOD:

Limits of detection

MoE:

Margin-of-exposure

MOS:

Margin-of-safety

NOAEL:

No-observed-adverse-effect-level

OECD:

Organisation for economic co-operation and development

PoD:

Point-of-departure

PPAR:

Peroxisome proliferator–activated receptors

PR:

Progesterone receptor

T3:

Triiodothyronine

T4:

Thyroxine

TBBPA:

2,2′,6,6′-Tetrabromo-4,4′-isopropylidenediphenol; tetrabromobisphenol A

TH:

Thyroid hormone

TTR:

Thyroid hormone-binding transport protein

References

  • Abdallah MA, Harrad S (2011) Tetrabromobisphenol-A, hexabromocyclododecane and its degradation products in UK human milk: relationship to external exposure. Environ Int 37:443–448. doi:10.1016/j.envint.2010.11.008

    CAS  PubMed  Article  Google Scholar 

  • Al-Mousa F, Michelangeli F (2012) Some commonly used brominated flame retardants cause Ca2+ -ATPase inhibition, beta-amyloid peptide release and apoptosis in SH-SY5Y neuronal cells. PLoS ONE 7:33059

    Article  Google Scholar 

  • Alberta (2008) Chemicals in serum of pregnant women in Alberta. Alberta Health and Wellness, Alberta Biomonitoring Program, Edmonton Surveillance and Environmental Health, Public Health Division ISBN: 978-0-7785-6695-3, pp 148. http://www.health.alberta.ca/documents/Chemical-Biomonitoring-2008.pdf

  • Arcadis (2011) Evaluation of data on flame retardants in consumer products—final report prepared for European Commission—DG Health and Consumers, Brussel by ARCADIS, Berchem, Belgium Contract number 17020200/09/549040

  • Banasik M, Hardy M, Harbison RD, Hsu CH, Stedeford T (2009) Tetrabromobisphenol A and model-derived risks for reproductive toxicity. Toxicology 260:150–152 (author reply 153–154)

    Google Scholar 

  • Batterman S, Godwin C, Chernyak S, Jia C, Charles S (2010) Brominated flame retardants in offices in Michigan, USA. Environ Int 36:548–556. doi:10.1016/j.envint.2010.04.008

    CAS  PubMed  Article  Google Scholar 

  • BfR (2011) Joint DE—UK position paper. Regulatory definition of an endocrine disrupter in relation to potential threat to human health. Bundesinstitut für Risikobewertung. http://www.bfr.bund.de/cm/349/regulatory_definition_of_an_endocrine_disrupter_in_relation_to_potential_threat_to_human_health.pdf. Accessed 12 Nov 2012

  • Brady UE (1979) Pharmacokinetic study of tetrabromobisphenol A (BP-4A) in rats. Report from Athens, Georgie, University of Georgia (Report to Velsicol Chemical Corporation, Chicago, submitted to WHO by the Brominated Flame Retardant Industry Panel) as cited in WHO/IPCS (1995)

  • Butt CM, Wang D, Stapleton HM (2011) Halogenated phenolic contaminants inhibit the in vitro activity of the thyroid-regulating deiodinases in human liver. Toxicol Sci 124:339–347. doi:10.1093/toxsci/kfr117

    CAS  PubMed  Article  Google Scholar 

  • Canada (2012) Draft screening assessment report of phenol, 4,4’-(1-methylethylidene) bis[2,6-dibromo- (Tetrabromobisphenol A, TBBPA; CAS 79-94-7), ethanol, 2,2′-[(1-methylethylidene)bis[(2,6-dibromo-4,1-phenylene)oxy]]bis (known as TBBPA bis(2-hydroxyethyl ether, CAS 4162-45-2) and benzene, 1,1’-(1-methylethylidene)bis[3,5-dibromo-4-(2-propenyloxy)-(TBBPA bis(allylether, CAS 25327-89-3). Environment Canada, Ministry of Environment and Health

  • Canton RF, Sanderson JT, Nijmeijer S, Bergman A, Letcher RJ, van den Berg M (2006) In vitro effects of brominated flame retardants and metabolites on CYP17 catalytic activity: a novel mechanism of action? Toxicol Appl Pharmacol 216:274–281. doi:10.1016/j.taap.2006.05.007

    CAS  PubMed  Article  Google Scholar 

  • Carignan CC, Abdallah MA, Wu N, Heiger-Bernays W, McClean MD, Harrad S, Webster TF (2012) Predictors of tetrabromobisphenol-A (TBBP-A) and hexabromocyclododecanes (HBCD) in milk from Boston mothers. Environ Sci Technol 46:12146–12153. doi:10.1021/es302638d

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • 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. doi:10.1016/j.chemosphere.2008.07.084

    CAS  PubMed  Article  Google Scholar 

  • Choksi NY, Jahnke GD, St Hilaire C, Shelby M (2003) Role of thyroid hormones in human and laboratory animal reproductive health. Birth Defects Res B Dev Reprod Toxicol 68:479–491. doi:10.1002/bdrb.10045

    CAS  PubMed  Article  Google Scholar 

  • Christen V, Crettaz P, Oberli-Schrammli A, Fent K (2010) Some flame retardants and the antimicrobials triclosan and triclocarban enhance the androgenic activity in vitro. Chemosphere 81:1245–1252. doi:10.1016/j.chemosphere.2010.09.031

    CAS  PubMed  Article  Google Scholar 

  • Christian MS, Trenton NA (2003) Evaluation of thyroid function in neonatal and adult rats: the neglected endocrine mode of action. Pure Appl Chem 75:2055–2068 doi:10.1351/pac200375112055

    Google Scholar 

  • COT (2004) COT statement on tetrabromobisphenol A—review of toxicological data. UK Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment

  • Covaci A, Voorspoels S, Abdallah MA, Geens T, Harrad S, Law RJ (2009) Analytical and environmental aspects of the flame retardant tetrabromobisphenol-A and its derivatives. J Chromatogr A 1216:346–363. doi:10.1016/j.chroma.2008.08.035

    CAS  PubMed  Article  Google Scholar 

  • D’Hollander W, Roosens L, Covaci A, Cornelis C, Reynders H, Campenhout KV, Voogt P, Bervoets L (2010) Brominated flame retardants and perfluorinated compounds in indoor dust from homes and offices in Flanders, Belgium. Chemosphere 81:478–487. doi:10.1016/j.chemosphere.2010.07.043

    PubMed  Article  Google Scholar 

  • Dallaire R, Ayotte P, Pereg D, Dery S, Dumas P, Langlois E, Dewailly E (2009) Determinants of plasma concentrations of perfluorooctanesulfonate and brominated organic compounds in Nunavik Inuit adults (Canada). Environ Sci Technol 43:5130–5136

    CAS  PubMed  Article  Google Scholar 

  • de Winter-Sorkina R, Bakker MI, van Donkersgoed G, van Klaveren JD (2003) Dietary intake of brominated flame retardants by the Dutch population. RIVM report 31305001/2003. RIVM, Netherlands Institute of Public Health and the Environment

  • Decherf S, Demeneix BA (2011) The obesogen hypothesis: a shift of focus from the periphery to the hypothalamus. J Toxicol Environ Health B Crit Rev 14:423–448. doi:10.1080/10937404.2011.578561

    CAS  PubMed  Article  Google Scholar 

  • Decherf S, Seugnet I, Fini JB, Clerget-Froidevaux MS, Demeneix BA (2010) Disruption of thyroid hormone-dependent hypothalamic set-points by environmental contaminants. Mol Cell Endocrinol 323:172–182. doi:10.1016/j.mce.2010.04.010

    CAS  PubMed  Article  Google Scholar 

  • Dominick MA, White MR, Sanderson TP, Van Vleet T, Cohen SM, Arnold LE, Cano M, Tannehill-Gregg S, Moehlenkamp JD, Waites CR, Schilling BE (2006) Urothelial carcinogenesis in the urinary bladder of male rats treated with muraglitazar, a PPAR alpha/gamma agonist: Evidence for urolithiasis as the inciting event in the mode of action. Toxicol Pathol 34:903–920. doi:10.1080/01926230601072327

    CAS  PubMed  Article  Google Scholar 

  • Driffield M, Harmer N, Bradley E, Fernandes AR, Rose M, Mortimer D, Dicks P (2008) Determination of brominated flame retardants in food by LC-MS/MS: diastereoisomer-specific hexabromocyclododecane and tetrabromobisphenol A. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 25:895–903. doi:10.1080/02652030701882999

    CAS  PubMed  Article  Google Scholar 

  • EC-CSTEE (2001) Scientific committee on toxicity, ecotoxicity and the environment: position paper on margins of safety (MOS) in human health risk assessment expressed at the 22nd CSTEE plenary meeting, Brussels, 06/07 March 2001

  • EC-EFSA (2012) european food safety authority scientific committee: scientific opinion on the applicability of the margin of exposure approach for the safety assessment of impurities which are both genotoxic and carcinogenic in substances added to food/feed. The EFSA J 10:2578

    Google Scholar 

  • EC-SCENIHR (2005) Scientific committee on emerging and newly identified health risks: memorandum on the use of the scientific literature for human health risk assessment purposes—weighing of evidence and expression of uncertainty. Adopted by the SCENIHR at its 17th plenary of 19 March 2012

  • EC-SCHER (2005) Scientific committee on health and environmental risks opinion on: risk assessment report on tetrabromobisphenol-a human health part CAS No.: 79-94-7 EINECS No.: 201-236-9 Adopted by the SCHER during the 7th plenary of 23 September 2005

  • EC-SCHER (2008) Scientific committee on health and environmental risks opinion on: 2,2′,6,6′-tetrabromo-4,4′-isopropylidene diphenol (tetrabromobisphenol-A) Environmental Part Adopted by the SCHER during the 21st plenary of 15 January 2008

  • ECB (2006) European union risk assessment report—2,2′,6,6′-tetrabromo-4,4′-isopropylidenediphenol (tetrabromobisphenol-A or TBBP-A) (CAS: 79-94-7) Part II—human health, vol 63, EUR 22161 EN. Institute for Health and Consumer Protection, European Chemicals Bureau, European Commission Joint Research Centre, 4th Priority List, Luxembourg: Office for Official Publications of the European Communities

  • ECB (2008) European Union risk assessment report—2,2′,6,6′-tetrabromo-4,4′-isopropylidenediphenol (tetrabromobisphenol-A or TBBP-A) (CAS: 79-94-7) Part I—environment (final draft)

  • ECHA (2011) European chemicals agency guidance on information requirements and chemical safety assessment. Part B. Hazard assessment. (version 2.1), 2011

  • ECHA (2013) Registered substances CAS 74-94-7. http://www.echa.europa.eu/web/guest/information-on-chemicals/registered-substances

  • EFSA (2011) EFSA panel on contaminants in the food chain (CONTAM): scientific opinion on tetrabromobisphenol A (TBBPA) and its derivatives in food EFSA panel on contaminants in the food chain. EFSA J9:2477 (61)

    Google Scholar 

  • Eriksson P, Jakobsson E, Fredriksson A (2001) Brominated flame retardants: a novel class of developmental neurotoxicants in our environment? Environ Health Perspect 109:903–908

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Fini JB, Riu A, Debrauwer L, Hillenweck A, Le Mevel S, Chevolleau S, Boulahtouf A, Palmier K, Balaguer P, Cravedi JP, Demeneix BA, Zalko D (2012) Parallel biotransformation of tetrabromobisphenol A in Xenopus laevis and mammals: Xenopus as a model for endocrine perturbation studies. Toxicol Sci 125:359–367. doi:10.1093/toxsci/kfr312

    CAS  PubMed  Article  Google Scholar 

  • Freitas J, Cano P, Craig-Veit C, Goodson ML, Furlow JD, Murk AJ (2011) Detection of thyroid hormone receptor disruptors by a novel stable in vitro reporter gene assay. Toxicol In Vitro 25:257–266. doi:10.1016/j.tiv.2010.08.013

    CAS  PubMed  Article  Google Scholar 

  • Fromme H, Gruber L, Schuster R, Schlummer M, Kiranoglu M, Bolte G, Volkel W (2013) Phthalate and di-(2-ethylhexyl) adipate (DEHA) intake by German infants based on the results of a duplicate diet study and biomonitoring data (INES 2). Food Chem Toxicol 53:272–280. doi:10.1016/j.fct.2012.12.004

    CAS  PubMed  Article  Google Scholar 

  • FSAI (2010) Investigation into levels of chlorinated and brominated organic pollutants in carcass fat, offal, eggs and milk produced in Ireland. Food Safety Authority of Ireland, Monitoring & Surveillance Series

  • Fukuda N, Ito Y, Yamaguchi M, Mitumori K, Koizumi M, Hasegawa R, Kamata E, Ema M (2004) Unexpected nephrotoxicity induced by tetrabromobisphenol A in newborn rats. Toxicol Lett 150:145–155

    CAS  PubMed  Article  Google Scholar 

  • Gelbke HP, Fleig H, Meder M (2004) SIDS reprotoxicity screening test update: testing strategies and use. Regul Toxicol Pharmacol 39:81–86. doi:10.1016/j.yrtph.2003.12.001

    CAS  PubMed  Article  Google Scholar 

  • Hakk H, Larsen G, Bergman A, Orn U (2000) Metabolism, excretion and distribution of the flame retardant tetrabromobisphenol-A in conventional and bile-duct cannulated rats. Xenobiotica 30:881–890. doi:10.1080/004982500433309

    CAS  PubMed  Article  Google Scholar 

  • Hakk H, Letcher RJ (2003) Metabolism in the toxicokinetics and fate of brominated flame retardants–a review. Environ Int 29:801–828

    CAS  PubMed  Article  Google Scholar 

  • Hamers T, Kamstra JH, Sonneveld E, Murk AJ, Kester MH, Andersson PL, Legler J, Brouwer A (2006) In vitro profiling of the endocrine-disrupting potency of brominated flame retardants Toxicol Sci 92:157–173

    Google Scholar 

  • Harrad S, Abdallah MA, Rose NL, Turner SD, Davidson TA (2009) Current-use brominated flame retardants in water, sediment, and fish from English lakes. Environ Sci Technol 43:9077–9083. doi:10.1021/es902185u

    CAS  PubMed  Article  Google Scholar 

  • Hass H, Wamberg C, Ladefoged O, Dalgaard M, Rye Lam H, Vinggard A (2003) Developmental neurotoxicity of tetrabromobisphenol A in rats. (unpublished)

  • Heck HD, Tyl RW (1985) The induction of bladder stones by terephthalic acid, dimethyl terephthalate, and melamine (2,4,6-triamino-s-triazine) and its relevance to risk assessment. Regul Toxicol Pharmacol 5:294–313

    CAS  PubMed  Article  Google Scholar 

  • Hendriks HS, van Kleef RG, van den Berg M, Westerink RH (2012) Multiple novel modes of action involved in the in vitro neurotoxic effects of tetrabromobisphenol-A. Toxicol Sci 128:235–246. doi:10.1093/toxsci/kfs136

    CAS  PubMed  Article  Google Scholar 

  • Henry CJ (2003) Evolution of toxicology for risk assessment. Int J Toxicol 22:3–7

    CAS  PubMed  Article  Google Scholar 

  • IARC (1999) Species differences in thyroid, kidney and urinary bladder carcinogenesis. International Agency for Research on Cancer (IARC) Scientific Publications No 147. http://www.monographs.iarc.fr/ENG/Publications/pub147/IARCpub147.pdf

  • Imai T, Takami S, Cho YM, Hirose M, Nishikawa A (2009) Modifying effects of prepubertal exposure to potassium perchlorate and tetrabromobisphenol A on susceptibility to N-bis(2-hydroxypropyl)nitrosamine- and 7,12-dimethylbenz(a)anthracene-induced carcinogenesis in rats. Toxicol Lett 185:160–167. doi:10.1016/j.toxlet.2008.12.013

    CAS  PubMed  Article  Google Scholar 

  • Jahnke GD, Choksi NY, Moore JA, Shelby MD (2004) Thyroid toxicants: assessing reproductive health effects. Environ Health Perspect 112:363–368

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Judson RS, Kavlock RJ, Setzer RW, Hubal EA, Martin MT, Knudsen TB, Houck KA, Thomas RS, Wetmore BA, Dix DJ (2011) Estimating toxicity-related biological pathway altering doses for high-throughput chemical risk assessment. Chem Res Toxicol 24:451–462. doi:10.1021/tx100428e

    CAS  PubMed  Article  Google Scholar 

  • 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. doi:10.1080/15287390903212907

    CAS  PubMed  Article  Google Scholar 

  • Kitamura S, Kato T, Iida M, Jinno N, Suzuki T, Ohta S, Fujimoto N, Hanada H, Kashiwagi K, Kashiwagi A (2005a) 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. doi:10.1016/j.lfs.2004.08.030

    CAS  PubMed  Article  Google Scholar 

  • Kitamura S, Suzuki T, Sanoh S, Kohta R, Jinno N, Sugihara K, Yoshihara S, Fujimoto N, Watanabe H, Ohta S (2005b) Comparative study of the endocrine-disrupting activity of bisphenol A and 19 related compounds. Toxicol Sci 84:249–259

    CAS  PubMed  Article  Google Scholar 

  • Klimisch HJ, Andreae M, Tillmann U (1997) A systematic approach for evaluating the quality of experimental toxicological and ecotoxicological data. Regul Toxicol Pharmacol 25:1–5. doi:10.1006/rtph1996.1076

    CAS  PubMed  Article  Google Scholar 

  • Kuester RK, Solyom AM, Rodriguez VP, Sipes IG (2007) The effects of dose, route, and repeated dosing on the disposition and kinetics of tetrabromobisphenol A in male F-344 rats. Toxicol Sci 96:237–245. doi:10.1093/toxsci/kfm006

    CAS  PubMed  Article  Google Scholar 

  • Labadie P, Tlili K, Alliot F, Bourges C, Desportes A, Chevreuil M (2010) Development of analytical procedures for trace-level determination of polybrominated diphenyl ethers and tetrabromobisphenol A in river water and sediment. Anal Bioanal Chem 396:865–875. doi:10.1007/s00216-009-3267-x

    CAS  PubMed  Article  Google Scholar 

  • Levy-Bimbot M, Major G, Courilleau D, Blondeau JP, Levi Y (2012) Tetrabromobisphenol-A disrupts thyroid hormone receptor alpha function in vitro: use of fluorescence polarization to assay corepressor and coactivator peptide binding. Chemosphere 87:782–788. doi:10.1016/j.chemosphere.2011.12.080

    CAS  PubMed  Article  Google Scholar 

  • Li J, Ma M, Wang Z (2010) In vitro profiling of endocrine disrupting effects of phenols. Toxicol In Vitro 24:201–207. doi:10.1016/j.tiv.2009.09.008

    CAS  PubMed  Article  Google Scholar 

  • 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. doi:10.1016/j.tox.2008.01.007

    CAS  PubMed  Article  Google Scholar 

  • MacDonald JS (2004) Human carcinogenic risk evaluation, part IV: assessment of human risk of cancer from chemical exposure using a global weight-of-evidence approach. Toxicol Sci 82:3–8. doi:10.1093/toxsci/kfh189

    CAS  PubMed  Article  Google Scholar 

  • Meerts IATM, Assink Y, Cenijn PH, van den Berg JHJ, Bergman C, Koeman JH, Brouwer A (1999) Distribution of the flame retardant tetrabromobisphenol A in pregnant and fetal rats and effect on thyroid hormone homeostasis. Organohalogen Compd 40:375–378

    CAS  Google Scholar 

  • Meerts IA, van Zanden JJ, Luijks EA, van Leeuwen-Bol I, Marsh G, Jakobsson E, Bergman A, Brouwer A (2000) Potent competitive interactions of some brominated flame retardants and related compounds with human transthyretin in vitro. Toxicol Sci 56:95–104

    CAS  PubMed  Article  Google Scholar 

  • Molina-Molina JM, Amaya E, Grimaldi M, Saenz JM, Real M, Fernandez MF, Balaguer P, Olea N (2013) In vitro study on the agonistic and antagonistic activities of bisphenol-S and other bisphenol-A congeners and derivatives via nuclear receptors. Toxicol Appl Pharmacol. doi:10.1016/j.taap.2013.05.015

    PubMed  Google Scholar 

  • MPI-Research (2001) Final report—an oral prenatal developmental toxicity study with tetrabromobisphenol-A in rats (unpublished)

  • MPI-Research (2002) An oral two-generation reproductive, fertility, and developmental neurobehavioural study of tetrabromobisphenol A in rats. Performed by MPI Research Inc., Mattawan, MI for the American Chemistry Council BFRIP, Arlington, VA. Study Number: 474-004, pp 2199

  • MPI-Research (2003) Amendment to the final report: an oral two-generation reproductive, fertility, and developmental neurobehavioural study of tetrabromobisphenol A in rats. Performed by MPI Research Inc., Mattawan, MI for the American Chemistry Council BFRIP, Arlington, VA. Study Number: 474-004, pp 16

  • Nakagawa Y, Suzuki T, Ishii H, Ogata A (2007) Biotransformation and cytotoxicity of a brominated flame retardant, tetrabromobisphenol A, and its analogues in rat hepatocytes. Xenobiotica 37:693–708. doi:10.1080/00498250701397697

    CAS  PubMed  Article  Google Scholar 

  • 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. doi:10.1016/j.toxlet.2009.05.003

    CAS  PubMed  Article  Google Scholar 

  • NIEHS (2002) Tetrabromobisphenol A bis(2,3-dibromopropyl ether) [21850-44-2] review of toxicological literature. Prepared for Scott Masten, National Institute of Environmental Health Sciences, Contract No. N01-ES-65402. Submitted by Karen E. Haneke, Integrated Laboratory Systems, Inc., Research Triangle Park, NC

  • OECD (2002) Conceptual framework for the testing and assessment of endocrine disrupting chemicals. Organisation for Economic Co-operation and Development, http://www.oecd.org/document/58/0,3343,en_2649_34377_2348794_1_1_1_1,00.html. Accessed 12 Nov 2012

  • OECD (2010a) Draft guidance document 116 on the design and conduct of chronic toxicity and carcinogenicity studies, supporting TG 451, 452 and 453. Organisation for Economic Co-operation and Development, http://www.oecd.org/chemicalsafety/testingofchemicals/46766792.pdf. Accessed 23 Nov 2012

  • OECD (2010b) Guidance document on the assessment of chemicals for endocrine disruption, version 9. Organisation for Economic Co-operation and Development, http://www.oecd.org/chemicalsafety/testingofchemicals/46436593.pdf. Accessed 23 Nov 2012

  • Ogasawara H, Imaida K, Ishiwata H, Toyoda K, Kawanishi T, Uneyama C, Hayashi S, Takahashi M, Hayashi Y (1995) Urinary bladder carcinogenesis induced by melamine in F344 male rats: correlation between carcinogenicity and urolith formation. Carcinogenesis 16:2773–2777

    CAS  PubMed  Article  Google Scholar 

  • Ogunbayo OA, Lai PF, Connolly TJ, Michelangeli F (2008) Tetrabromobisphenol A (TBBPA), induces cell death in TM4 Sertoli cells by modulating Ca2+ transport proteins and causing dysregulation of Ca2+ homeostasis. Toxicol In Vitro 22:943–952. doi:10.1016/j.tiv.2008.01.015

    CAS  PubMed  Article  Google Scholar 

  • Ogunbayo OA, Michelangeli F (2007) The widely utilized brominated flame retardant tetrabromobisphenol A (TBBPA) is a potent inhibitor of the SERCA Ca2+ pump. Biochem J 408:407–415. doi:10.1042/BJ20070843

    CAS  PubMed  Article  Google Scholar 

  • Reistad T, Mariussen E, Fonnum F (2005) The effect of a brominated flame retardant, tetrabromobisphenol-A, on free radical formation in human neutrophil granulocytes: the involvement of the MAP kinase pathway and protein kinase C. Toxicol Sci 83:89–100. doi:10.1093/toxsci/kfh298

    CAS  PubMed  Article  Google Scholar 

  • Reistad T, Mariussen E, Ring A, Fonnum F (2007) In vitro toxicity of tetrabromobisphenol-A on cerebellar granule cells: cell death, free radical formation, calcium influx and extracellular glutamate. Toxicol Sci 96:268–278. doi:10.1093/toxsci/kfl198

    CAS  PubMed  Article  Google Scholar 

  • Riu A, le Maire A, Grimaldi M, Audebert M, Hillenweck A, Bourguet W, Balaguer P, Zalko D (2011) Characterization of novel ligands of ERalpha, Erbeta, and PPARgamma: the case of halogenated bisphenol A and their conjugated metabolites. Toxicol Sci 122:372–382. doi:10.1093/toxsci/kfr132

    CAS  PubMed  Article  Google Scholar 

  • Saegusa Y, Fujimoto H, Woo GH, 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. doi:10.1016/j.reprotox.2009.06.011

    CAS  PubMed  Article  Google Scholar 

  • Schauer UM, Volkel W, Dekant W (2006) Toxicokinetics of tetrabromobisphenol a in humans and rats after oral administration. Toxicol Sci 91:49–58. doi:10.1093/toxsci/kfj132

    CAS  PubMed  Article  Google Scholar 

  • Shi ZX, Wu YN, Li JG, Zhao YF, Feng JF (2009) Dietary exposure assessment of Chinese adults and nursing infants to tetrabromobisphenol-A and hexabromocyclododecanes: occurrence measurements in foods and human milk. Environ Sci Technol 43:4314–4319

    CAS  PubMed  Article  Google Scholar 

  • Strack S, Detzel T, Wahl M, Kuch B, Krug HF (2007) Cytotoxicity of TBBPA and effects on proliferation, cell cycle and MAPK pathways in mammalian cells. Chemosphere 67:S405–S411. doi:10.1016/j.chemosphere.2006.05.136

    CAS  PubMed  Article  Google Scholar 

  • Strain GM, Banasik M, Hardy M, Stedeford T (2009) Tetrabromobisphenol A (TBBPA) and model-derived risks for neurobehavioral effects in offspring from a one-generation reproduction study. Toxicology 260:155–157 (author reply 158–161). doi:10.1016/j.tox.2009.03.011

  • Tada Y, Fujitani T, Yano N, Takahashi H, Yuzawa K, Ando H, Kubo Y, Nagasawa A, Ogata A, Kamimura H (2006) Effects of tetrabromobisphenol A, brominated flame retardant, in ICR mice after prenatal and postnatal exposure. Food Chem Toxicol 44:1408–1413. doi:10.1016/j.fct.2006.03.006

    CAS  PubMed  Article  Google Scholar 

  • Terasaki M, Kosaka K, Kunikane S, Makino M, Shiraishi F (2011) Assessment of thyroid hormone activity of halogenated bisphenol A using a yeast two-hybrid assay. Chemosphere 84:1527–1530. doi:10.1016/J.Chemosphere.2011.04.045

    CAS  PubMed  Article  Google Scholar 

  • Van der Ven LT, Van de Kuil T, Verhoef A, Verwer CM, Lilienthal H, Leonards PE, Schauer UM, Canton RF, Litens S, De Jong FH, Visser TJ, Dekant W, Stern N, Hakansson 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. doi:10.1016/j.tox.2007.12.009

    PubMed  Article  Google Scholar 

  • Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, Jacobs DR, Jr., Lee DH, Shioda T, Soto AM, vom Saal FS, Welshons WV, Zoeller RT, Myers JP (2012) Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr Rev 33:378–455. doi:10.1210/er.2011-1050

    Google Scholar 

  • Viberg H, Eriksson P (2011) Differences in neonatal neurotoxicity of brominated flame retardants, PBDE 99 and TBBPA, in mice. Toxicology 289:59–65. doi:10.1016/j.tox.2011.07.010

    CAS  PubMed  Article  Google Scholar 

  • WHO/ICPS (1995) Tetrabromobisphenol A and derivatives. Environmental Health Criteria 172, World Health Organization, Geneva, Switzerland, 72 pp. http://www.inchem.org/documents/ehc/ehc/ehc172.htm

  • WHO/IPCS (2002) Global assessment of the state-of-the-science of endocrine disruptors. WHO/PCS/EDC/02.2, World Health Organisation, Geneva

  • WHO/IPCS (2004) Exposure assessment and risk assessment terminology. http://www.who.int/ipcs/methods/harmonization/areas/terminology/en/index.html. Accessed 12 Nov 2012

  • Williams AL, DeSesso JM (2010) The potential of selected brominated flame retardants to affect neurological development. J Toxicol Environ Health B Crit Rev 13:411–448. doi:10.1080/10937401003751630

    CAS  PubMed  Article  Google Scholar 

  • Wu KM, Farrelly JG (2006) Preclinical development of new drugs that enhance thyroid hormone metabolism and clearance: inadequacy of using rats as an animal model for predicting human risks in an IND and NDA. Am J Ther 13:141–144. doi:10.1097/01.mjt.0000209673.01885.b0

    PubMed  Article  Google Scholar 

  • Zatecka E, Ded L, Elzeinova F, Kubatova A, Dorosh A, Margaryan H, Dostalova P, Peknicova J (2013) Effect of tetrabromobisphenol A on induction of apoptosis in the testes and changes in expression of selected testicular genes in CD1 mice. Reprod Toxicol 35:32–39. doi:10.1016/j.reprotox.2012.05.095

    CAS  PubMed  Article  Google Scholar 

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Acknowledgments

The preparation of this review was supported in part through an honorarium to Thomas Colnot and Sam Kacew from the Bromine Science and Environmental Forum (BSEF), which is the bromine industry’s global organization. Work in Wolfgang Dekants laboratory on TBBPA was supported by the fifth Framework Programme of the European Commission in the “FIRE” project. This review represents the individual professional views of the authors.

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Correspondence to Wolfgang Dekant.

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Colnot, T., Kacew, S. & Dekant, W. Mammalian toxicology and human exposures to the flame retardant 2,2′,6,6′-tetrabromo-4,4′-isopropylidenediphenol (TBBPA): implications for risk assessment. Arch Toxicol 88, 553–573 (2014). https://doi.org/10.1007/s00204-013-1180-8

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  • DOI: https://doi.org/10.1007/s00204-013-1180-8

Keywords

  • Endocrine toxicity
  • Exposure assessment
  • Repeated-dose toxicity
  • Role of in vitro assays
  • Two-generation studies
  • Toxicokinetics
  • Bioaccumulation