Abstract
Hexabromocyclododecane (HBCD ) is a brominated flame retardant widely used in flame retardant for various industrial and consumer products.Due to its high biotoxicity,bioaccumulation,pollution persistence,and long -range transport capacity,HBCD has been included in the Stockholm Convention list of persistent organic pollutants (POPs ) and is being phased out globally.In this paper,the contamination of HBCD,additive brominated flame retardants,in daily diet and the characteristics of HBCD absorption and metabolism in the body are briefly described.Then,the evaluation of HBCD exposure toxicity by bioinformatics,in vitro primary cell models,and cell line models are reviewed.Subsequently,the effects of HBCD intervention on the toxicology of zebrafish models,mouse models,and rat models in vivo are compared.Finally,the total dietary exposure and breast milk exposure in the HBCD population are analyzed.
Publication Date
6-13-2025
First Page
1
Last Page
9
DOI
10.13652/j.spjx.1003.5788.2025.80171
Recommended Citation
Zirui, ZHAO; Hainan, JI; Chan, ZHAO; Guolin, SHEN; and Mengling, ZHANG
(2025)
"Status of persistent organic pollutant of brominated flame retardant HBCD in daily diet and its potential health risks,"
Food and Machinery: Vol. 41:
Iss.
5, Article 1.
DOI: 10.13652/j.spjx.1003.5788.2025.80171
Available at:
https://www.ifoodmm.cn/journal/vol41/iss5/1
References
[1] MARQUES M L,CAIRRAO E.Occurrence and health effects of hexabromocyclododecane:an updated review [J].Toxics,2023,11(5):409.
[2] FEITEIRO J,MARIANA M,CAIRRÃO E.Health toxicity effects of brominated flame retardants:from environmental to human exposure [J].Environmental Pollution,2021,285:117475.
[3] LIM D C,NAJAFI A,AFIFI L,et al.The need to promote sleep health in public health agendas across the globe [J].The Lancet Public Health,2023,8(10):e820-e826.
[4] WU D Y,KONG Y B,ZHANG R T,et al.Hexabromocyclododecane (HBCD ) exposure induced premature testicular aging via NCOA 4/Fe2+/ROS mediation [J].International Immunopharmacology,2024,139:112746.
[5] LIN L J,LI H Y,HONG H L,et al.Enhanced heavy metal adsorption on microplastics by incorporating flame retardant hexabromocyclododecanes:mechanisms and potential migration risks [J].Water Research,2022,225:119144.
[6] 上官佳,吴海智,梁军,等.婴幼儿乳粉中新兴持久性有机污染物的来源、检测技术及污染水平研究进展 [J].食品与机械,2023,39(2):227-235.SHANG G J,WU H Z,LIANG J,et al.Progress on source,detection technique and pollution level of the new persistent organic pollutant in infant milk powder [J].Food & Machinery,2023,39(2):227-235.
[7] LI Y Y,SHI Z Y,XIONG Y M,et al.Bioaccumulation and male reproductive toxicity of the new brominated flame retardant tetrabromobisphenol a-bis (2,3-dibromo- 2-methylpropyl ether ) in comparison with hexabromocyclododecane [J].Environmental Science & Technology,2024,58(9):4 127-4 136.
[8] WU T,LI X X,ZHENG Z Y,et al.Hexabromocyclododecanes in surface soil-maize system around Baiyangdian Lake in North China:distribution,enantiomer-specific accumulation,transport,temporal trend and dietary risk [J].Journal of Hazardous Materials,2023,451:131180.
[9] DENG J L,LIU W B,GAO L R,et al.A review of distribution and profiles of HBCD in different environmental media of China[J].Molecules,2023,29(1):36.
[10] YANG X,HUANG L L,ZHANG L,et al.Distribution and biomagnification of Hexabromocyclododecanes (HBCDs ) in edible marine fish in the Beibu Gulf,China:implication for |seafood dietary risk [J].Marine Pollution Bulletin,2024,206:116737.
[11] ZHANG Y W,SUN H W,LIU F,et al.Hexabromocyclododecanes in limnic and marine organisms and terrestrial plants from Tianjin,China:diastereomer- and enantiomer-specific profiles,biomagnification,and human exposure [J].Chemosphere,2013,93(8):1 561-1 568.
[12] LI Y N,ZHOU Q X,WANG Y Y,et al.Fate of tetrabromobisphenol A and hexabromocyclododecane brominated flame retardants in soil and uptake by plants [J].Chemosphere,2011,82(2):204-209.
[13] TÖRNKVIST A,GLYNN A,AUNE M,et al.PCDD/F,PCB,PBDE,HBCD and chlorinated pesticides in a Swedish market basket from 2005 -levels and dietary intake estimations [J].Chemosphere,2011,83(2):193-199.
[14] BARGHI M,SHIN E S,SON M H,et al.Hexabromocyclododecane (HBCD ) in the Korean food basket and estimation of dietary exposure [J].Environmental Pollution,2016,213:268-277.
[15] SCHECTER A,SZABO D T,MILLER J,et al.Hexabromocyclododecane (HBCD ) stereoisomers in U.S.food from Dallas,Texas [J].Environmental Health Perspectives,2012,120(9):1 260-1 264.
[16] MENG X Z,XIANG N,DUAN Y P,et al.Hexabromocyclododecane in consumer fish from South China:implications for human exposure via dietary intake [J].Environmental Toxicology and Chemistry,2012,31(7):1 424-1 430.
[17] JO H,SON M H,SEO S H,et al.Matrix-specific distribution and diastereomeric profiles of hexabromocyclododecane (HBCD ) in a multimedia environment:air,soil,sludge,sediment,and fish [J].Environmental Pollution,2017,226:515-522.
[18] JEONG G H,HWANG N R,HWANG E H,et al.Hexabromocyclododecanes in crucian carp and sediment from the major rivers in Korea [J].Science of the Total Environment,2014,470/471:1 471-1 478.
[19] XIA C H,LAM J C W,WU X G,et al.Hexabromocyclododecanes (HBCDs ) in marine fishes along the Chinese coastline [J].Chemosphere,2011,82(11):1 662-1 668.
[20] WANG W T,CHOO G,CHO H S,et al.The occurrence and distribution of hexabromocyclododecanes in freshwater systems,focusing on tissue-specific bioaccumulation in crucian carp [J].Science of the Total Environment,2018,635:470-478.
[21] HAKK H.Comparative metabolism studies of hexabromocyclododecane (HBCD ) diastereomers in male rats following a single oral dose [J].Environmental Science & Technology,2016,50(1):89-96.
[22] SANDERS J M,KNUDSEN G A,BIRNBAUM L S.The fate of β-hexabromocyclododecane in female C 57BL/6 mice [J].Toxicological Sciences,2013,134(2):251-257.
[23] DU M M,FANG C,QIU L,et al.Diastereoisomer-specific effects of hexabromocyclododecanes on hepatic aryl hydrocarbon receptors and cytochrome P 450s in zebrafish (Danio rerio )[J].Chemosphere,2015,132:24-31.
[24] ERRATICO C,ZHENG X B,VAN DEN EEDE N,et al.Stereoselective metabolism of α-,β-,and γ-hexabromocyclododecanes (HBCDs ) by human liver microsomes and CYP 3A4[J].Environmental Science & Technology,2016,50(15):8 263-8 273.
[25] HAKK H,SZABO D T,HUWE J,et al.Novel and distinct metabolites identified following a single oral dose of α- or γ-hexabromocyclododecane in mice [J].Environmental Science & Technology,2012,46(24):13 494-13 503.
[26] ZAINAB B,AYAZ Z,RASHID U,et al.Role of persistent organic pollutants in breast cancer progression and identification of estrogen receptor alpha inhibitors using in-silico mining and drug-drug interaction network approaches [J].Biology,2021,10(7):681.
[27] DAI W N,TANG T T,DAI Z H,et al.Probing the mechanism of hepatotoxicity of hexabromocyclododecanes through toxicological network analysis [J].Environmental Science & Technology,2020,54(23):15 235-15 245.
[28] NI Y,WANG W K,JIANG L H,et al.Exploring the molecular interface of gene expression dynamics and prostate cancer susceptibility in response to HBCD exposure [J].Toxicology Research,2025,14(1):tfaf016.
[29] PROENÇA S,VAN SABBEN N,LEGLER J,et al.The effects of hexabromocyclododecane on the transcriptome and hepatic enzyme activity in three human HepaRG-based models [J].Toxicology,2023,485:153411.
[30] JIN Y Y,SHANG Y,ZHANG D P,et al.Hexabromocyclododecanes promoted autophagy through the PI3K/Akt/mTOR pathway in L 02 cells [J].Journal of Environmental Management,2019,244:77-82.
[31] WANG F D,ZHANG H J,GENG N B,et al.New insights into the cytotoxic mechanism of hexabromocyclododecane from a metabolomic approach [J].Environmental Science & Technology,2016,50(6):3 145-3 153.
[32] HUANG X M,CHEN C,SHANG Y,et al.In vitro study on the biotransformation and cytotoxicity of three hexabromocyclododecane diastereoisomers in liver cells [J].Chemosphere,2016,161:251-258.
[33] WAN K Y,WU D T,XIE G S,et al.Different cytotoxicity induced by hexabromocyclododecanes on mouse neuroblastoma N 2a cells via oxidative stress and mitochondrial apoptotic pathway [J].Toxics,2024,12(9):665.
[34] CHEN X Y,LI Y Y,LV L,et al.The brominated flame retardant tetrabromobisphenol A-bis (2,3-dibromo- 2-methylpropyl ether ) as well as hexabromocyclododecane lead to lipid disorders in mice [J].Environmental Pollution,2024,341:122895.
[35] IBHAZEHIEBO K,IWASAKI T,SHIMOKAWA N,et al.1,2,5,6,9,10-αHexabromocyclododecane (HBCD ) impairs thyroid hormone-induced dendrite arborization of Purkinje cells and suppresses thyroid hormone receptor-mediated transcription [J].The Cerebellum,2011,10(1):22-31.
[36] GENSKOW K R,BRADNER J M,HOSSAIN M M,et al.Selective damage to dopaminergic transporters following exposure to the brominated flame retardant,HBCDD [J].Neurotoxicology and Teratology,2015,52:162-169.
[37] AL-MOUSA F,MICHELANGELI F.The sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA ) is the likely molecular target for the acute toxicity of the brominated flame retardant hexabromocyclododecane (HBCD ) [J].Chemico-Biological Interactions,2014,207:1-6.
[38] SHI X L,WEN B,HUANG H L,et al.Cytotoxicity of hexabromocyclododecane,1,2-dibromo- 4-(1,2-dibromoethyl ) cyclohexane and 1,2,5,6-tetrabromocyclooctane in human SH-SY 5Y neuroblastoma cells [J].Science of the Total Environment,2020,739:139650.
[39] SHI X L,ZHA J M,WEN B,et al.Diastereoisomer-specific neurotoxicity of hexabromocyclododecane in human SH-SY5Y neuroblastoma cells [J].Science of the Total Environment,2019,686:893-902.
[40] ABE N,SASAKI M,NAKAJIMA A.Tetrabromobisphenol A and hexabromocyclododecane,brominated flame retardants,trigger endoplasmic reticulum stress and activate necroptosis signaling in PC 12 cells [J].Environmental Toxicology and Pharmacology,2023,98:104056.
[41] ANISUZZAMAN S,WHALEN M M.Tetrabromobisphenol A and hexabromocyclododecane alter secretion of IL- 1β from human immune cells [J].Journal of Immunotoxicology,2016,13(3):403-416.
[42] FA S,POGRMIC-MAJKIC K,SAMARDZIJA D,et al.HBCDD-induced sustained reduction in mitochondrial membrane potential,ATP and steroidogenesis in peripubertal rat Leydig cells [J].Toxicology and Applied Pharmacology,2015,282(1):20-29.
[43] LI R J,GAO H,NA G S,et al.Hexabromocyclododecane-induced genotoxicity in cultured human breast cells through DNA damage [J].Biomedical and Environmental Sciences,2017,30(4):296-300.
[44] 倪策,曹天红,陈敏,等.核桃粕源抗氧化活性肽的酶解制备及活性分析 [J].食品与机械,2024,40(5):51-61.NI C,CAO T H,CHEN M,et al.Enzymatic hydrolysis preparation and activity analysis of antioxidant peptides derived from walnut dregs [J].Food & Machinery,2024,40(5):51-61.
[45] WU M F,ZUO Z H,LI B W,et al.Effects of low-level hexabromocyclododecane (HBCD ) exposure on cardiac development in zebrafish embryos [J].Ecotoxicology,2013,22(8):1 200-1 207.
[46] WU M F,WU D,WANG C G,et al.Hexabromocyclododecane exposure induces cardiac hypertrophy and arrhythmia by inhibiting miR- 1 expression via up-regulation of the homeobox gene Nkx 2.5[J].Journal of Hazardous Materials,2016,302:304-313.
[47] CAO M,XU T,SONG Y Q,et al.Brominated flame retardant HBCD and artificial light at night synergically caused visual disorder and sleep difficulty in zebrafish larvae [J].Environmental Science & Technology,2024,58(39):17 247-17 258.
[48] GUO Z,ZHANG L J,LIU X Y,et al.The enrichment and purification of hexabromocyclododecanes and its effects on thyroid in zebrafish [J].Ecotoxicology and Environmental Safety,2019,185:109690.
[49] DU M M,LIN L F,YAN C Z,et al.Diastereoisomer- and enantiomer-specific accumulation,depuration,and bioisomerization of hexabromocyclododecanes in zebrafish (Danio rerio ) [J].Environmental Science & Technology,2012,46(20):11 040-11 046.
[50] BERNHARD A,BERNTSSEN M H G,LUNDEBYE A K,et al.Marine fatty acids aggravate hepatotoxicity of α-HBCD in juvenile female BALB/c mice [J].Food and Chemical Toxicology,2016,97:411-423.
[51] MARANGHI F,TASSINARI R,MORACCI G,et al.Dietary exposure of juvenile female mice to polyhalogenated seafood contaminants (HBCD,BDE- 47,PCB- 153,TCDD ):comparative assessment of effects in potential target tissues [J].Food and Chemical Toxicology,2013,56:443-449.
[52] RASINGER J D,CARROLL T S,LUNDEBYE A K,et al.Cross-omics gene and protein expression profiling in juvenile female mice highlights disruption of calcium and zinc signalling in the brain following dietary exposure to CB- 153,BDE- 47,HBCD or TCDD [J].Toxicology,2014,321:1-12.
[53] REFFATTO V,RASINGER J D,CARROLL T S,et al.Parallel in vivo and in vitro transcriptomics analysis reveals calcium and zinc signalling in the brain as sensitive targets of HBCD neurotoxicity [J].Archives of Toxicology,2018,92(3):1 189-1 203.
[54] WANG J,DAI G D.Comparative effects of brominated flame retardants BDE- 209,TBBPA,and HBCD on neurotoxicity in mice [J].Chemical Research in Toxicology,2022,35(9):1 512-1 518.
[55] YANAGISAWA R,KOIKE E,WIN-SHWE T T,et al.Impaired lipid and glucose homeostasis in hexabromocyclododecane-exposed mice fed a high-fat diet [J].Environmental Health Perspectives,2014,122(3):277-283.
[56] XIE X N,YU C X,REN Q D,et al.Exposure to HBCD promotes adipogenesis both in vitro and in vivo by interfering with Wnt 6 expression [J].Science of the Total Environment,2020,705:135917.
[57] SZABO D T,PATHMASIRI W,SUMNER S,et al.Serum metabolomic profiles in neonatal mice following oral brominated flame retardant exposures to |hexabromocyclododecane (HBCD ) alpha,gamma,and commercial mixture [J].Environmental Health Perspectives,2017,125(4):651-659.
[58] TIAN F J,SUN J B,YUE J M,et al.Hexabromocyclododecane (HBCD ) induced PANoptosis of chondrocytes via activation of the NLRP 3 inflammasome and decreased the exercise ability of mice in vivo [J].Toxicology,2023,499:153659.
[59] SHOCKLEY K R,CORA M C,MALARKEY D E,et al.Comparative toxicity and liver transcriptomics of legacy and emerging brominated flame retardants following 5-day exposure in the rat [J].Toxicology Letters,2020,332:222-234.
[60] MILLER I,SERCHI T,CAMBIER S,et al.Hexabromocyclododecane (HBCD ) induced changes in the liver proteome of Eu- and hypothyroid female rats [J].Toxicology Letters,2016,245:40-51.
[61] VAN DER VEN L T M,VERHOEF A,VAN DE KUIL T,et al.A 28-day oral dose toxicity study enhanced to detect endocrine effects of hexabromocyclododecane in Wistar rats [J].Toxicological Sciences,2006,94(2):281-292.
[62] MILLER-RHODES P,POPESCU M,GOEKE C,et al.Prenatal exposure to the brominated flame retardant hexabromocyclododecane (HBCD ) impairs measures of sustained attention and increases age-related morbidity in the Long-Evans rat [J].Neurotoxicology and Teratology,2014,45:34-43.
[63] SHI Z X,ZHANG L,ZHAO Y F,et al.Dietary exposure assessment of Chinese population to tetrabromobisphenol-A,hexabromocyclododecane and decabrominated diphenyl ether:results of the 5th Chinese total diet study [J].Environmental Pollution,2017,229:539-547.
[64] GOSCINNY S,VANDEVIJVERE S,MALEKI M,et al.Dietary intake of hexabromocyclododecane diastereoisomers (α-,β-,and γ-HBCD ) in the Belgian adult population [J].Chemosphere,2011,84(3):279-288.
[65] DRAGE D S,MUELLER J F,HOBSON P,et al.Demographic and temporal trends of hexabromocyclododecanes (HBCDD ) in an Australian population [J].Environmental Research,2017,152:192-198.
[66] FUJII Y,POMA G,MALARVANNAN G,et al.Estimation of dietary intake and sources of organohalogenated contaminants among infants:24-h duplicate diet survey in Fukuoka,Japan[J].Environmental Research,2021,195:110745.
[67] SHI Z X,WU Y N,LI J G,et al.Dietary exposure assessment of Chinese adults and nursing infants to tetrabromobisphenol-A and hexabromocyclododecanes:occurrence measurements in foods and human milk [J].Environmental Science & Technology,2009,43(12):4 314-4 319.[68] SHI Z X,ZHANG L,ZHAO Y F,et al.A national survey of tetrabromobisphenol-A,hexabromocyclododecane and decabrominated diphenyl ether in human milk from China:occurrence and exposure assessment [J].Science of the Total Environment,2017,599/600:237-245.
[69] SHI Z X,JIAO Y,HU Y,et al.Levels of tetrabromobisphenol A,hexabromocyclododecanes and polybrominated diphenyl ethers in human milk from the general population in Beijing,China [J].Science of the Total Environment,2013,452/453:10-18.
[70] HUANG M R,LI J,XIAO Z X,et al.Tetrabromobisphenol A and hexabromocyclododecane isomers in breast milk from the general population in Beijing,China:contamination levels,temporal trends,nursing infant's daily intake,and risk assessment [J].Chemosphere,2020,244:125524.
[71] LU S Y,TAN Z,JIANG Y S,et al.Hexabromocyclododecanes in breast milk from residents in Shenzhen,China:Implications for infant exposure [J].Science of the Total Environment,2018,622/623:1 090-1 097.
[72] TAO F,ABOU-ELWAFA ABDALLAH M,ASHWORTH D C,et al.Emerging and legacy flame retardants in UK human milk and food suggest slow response to restrictions on use of PBDEs and HBCDD [J].Environment International,2017,105:95-104.
[73] ABDALLAH M A,HARRAD S.Tetrabromobisphenol-A,hexabromocyclododecane and its degradation products in UK human milk:relationship to external exposure [J].Environment International,2011,37(2):443-448.
[74] HARRAD S,ABDALLAH M A.Concentrations of polybrominated diphenyl ethers,hexabromocyclododecanes and tetrabromobisphenol-a in breast milk from United Kingdom women do not decrease over twelve months of lactation [J].Environmental Science & Technology,2015,49(23):13 899-13 903.
[75] INTHAVONG C,HOMMET F,BORDET F,et al.Simultaneous liquid chromatography-tandem mass spectrometry analysis of brominated flame retardants (tetrabromobisphenol A and hexabromocyclododecane diastereoisomers ) in French breast milk [J].Chemosphere,2017,186:762-769.
[76] ONGONO J S,DOW C,GAMBARETTI J,et al.Dietary exposure to brominated flame retardants and risk of type 2 diabetes in the French E 3N cohort [J].Environment International,2019,123:54-60.
[77] KIM U J,OH J E.Tetrabromobisphenol A and hexabromocyclododecane flame retardants in infant-mother paired serum samples,and their relationships with thyroid hormones and environmental factors [J].Environmental Pollution,2014,184:193-200.