TETRABROMOBISPHENOL A (TETRABROMOBSFENOL A)

TETRABROMOBISPHENOL A (TETRABROMOBSFENOL A)

Tetrabromobisphenol A (Tetrabromobisfenol A) CAS No: 79-94-7
Synonyms:
TETRABROMOBISPHENOL A CARBONATE OLIGOMER;3,5,3′,5′-Tetrabromobisphenol A;3,5,3′,5′-tetrabromobisphenola;4,4′-(1-methylethylidene)bis(2,6-dibromo-pheno;4,4′-(1-methylethylidene)bis(2,6-dibromophenol);4,4′-(1-methylethylidene)bis[2,6-dibromo-pheno;4,4′-(1-methylethylidene)bis[2,6-dibromo-Phenol;Great lakes BA-59P; Tetrabromobisphenol A; 79-94-7; 3,3′,5,5′-Tetrabromobisphenol A; Bromdian; bromdiyan; 4,4′-(propane-2,2-diyl)bis(2,6-dibromophenol); 2,2-Bis(3,5-dibromo-4-hydroxyphenyl)propane; 4,4′-Isopropylidenebis(2,6-dibromophenol); Firemaster BP 4A; Tetrabromodian; tetrabromodiyan; TBBPA; Fire Guard 2000; Great Lakes BA-59P; 2,2′,6,6′-TETRABROMOBISPHENOL A; Saytex RB 100PC; Phenol, 4,4′-(1-methylethylidene)bis[2,6-dibromo-; Tetrabromodiphenylopropane; Firemaster BP4A; tetrabromodifenilopropan; difenil propan; FG 2000; 4,4′-propane-2,2-diylbis(2,6-dibromophenol); UNII-FQI02RFC3A; 4,4′-(1-Methylethylidene)bis(2,6-dibromophenol); BA 59; dibromofenol, tetra bromo bisfenol A; bis fenol A; 3,5,3′,5′-Tetrabromobisphenol A; NSC 59775; CCRIS 6274; HSDB 5232; Saytex RB-100; 4,4′-Isopropylylidenebis(2,6-dibromophenol); 2,2-Bis(4-hydroxy-3,5-dibromophenyl)propane; EINECS 201-236-9; FQI02RFC3A; 2,2′,6,6′-Tetrabromo-4,4′-isopropylidenediphenol;2,6-dibromo-4-[2-(3,5-dibromo-4-hydroxyphenyl)propan-2-yl]phenol; 4,4′-(2,2-PROPANEDIYL)BIS(2,6-DIBROMOPHENOL); CHEMBL184450; DTXSID1026081; CHEBI:33217; Phenol, 4,4′-isopropylidenebis(2,6-dibromo-; Phenol, 4,4′-isopropylidenebis[2,6-dibromo-; 4,4′-(2,2-propanediyl) bis[2,6-dibromo]phenol; MFCD00013962; Phenol, 4,4′-(1-methylethylidene)bis(2,6-dibromo-; FR-1524; DSSTox_CID_6081; 4,4′-(1-Methylethylidene)bis(2,6-dibromophenol)2,2-bis(3,5-dibromo-4-hydroxyphenyl)propane; DSSTox_RID_78008; DSSTox_GSID_26081; W-104257; 2,6-dibromo-4-[1-(3,5-dibromo-4-hydroxyphenyl)-1-methylethyl]phenol; CAS-79-94-7; TetrabromobisphenolA; 25639-54-7; Tetrabromo bisphenol A; 4,4′-(1-methylethylidene)bis[2,6-dibromophenol]; 3,3′,5,5′-Tetrabromo bisphenol A; FLAME CUT 120G; 33’55’-Tetrabromobisphenol A; 3osw; XDI; 4,6-dibromophenol); Saytex RB-100 ABS; 2,5-dibromophenyl)propane; TETRABROMO-4,4′-ISOPROPYLIDENEDIPHENOL; bmse000567; Tetrabromobisphenol ”A”; EC 201-236-9; Oprea1_822733; SCHEMBL18647; MLS002152878; BIDD:ER0631; C15H12Br4O2; 330396_ALDRICH; ARONIS002155; 2,6,6′-Tetrabromobisphenol A; CTK4F6165; KS-00003VGG; 3,3′,5′-Tetrabromobisphenol A; BBC/271; 2,5-dibromo-4-hydroxyphenyl)propane; BDBM50150793; c0763; NSC-59775; SBB080626; STK048486; ZINC01689786; 2,6-dibromo-4-[1-(3,5-dibromo-4-hydroxy-phenyl)-1-methyl-ethyl]phenol; AKOS000491577; 2,2”,6,6”-Tetrabromobisphenol A; 3,3”,5,5”-tetrabromobisphenol A; 3,3′,5,5′-tetrabromobisphenol A; LS-1786; MCULE-8578472069; NCGC00091463-01; NCGC00091463-02; NCGC00091463-03; NCGC00091463-04; NCGC00091463-05; NCGC00091463-06; NCGC00254356-01; NCGC00258734-01; NCGC00259530-01; 30496-13-0; AC-11719; AK113742; AS-12834; SMR001224492; Phenol,4′-isopropylidenebis[2,6-dibromo-; 3,3′,5,5′-Tetrabromobisphenol A, 97%; AX8153220; phenol, 4,4′-isopropylidenebis (dibromo-); 2,2-bis(3,5dibromo-4-hydroxyphenyl)propane; 4,4”-Isopropylidenebis(2,6-dibromophenol); 4,4′-isopropylidene-bis(2,6-dibromophenol); FT-0617111; FT-0682679; 2,2-bis(3,5-dibromo-4-hydroxyphenyl)-propane; 2,2-bis-(3,5-dibromo-4-hydroxyphenyl)propane; C13620; Z-0813; 2,2-bis-(3,5-dibromo-4-hydroxyphenyl)-propane; tetrabromobisphenol A 100 microg/mL in Methanol; Phenol,4′-(1-methylethylidene)bis[2,6-dibromo-; Q425246; SR-01000596914; Tetrabromodian: tetrabromodihydroxy diphenylpropane; 4,4”-(1-Methylethylidene)bis(2,6-dibromophenol); 4,4”-(2,2-propanediyl) bis[2,6-dibromo]phenol; 4,4”-(propane-2,2-diyl)bis(2,6-dibromophenol); SR-01000596914-1; 2,2′,6,6′-Tetrabromo-4,4′-isopropylidene bisphenol; 2,2-bis-(4′-hydroxy-3′,5′-dibromophenyl)-propane; 3,3′,5,5′-Tetrabromobisphenol A, analytical standard; phenol, 4,4′-isopropylidenebis(2,6-dibromo- (8CI); 3,3′,5,5′-Tetrabromo-4,4-dihydroxy-2,2-diphenylpropane; 3,3′,5,5′-Tetrabromo-4,4′-dihydroxy-diphenyl-dimethyl-methane; 4-[1-(3,5-dibromo-4-hydroxyphenyl)-isopropyl]-2,6-dibromophenol; 3,3′,5,5′-Tetrabromobisphenol A, certified reference material, TraceCERT(R)
CAS: 79-94-7
MF: C15H12Br4O2
MW: 543.87
EINECS: 201-236-9
Product Categories: Functional Materials;Reagent for High-Performance Polymer Research;Flame retardant series;Organics;Bisphenol A type Compounds (for High-Performance Polymer Research);Color Former & Related Compounds;Developer
Mol File: 79-94-7.mol
Tetrabromobisphenol A Chemical Properties
Melting point 178-181 °C(lit.)
Boiling point 316 °C
density 2.1
refractive index 1.5000 (estimate)
storage temp. 2-8°C
solubility Insoluble
pka 8.50±0.10(Predicted)
form neat
Water Solubility Insoluble
BRN 1889048
CAS DataBase Reference 79-94-7(CAS DataBase Reference)
IARC 2A (Vol. 115) 2018
NIST Chemistry Reference Phenol, 4,4′-(2,2-propanediyl) bis[2,6-dibromo]-(79-94-7)
EPA Substance Registry System Tetrabromobisphenol A (79-94-7)
Safety Information
Hazard Codes Xi,N
Risk Statements 36/37/38-50/53
Safety Statements 26-36-37/39-61-60
RIDADR UN 3077 9/PG 3
WGK Germany 1
RTECS SM0894500
TSCA Yes
HazardClass 9
PackingGroup II
HS Code 29081990
Hazardous Substances Data 79-94-7(Hazardous Substances Data)
Toxicity LD50 inhalation in guinea pig: > 500mg/m3/8H
Chemical Properties Tetrabromobisphenol A is a white to pale cream or pale yellow crystalline with a moderately high molecular weight, low water solubility, and moderately high lipophilicity (as indicated by log Kow). Only about 4% of the particles are <15 μm in diameter, and thus, little (<4%) is expected to be respirable (<10 μm in diameter) and absorbed from the lung after inhalation exposure.
Tetrabromobisphenol A
Tetrabromobisphenol A (TBBPA) is a brominated flame retardant used in a variety of reactive and additive applications. It is reacted (i.e., covalently bound) with epoxy, vinyl esters, and polycarbonate systems (e.g., high impact polystyrene (HIPS), and is used as an additive in acrylonitrile-butadiene-styrene (ABS) thermoplastic resins (Albemarle, 1999). Its primary application is in printed wire boards (PWBs) as a reactive flame retardant (BSEF, 2012).
Uses tetrabromobisphenol A is widely used as a reactive flame retardant to produce a bromine-containing epoxy resin and polycarbonate, and as intermediates for the synthesis of other complex flame retardant, also as an additive flame retardant for ABS, HIPS, unsaturated polyester rigid polyurethane foams, adhesives and coatings.
Definition ChEBI: A bromobisphenol that is 4,4′-methanediyldiphenol in which the methylene hydrogens are replaced by two methyl groups and the phenyl rings are substituted by bromo groups at positions 2, 2′, 6 and 6′. It is a brominated flame retardant.
General Description White powder. A monomer for flame-retardant epoxy, polyester and polycarboante resins.
Air & Water Reactions Insoluble in water.
Reactivity Profile Tetrabromobisphenol A is monomer.
Hazard Moderately toxic by inhalation and skincontact. An eye irritant.
Fire Hazard Tetrabromobisphenol A is nonflammable.
Environmental Fate Its physicochemical properties suggest that it will partition to all compartments (i.e., water, sediment, and soil), predominantly to sediment and soil through binding to the organic fraction of a particulate matter. Available environmental fate studies indicated that TBBPA is persistent in water (half-life [t1/2] 182 days), soil (t1/2 182 days), and sediment (t1/2 365 days) (Canada, 2013).It lacks functional groups that are expected to undergo hydrolysis (Canada, 2013). A number of laboratory studies (ECHA, 2013) showed that it can degrade to bisphenol A under aerobic conditions (Canada, 2013).
Tetrabromobisphenol A is identified as a persistent, bioaccumulative, and toxic (PBT) compound under the U.S. Environmental Protection Agency s Toxic Release Inventory (EPA, 2013). It was also placed on the State of Washington s Department of Ecology s PBT List (DOC, 2013). However, Environment Canada and Health Canada concluded that TBBPA did not meet their criteria for bioaccumulation (i.e., bioaccumulation factor >5000) (Canada, 2013). This conclusion was based on TBBPA s low bioaccumulation potential from its physicochemical properties (e.g., maximum diameter of 1.3 1.4 nm, ionization at environmentally relevant pH, and variable logKOW), as well as from studies that showed TBBPA is rapidly metabolized and excreted in aquatic and terrestrial organisms (Canada, 2013).
Tetrabromobisphenol A Preparation Products And Raw materials
Raw materials Ethanol–>Government regulation–>Chlorine–>Bisphenol A
Preparation Products 6-Mercaptopurine–>Tetrabromobisphenol A bis(dibromopropyl ether)–>2,2′,6,6′-Tetrabromobisphenol A diallyl ether
Tetrabromobisphenol A (TBBPA) is a brominated flame retardant. The compound is a white solid (not colorless), although commercial samples appear yellow. It is one of the most common fire retardants.
Production and use
TBBPA is produced by the reaction of bromine with bisphenol A. Most commercial TBBPA products consist of a mixture that differ in the degree of bromination with the formula C15H16-xBrxO2 where x = 1 to 4. Its fire-retarding properties correlate with %Br.The annual consumption in Europe has been estimated as 6.200 tons in 2004.[3]
TBBPA is mainly used as a reactive component of polymers, meaning that it is incorporated into the polymer backbone. It is used to prepare fire-resistant polycarbonates by replacing some bisphenol A. A lower grade of TBBPA is used to prepare epoxy resins, used in printed circuit boards.
Toxicity
A study was published by the European Food Safety Authority (EFSA) in December 2011 on the exposure of TBBPA and its derivatives in food. The study, which examined at 344 food samples from the fish and other seafood food group, concluded that “current dietary exposure to TBBPA in the European Union does not raise a health concern.” EFSA also determined that “additional exposure, particularly of young children, to TBBPA from house dust is unlikely to raise a health concern”.[4]
Some studies suggest that TBBPA may be an endocrine disruptor and immunotoxicant. As an endocrine disruptor, TBBPA may interfere with both estrogens and androgens.[5] Further, TBBPA structurally mimics the thyroid hormone thyroxin (T4) and can bind more strongly to the transport protein transthyretin than T4 does, likely interfering with normal T4 activity. TBBPA likely also suppresses immune responses by inhibiting expression of CD25 receptors on T cells, preventing their activation, and by reducing natural killer cell activity.[6][7]
A 2013 literature review on TBBPA concludes that TBBPA does not produce “adverse effects that might be considered to be related to disturbances in the endocrine system”.[8] 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. Exposures of the general population are also well below the derived-no-effect-levels (DNELs) derived for endpoints of potential concern in REACH.
TBBPA degrades to bisphenol A and to TBBPA dimethyl ether, and experiments in zebrafish (Danio rerio) suggest that during development, TBBPA may be more toxic than either BPA or TBBPA dimethyl ether.[9]
Occurrence
TBBPA emits can be found in trace concentration in the hydrosphere, soil, and sediments. It also occurs in sewage sludge and house dust.[10] TBBPA has been the subject of an eight-year evaluation under the EU Risk Assessment procedure which reviewed over 460 studies. The Risk Assessment was published on the EU Official Journal in June 2008.[11] The conclusions of the Risk Assessment were confirmed by the European Commission SCHER Committee (Scientific Committee on Health and Environmental Risks[12]). TBBPA has been registered under REACH.
Properties
Chemical formula C15H12Br4O2
Molar mass 543.9 g·mol-1
Density 2,12 g·cm-3 (20 °C)[1]
Melting point 178 °C (352 °F; 451 K)[1]
Boiling point 250 °C (482 °F; 523 K) (decomposition)[1]
Solubility in water insoluble
Hazards
Main hazards N[1]
R-phrases (outdated) R50/53[1]
S-phrases (outdated) S60 S61[
Application: EcoFlameRetardant B-51 is an aromatic brominated flame retardant that is especially efficient as an additive flame retardant for EPS and in foam polystyrene. The unsaturated end groups provide the unique function of initiating FR performance. EcoFlameRetardant B-51 is also used at low levels with other flame retardants, such as EcoFlameRetardant 8-641 to provide a synergistic response to fire tests. EcoFlameRetardant 8- 51 has excellent UV stability and styrene solubility for a broad range of uses.
Packing: EcoFlameRetardant B-51 is packed in 25kg paper bag, 40 bags on pallet, Or Jumbo bag. Total 20Mt per 20’FCL.
Production (a) Production methods The production process for tetrabromobisphenol A involves the bromination of bisphenol A in the presence of a solvent, such as methanol, a halocarbon alone, or a halocarbon with water, or 50% hydrobromic acid, or aqueous alkyl monoethers (ECHA, 2006). Due to the nature of the process and the by-products (e.g. hydrobromic acid and methyl bromide) that can be formed, the production process is largely conducted in closed systems (Covaci et al., 2009). (b) Production volume Tetrabromobisphenol A is a compound with a high production volume that is currently produced in China, Israel, Japan, Jordan, and the USA, but no longer in the European Union. The total global production volume of tetrabromobisphenol A is estimated at > 100 000 tonnes per year (ECHA, 2008). Except for a minor reduction in production between 2000 and 2002, an overall increasing trend was observed in the estimated global market demand for tetrabromobisphenol A from 109 000 tonnes per year in 1975 to 170 000 tonnes per year in 2004 (Fig. 1.1). 1.2.2 Use Approximately 58% of tetrabromobisphenol A is used as a reactive brominated flame retardant in epoxy, polycarbonate and phenolic resins in printed circuit boards, 18% is used for the production of tetrabromobisphenol A derivatives and oligomers, while 18% is used as additive flame retardant in the manufacture of acrylonitrile- butadiene-styrene resins or high impact polystyrene (Covaci et al., 2009). Fig. 1.1 Global market demand for tetrabromobisphenol A, 1995-2004 109 000 111 000 122 300 119 500 127 000 139 200 104 000 129 000 135 000 170 000 80 000 100 000 120 000 140 000 160 000 180 000 1994 1996 1998 2000 2002 2004 Year Market size (tonnes) From Covaci et al. (2009); numbers were calculated from data published in ECHA (2008) Tetrabromobisphenol A 249 (a) Reactive applications Tetrabromobisphenol A is used primarily as an intermediate in the manufacture of polycarbonate unsaturated polyester and epoxy resins, in which it becomes covalently bound in the polymer. Polycarbonates are used in communication and electronic equipment, electronic appliances, transportation devices, sports and recreational equipment, and lighting fixtures and signs. Unsaturated polyesters are used in the manufacture of simulated marble floor tiles, bowling balls, furniture, coupling compounds for sewer pipes, buttons, and automotive patching compounds. Flame-retardant epoxy resins may be used mainly for the manufacture of printed circuit boards (Lassen et al., 1999). Moreover, epoxy resins containing tetrabromobisphenol A are used to encapsulate certain electronic components (e.g. plastic/paper capacitors, microprocessors, bipolar power transistors, “integrated gate bipolar transistor power modules” and “application specific integrated circuits” on printed circuit boards) (ECHA, 2008). (b) Additive applications Tetrabromobisphenol A is generally used with antimony oxide for optimum performance as an additive fire retardant (IPCS, 1995) that is applied in acrylonitrile-butadiene-styrene resins that are used in automotive parts, pipes and fittings, refrigerators, business machines and telephones (ECHA, 2008), and can also be applied to high-impact polystyrene resins used in casings of electrical and electronic equipment, furniture, building and construction materials (IPCS, 1995). The largest additive use of tetrabromobisphenol A is in television casings for which approximately 450 tonnes are used per year. Other uses include: personal computer monitor casings, components in printers, fax machines and photocopiers, vacuum cleaners, coffee machines and plugs/sockets (ECHA, 2008). As additive flame retardant, tetrabromobisphenol A does not react chemically with the other components of the polymer, and may therefore leach out of the polymer matrix after incorporation (Covaci et al., 2009). 1.3 Measurement and analysis Several studies have reported on different methods for extraction of tetra-bromobisphenol A from different environmental and biological matrices (Table 1.1; Covaci et al., 2009). Solidphase extraction on pre-packed C18 cartridges was the most commonly reported method for the extraction/clean-up of tetrabromobisphenol A from liquid samples, including water (Wang et al., 2015a), plasma (Chu & Letcher, 2013) and milk (Nakao et al., 2015). More aggressive extraction techniques such as Soxhlet extraction, pressurized liquid extraction, ultrasound-assisted extraction and microwave-assisted extraction were required for the efficient extraction of tetrabromobisphenol A from solid samples, including dust (Abdallah et al., 2008), soil (Tang et al., 2014), sediment (Labadie et al., 2010), sewage sludge (Guerra et al., 2010), polymers (Vilaplana et al., 2009), and frozen animal tissues (Tang et al., 2015). The inclusion of a relatively polar organic solvent (e.g. dichloromethane or acetone) was found to be necessary for the efficient extraction of tetrabromobisphenol A (Covaci et al., 2009). Hyphenated chromatographic methods coupled to mass spectrometric detection were commonly applied for the quantitative determination of tetrabromobisphenol A in various media (Table 1.1; Covaci et al., 2009). Other methods of analysis including enzymelinked immunosorbent assay (Bu et al., 2014) and capillary electrophoresis (Blanco et al., 2005) were also reported for the determination of tetrabromobisphenol A in environmental samples.
Natural occurrence Tetrabromobisphenol A does not occur naturally (ECHA, 2006). 1.4.2 Environmental occurrence Tetrabromobisphenol A was first detected in the environment in 1983 at a level of 20 ng/g in sediment from the Neya River in Japan (Watanabe et al., 1983). Several studies have detected tetrabromobisphenol A in various biotic and abiotic matrices from different parts of the world over the past few years (Table 1.2 and Table 1.3). This chemical was detected in air, dust, water, soil, sediment, and sewage sludge from various areas across the globe (Covaci et al., 2009), including the Arctic, which indicates its ability to undergo long-range transport (Xie et al., 2007; de Wit et al., 2010). The frequent detection of tetrabromobisphenol A and the ubiquitous nature of this contaminant indicates that it is continuously released into the environment due to its reported half-life in the soil (t0.5 = 48-84 days) (NTP, 2014). Moreover, tetrabromobisphenol A is frequently detected in biotic samples, including fish, birds, and human tissue (Covaci et al., 2009; Table 1.3). A recent review reported that China was the region most affected by pollution with tetrabromobisphenol A. The most serious cases of tetrabromobisphenol A pollution were found in Guiyu, Guangdong (a primitive e-waste dismantling site), with concentrations reaching 66 010-95 040 pg/m3 in the air (mean, 82 850 pg/m3), in Shouguang, Shandong (a tetrabromobisphenol A-manufacturing site) with concentrations ranging from 1.64 to 7758 ng/g dry weight in the soil (mean, 672 ng/g) and in Chaohu Lake, Anhui (industrial concentration site), with concentrations reaching 850-4870 ng/L in water (Liu et al., 2016). 1.4.3 Occupational exposure Occupational exposures to tetrabromobisphenol A have been measured in facilities manufacturing electronic products and, at higher concentrations, in recycling facilities. Mean concentrations of tetrabromobisphenol A in the air were reported to be 30 ng/m3 in the dismantling hall and 140 ng/m3 in the shredder at an electronic products recycling plant, and to be several orders of magnitude higher than those found in the other indoor microenvironments investigated (e.g. 0.036 ng/m3 in the offices) (Sjödin et al., 2001). A low concentration of tetrabromobisphenol A (0.011 ng/m3) was measured in the particulate matter collected from a medical equipment-manufacturing building (Batterman et al., 2010). Occupational exposure of workers to tetrabromobisphenol A at a Chinese printed circuit-board plant via ingestion, dermal absorption, and inhalation of dust varied widely by process, with the greatest estimated exposures being 1930, 431, and 96.5 pg/kg body weight (bw) per day, respectively. Raw-material warehouse workers were the most highly exposed, with an average overall exposure of 2413 pg/kg bw per day. Dust ingestion was the predominant pathway of exposure (Zhou et al., 2014). Low levels.
Exposure of the general population As a reactive flame retardant, the only potential for exposure is from unreacted tetrabromobisphenol A, which may exist where an excess has been added during the production process. When used as an additive (up to 22% by weight), the potential for the migration of tetrabromobisphenol A out of the matrix is greater, due to abrasion, weathering and high temperatures (ECHA, 2006). Exposure of the general population predominantly occurs through the diet and through ingestion of indoor dust. While intake by very young children is predominantly via ingestion of indoor dust, intake by adults occurs mainly via the diet. Very young children are estimated to have a higher daily intake than adults. Exposure may occur prenatally, and tetrabromobisphenol A has been measured in breast milk (see Table 1.3). Average estimated exposures of the population in the United Kingdom to tetrabromobisphenol A via inhalation of outdoor and indoor air from different microenvironments were 100-300 pg per day (Abdallah et al., 2008). In Japan, adults were reported to inhale tetrabromobisphenol A at 67-210 pg per day, while the exposure of children was 37-114 pg per day (Takigami et al., 2009). The daily intake of tetrabromobisphenol A in a Chinese population via inhalation and ingestion of indoor dust particles of different particle sizes accumulated in air-conditioner filters was estimated. The results revealed that approximately 28.7 pg/kg bw per day particulate matter (PM)2.5- bound tetrabromobisphenol A can be inhaled deep into the lungs, while 14.5 pg/kg bw per day PM10-bound tetrabromobisphenol A tends to be Species (No. of samples) Matrix or tissue Location Concentration Mean (range) or range (ng/g lipid weight)a Reference Bull shark (13) Muscle Florida, USA 0.03-35.6 Johnson-Restrepo et al. Atlantic sharpnose shark (2008) (3) Muscle Florida, USA 0.87 (0.5-1.4) African penguins (3) Muscle Gdansk zoo, Poland 2.7-8.9 Reindl & Falkowska Liver 4-9.3 (2015) Adipose 3-12 Brain 7-15 Egg 11.4 ± 2.6 Cormorant (2) Liver Wales and England, UK 2.5-14 Morris et al. (2004) Common tern (10) Egg Western Scheldt 99%) in corn oil by gavage at doses of 0 (control), 250, 500 or 1000 mg/kg bw on 5 days per week for up to 105 weeks (NTP, 2014). Survival of males and females at 1000 mg/kg bw was significantly lower than that of their respective vehicle-control group. Mean body weights of females at 1000 mg/kg bw were more than 10% lower than those of the vehicle controls after week 25. This decrease in survival at 1000 mg/kg bw was attributed to forestomach toxicity, which consisted of ulcers, inflammation, and/or hyperplasia. Because of the large decrease in survival of mice at 1000 mg/kg bw, this dose was not used in the statistical analysis for treatment-related tumour formation. In male mice, increases in the incidence of hepatoblastoma were observed at both 250 and 500 mg/kg bw (2/50 controls, 11/50 at 250 mg/kg bw (P = 0.006), and 8/50 at 500 mg/kg bw [not significant]). The incidence of hepatoblastoma in the treated groups exceeded the upper bound of the range for historical controls for this tumour in studies with gavage in corn oil and for all routes. The historical incidence of hepatoblastoma in male mice for studies with gavage in corn oil was 9/250 (3.6% ± 2.6%; range, 0-6%) and for all routes was 40/949 (4.2% ± 3.5%; range, 0-12%). [Hepatoblastomas are uncommon spontaneous neoplasms that may occur after chemical administration, and have been seen after other chemical treatments (Bhusari et al., 2015).] An increased incidence of liver foci (clear cell and eosinophilic foci) and a significant increase in the incidence of hepatocellular adenoma (multiple) were seen in treated males (12/50 controls, 20/50 at 250 mg/kg bw, and 28/50 at 500 mg/kg bw (P ≤ 0.05)). However, the incidence of hepatocellular adenoma (including multiple) was not increased in treated males (32/50 controls, 33/50 at 250 mg/kg bw, and 38/50 at 500 mg/kg bw). The historical incidence of hepatocellular adenoma (including multiple) in male mice in studies in which tetrabromobisphenol A was administered by gavage in corn oil was 145/250 (58.0% ± 5.1%; range, 52-64%), and for administration by all routes was 594/949 (62.6% ± 9.1%; range, 48-78%). The incidence of hepatocellular carcinoma was not significantly increased in male mice (11/50 controls, 15/50 at 250 mg/kg bw, and 17/50 at 500 mg/kg bw) and was within the historical ranges; the historical incidence of hepatocellular carcinoma in male mice in gavage studies (in corn oil) was 87/250 (34.8% ± 10.9%; range, 22-44%), and for administration by all routes was 348/949 (36.7% ± 11.4%; range, 22-56%). However, the incidence of hepatocellular carcinoma or hepatoblastoma (combined) was significantly increased at 250 mg/kg bw (12/50 controls, 24/50 at 250 mg/kg bw (P = 0.008), and 20/50.
at 500 mg/kg bw). The historical incidence of hepatocellular carcinoma or hepatoblastoma (combined) in male mice in gavage studies (in corn oil) was 93/250 (37.2% ± 10.0%; range, 24-48%) and for administration by all routes was 371/949 (39.1% ± 11.6%; range, 22-54%). The incidence of caecum or colon tumours (adenoma or carcinoma, combined) in male mice was 0/50 controls, 0/50 at 250 mg/kg bw, and 3/50 at 500 mg/kg bw, which was statistically significantly increased by the trend test (P = 0.039), but not by pairwise comparison. For the three male mice at 500 mg/kg bw with tumours of the large intestine, one had a caecum carcinoma, one had a colon carcinoma and one had a colon adenoma. The incidence of these tumours (3/50) exceeded the range for historical controls in gavage studies (in corn oil) and for administration by all routes. The historical incidence for caecum or colon adenoma or carcinoma (combined) in male mice in gavage studies (in corn oil) was 0/250 and for administration by all routes was 4/950 (0.4% ± 0.8%; range, 0-2%). A significant positive trend (P = 0.014) in the incidence of haemangiosarcoma (all organs) (1/50 controls, 5/50 at 250 mg/kg bw, and 8/50 at 500 mg/kg bw) was observed in males and the incidence at 500 mg/kg bw was also significantly increased (P = 0.019). The incidence of haemangiosarcoma (all organs) in historical controls in gavage studies (in corn oil) was 28/250 (11.2% ± 6.4%; range, 2-18%). No significant increase in the incidence of tumours was observed in female mice treated with tetrabromobisphenol A. Treatment-related non-neoplastic lesions were found in the forestomach in male and female mice, and in the kidney in male mice (NTP, 2014). [The strengths of this study, which complied with good laboratory practice, included the use of multiple doses, the large number of animals per group, and the treatment of males and females.] 3.2 Rat Groups of 50 male and 50 female Wistar Han [Crl:WI(Han)] rats (age, 6-7 weeks) were given tetrabromobisphenol A (purity, > 99%) by gavage at doses of 0 (control), 250, 500, or 1000 mg/kg bw on 5 days per week for up to 104 (males) or 105 (females) weeks (NTP, 2014). Mean body weights of the males at 500 and 1000 mg/kg bw were at least 10% lower than those of the vehicle-control group after week 25. The mean body weights in the other groups of treated males and all groups of treated females were similar to those of the corresponding controls. 3.2.1 Original transverse examination of the uterus In treated female rats, an increase in the incidence of uterine epithelial tumours was observed. The incidence of uterine adenoma was significantly increased according to trend statistics (P = 0.010), but not pairwise statistics (0/50 controls, 0/50 at 250 mg/kg bw, 3/50 at 500 mg/kg bw, and 4/50 at 1000 mg/kg bw), and the historical incidence in female rats was 0/150 (all routes). The incidence of uterine adenocarcinoma was also increased according to trend statistics (P = 0.016), but not pairwise statistics (3/50 controls, 3/50 at 250 mg/kg bw, 8/50 at 500 mg/kg bw, and 9/50 at 1000 mg/kg bw), and the historical incidence (all routes) in female rats was 7/150 (including one carcinoma of the endometrium). Malignant mixed Müllerian tumours were present in treated groups (0/50 controls, 4/50 at 250 mg/kg bw, 0/50 at 500 mg/kg bw, and 2/50 at 100 mg/kg bw), but were not seen in historical control data (all routes of exposure, 0/150). The incidence of uterine adenoma, adenocarcinoma, or malignant mixed Müllerian tumour (combined) was increased in treated groups (3/50 controls, 7/50 at 250 mg/kg bw, 11/50 at 500 mg/kg bw (P = 0.013), and 13/50 at 1000 mg/kg bw (P = 0.005)), with a statistically positive trend (P = 0.003), and the IARC MONOGRAPHS – 115 262 historical incidence for these uterine tumours (combined) by all routes was 7/150 (4.7% ± 2.3%; range, 2-6%). In addition, cystic endometrial hyperplasia was reported in this initial evaluation (8/50 controls, 13/50 at 250 mg/kg bw, 11/50 at 500 mg/kg bw, and 18/50 at 1000 mg/kg bw (P ≤ 0.05)). These findings were based on the traditional histopathology review of the uterus from the United States National Toxicology Program (NTP), with a transverse section through each uterine horn approximately 0.5 cm from the cervix of the uterus. The cervix and vagina were not investigated in most animals in this original review of uterine pathology. 3.2.2 Residual longitudinal examination of the uterus While the initial (original) review of the uterus showed a treatment-related carcinogenic effect, an additional examination of the uterus called the “residual longitudinal” examination was conducted to examine all remaining parts of the uterus, cervix, and vagina more completely. This residual longitudinal examination consisted of trimming, embedding and sectioning the remaining uterine tissue, cervix, and vagina (remaining in the formalin-fixed samples) longitudinally. Additional non-neoplastic and neoplastic uterine lesions were found in this review that supported the original carcinogenic findings. The findings in Table 3.1 are presented as: the original carcinogenic findings; the carcinogenic findings of the residual longitudinal examination; and the combined carcinogenic findings of the original and residual longitudinal examinations. There were no historical control data for the residual or residual and original (combined) uterine tumour findings (NTP, 2014). After the residual longitudinal examination of the uterus, the incidence of atypical endometrial hyperplasia was significantly increased in all treated groups (2/50 controls, 13/50 at 250 mg/kg bw (P ≤ 0.01), 11/50 at 500 mg/kg bw (P ≤ 0.01) and 13/50 at 1000 mg/kg bw (P ≤ 0.01)). This lesion had not been identified in the original transverse review. [This lesion is considered to be preneoplastic (Bartels et al., 2012; van der Zee et al., 2013; NTP, 2014).] The incidence of uterine tumours in the residual longitudinal examination was: uterine adenoma – 3/50 controls, 2/50 at 250 mg/kg bw, 1/50 at 500 mg/kg bw, and 3/50 at 1000 mg/kg bw; uterine adenocarcinoma (P for trend, 0.003) – 4/50 controls, 9/50 at 250 mg/kg bw, 15/50 at 500 mg/kg bw (P = 0.002), and 15/50 at 1000 mg/kg bw (P = 0.005); malignant mixed Müllerian tumours – 0/50 controls; 0/50 at 250 mg/kg bw, 0/50 at 500 mg/kg bw, and 1/50 at 1000 mg/kg bw; and uterine adenoma, adenocarcinoma, or malignant mixed Müllerian tumour (combined) (P for trend, 0.008) – 6/50 controls, 10/50 at 250 mg/kg bw, 16/50 at 500 mg/kg bw (P = 0.007), and 16/50 at 1000 mg/kg bw (P = 0.015) (NTP, 2014). 3.2.3 Original transverse and residual longitudinal examinations of the uterus (combined) The incidence of uterine tumours in the original and residual examinations (combined) was: uterine adenoma – 3/50 controls, 2/50 at 250 mg/kg bw, 4/50 at 500 mg/kg bw, and 6/50 at 1000 mg/kg bw; uterine adenocarcinoma (P for trend, 0.002) – 4/50 controls, 10/50 at 250 mg/kg bw, 15/50 at 500 mg/kg bw (P = 0.002), and 16/50 at 1000 mg/kg bw (P = 0.002); malignant mixed Müllerian tumours – 0/50 controls, 4/50 at 250 mg/kg bw, 0/50 at 500 mg/kg bw, and 2/50 at 1000 mg/kg bw; and uterine adenoma, adenocarcinoma or malignant mixed Müllerian tumours (combined) (P trend, < 1 ng/g of lipid, and were below the limit of detection in some subjects. In one study, adipose tissue obtained from cosmetic surgery contained about 0.05 ng/g of lipid (Johnson-Restrepo et al., 2008). The half-life of tetrabromobisphenol A was estimated to be 2.2 days in a study of four occupationally exposed humans (Hagmar et al., 2000b). In a study in vitro, human skin penetration was about 3.5% (of a total dose of 100 nmol/cm2) within 24 hours of application (Knudsen et al., 2015). (b) Experimental systems Tetrabromobisphenol A was readily absorbed after oral administration of [14C]-labelled doses in male or female rats (Hakk et al., 2000; Kuester et al., 2007; Knudsen et al., 2014). After dermal application in female rats, about 8% of the total dose (100 nmol/cm2) reached the systemic circulation within 24 hours (Knudsen et al., 2015). The extent of absorption was calculated to be 3-11% of a total dose to male rats by dermal exposure (6 hours per day for 90 days) to up to 600 mg/kg bw (Yu et al., 2016). Systemic bioavailability was < 1% remained in tissues at 72 hours (Knudsen et al., 2014). After oral administration to male Sprague-Dawley rats, > 90% of a total dose of 2 mg/kg bw of tetrabromobisphenol A was excreted in the faeces within 72 hours, and about 3% of the total dose was recovered in the tissues and cumulative urine (Hakk et al., 2000). In male Fischer 344 rats that received tetrabromobisphenol A as a single gavage dose of 2, 20, or 200 mg/kg bw, reduced excretion of the highest dose in the faeces indicated the saturation of absorption and/or elimination processes; however, the cumulative data on faecal elimination were similar for the lowest and highest doses at 72 hours. The total dose remaining in tissues was < 1% (Kuester et al., 2007). In gavaged (2.0 mg/kg bw per day) bile duct-cannulated male Sprague-Dawley rats, > 70% of the total radioactivity was excreted in the bile, mostly within 24 hours (Hakk et al., 2000). About 50% of a dose of 20 mg/kg bw was excreted in the bile of male Sprague-Dawley rats within 2 hours after administration by gavage (Kuester et al., 2007). The disposition of [14C]-labelled tetrabromobisphenol A (250 or 1000 mg/kg bw) administered intraperitoneally to female rats differed from that of an oral dose. The total dose excreted in the faeces was lower and the tissue burdens and elimination half-lives were longer after intraperitoneal injection (Szymańska et al., 2001). 4.1.2 Metabolism See Figure 4.1 (a) Humans A monoglucuronide and/or monosulfate were detected in the blood and urine after oral administration of tetrabromobisphenol A in humans (Schauer et al., 2006). The metabolism of tetrabromobisphenol A in human liver microsomes and metabolic activation preparations was described as being qualitatively similar to that observed in rat subcellular liver fractions. A glucuronide was formed in the metabolic activation system. Oxidative cleavage of the tetrabromobisphenol A molecule was a major pathway in microsomes (Zalko et al., 2006). (b) Experimental systems In male and female rats, tetrabromobisphenol A undergoes rapid metabolism catalysed by UDP glucuronosyltransferase and sulfotransferase isozymes to form glucuronide and sulfate conjugates (Hakk et al., 2000; Schauer et al., 2006; Kuester et al., 2007; Knudsen et al., 2014). The specific structures.
bis, and mixed), presence and relative abundance of these conjugates in the blood, bile and/or excreta were sex- and strain-dependent and may also be dose- and species-dependent (Schauer et al., 2006; Dunnick et al., 2015). Tetrabromobisphenol A was identified in the plasma and faeces at low concentrations and its monoglucuronide was detected in the urine of Sprague-Dawley rats treated by gavage (Schauer et al., 2006). A glucuronide was formed in metabolic activation systems after incubation. Rat hepatocytes metabolized tetrabromobisphenol A to a monoglucuronide and monosulfate conjugate (Nakagawa et al., 2007). Glucuronide and sulfate conjugates were detected in Xenopus laevis tadpoles exposed to tetrabromobisphenol A in water (Fini et al., 2012). Oxidative cleavage of tetrabromobisphenol A is possible in vivo. The 2,6-dibromobenzenosemiquinone radical, derived from 2,6-dibromohydroquinone, was identified in the bile of male Sprague-Dawley rats that received tetrabromobisphenol A by intraperitoneal injection (Chignell et al., 2008). In rat microsomal preparations, the major metabolites of tetrabromobisphenol A were products of oxidative cleavage (Zalko et al., 2006). 4.2 Mechanisms of carcinogenesis The evidence on the “key characteristics” of carcinogens (Smith et al., 2016) concerning whether tetrabromobisphenol A modulates receptor-mediated effects, induces oxidative stress, induces chronic inflammation, is immunosuppressive, alters cell proliferation, cell death, or nutrient supply, and is genotoxic, is summarized below. Fig. 4.1 Metabolic scheme for tetrabromobisphenol A in rats Br OGluc Br Br GlucO Br Br OH Br Br GlucO Br Br OSO3H Br Br GlucO Br Br OSO3H Br Br HO Br Br OH Br Br HO Br Br OH Br HO Br Br OH HO Br Br O O Br Br O Br O TBBPA bisglucuronide UGT C9H10Br2O2 Glucuronidases UGT [Gut microflora?] TBBPA monoglucuronide TBBPA Tribromobisphenol-A SULT SULT Sulfatases TBBPA glucuronide-sulfate TBBPA monosulfate UGT 2,6-Dibromohydroquinone Gluc, C6H9O6; SULT, sulfotransferase; TBBPA, tetrabromobisphenol A; UGT, uridine 5′-diphospho-glucuronosyltransferase Adapted from NTP (2014) Tetrabromobisphenol A 267 4.2.1 Receptor-mediated effects (a) Thyroid hormone pathway (i) Exposed humans Serum concentrations of tetrabromobisphenol A were positively correlated with serum concentrations of free thyroxine (T4), but negatively correlated with serum triiodothyronine (T3) in mothers of infants diagnosed with congenital hypothyroidism. No correlation was observed in the infants with congenital hypothyroidism, but they also had therapeutic T4 supplementation (Kim & Oh, 2014). Serum concentrations of tetrabromobisphenol A were not correlated with measures of thyroid function in another study of 515 adolescents (age, 13-17 years). These measurements included serum concentrations of free T4, T3 and thyroid-stimulating hormone (Kiciński et al., 2012). To determine whether tetrabromobisphenol A interferes with measures of T4 in human serum, McIver et al. (2013) tested several commercial immunoassays for serum total or free T4 or T3. The results indicated that high concentrations of tetrabromobisphenol A could displace tracer T4 in an in-house serum total T4 assay, but none of the other assays were disturbed. [This indicated that tetrabromobisphenol A may produce erroneously high T4 readings in some assays.] (ii) Human cells in vitro Tetrabromobisphenol A exhibited a potent interaction with human transthyretin, and had greater avidity for binding than T4 (displacing 125I-T4) (Meerts et al., 2000). Tetrabromobisphenol A demonstrated both agonist and antagonist activity on thyroid hormone receptor activation in HepG2 cells, activating a transiently transfected thyroid hormone-responsive reporter at or above 10 µM and also inhibiting transactivation of the reporter by T3 at 1 µM (Hofmann et al., 2009). In contrast, tetrabromobisphenol A did not show agonist or antagonist activity on human thyroid hormone receptor TRα1 or TRβ1 in human embryonic kidney HEK293 cells. This assay was a transient transfection paradigm using a palindromic thyroid hormone-responsive element (TRE) to avoid the requirement for a TR:retinoid X receptor heterodimer formation on the TRE (Oka et al., 2013). Tetrabromobisphenol A inhibited luciferase expression induced by T3 in human embryonic kidney HEK293 cells stably transfected with a construct that would allow the detection of changes in intracellular free T3 by one or more of several potential pathways. In a follow-up experiment using a murine cerebellar cell line expressing the TRα1 receptor, tetrabromobisphenol A significantly interfered with TRα1- mediated gene expression using a genome-wide RNa-Seq approach (Guyot et al., 2014). In human liver microsomes, tetrabromobisphenol A inhibited the ativity of type 1 deiodinase, which converts T4 to the more biologically active T3, in the micromolar concentration range; 1 µM of tetrabromobisphenol A inhibited the activity by 20% and 10 µM inhibited the activity by 80% (Butt et al., 2011). Tetrabromobisphenol A did not increase cell proliferation in human cervical cancer HeLa cells stably transfected with human TRα1, and did not appear to reduce the induction of luciferase activity by T3 driven by a death receptor-4 promoter in a transient transfection paradigm (Yamada-Okabe et al., 2005). [The Working Group noted that the authors did not appear to correct for the efficiency of transfection of the HeLa-TR cells, which may have altered the outcome.] (iii) Non-human mammalian systems in vivo Tetrabromobisphenol A (100, 1000, or 10 000 ppm) given to pregnant rats throughout lactation did not affect serum T4 or thyroid-stimulating hormone, but did slightly decrease levels of serum T3 (Saegusa et al., 2009). IARC MONOGRAPHS – 115 268 In a study of reproductive toxicity, tetrabromobisphenol A significantly reduced levels of serum T4 in male and female rats exposed orally to various concentrations throughout fetal life, lactation, and the end of the experiment at age 12 weeks. Reduced levels of serum T4 correlated with a cluster of measures related to thyroid function, including delayed onset of puberty and hearing deficits. However, in a short-term study, these effects were not observed in relation to the decrease in serum T4 (Van der Ven et al., 2008). Serum T4 was significantly reduced in males and females exposed to tetrabromobisphenol A at 100 and 1000 mg/kg bw, and in both the parental and F1 generations in a large multigeneration study of reproductive toxicity in SpragueDawley rats that complied with good laboratory practice. No effects were observed on serum T3 or thyroid-stimulating hormone (Cope et al., 2015). [Because the units of serum T4 were reported as ng/dL, the Working Group was unable to draw any conclusions on this study.] No effect was seen on serum T3 or thyroidstimulating hormone in CD/SD rats (age, 8 weeks) administered 0, 100, 300, and 1000 mg/kg bw of tetrabromobisphenol A by gavage in corn oil daily. In contrast, mean serum T4 concentrations (reported as ng/dL and ng/mL) were reduced at day 33 in males (4.96, 3.66, 3.42 and 3.39 at 0, 100, 300, and 1000 mg/kg bw, respectively) and females (4.27, 3.31, 3.24, and 3.33 at 0, 100, 300, and 1000 mg/kg bw, respectively) (Osimitz et al., 2016). [Because the units of serum T4 were reported as both ng/dL and ng/mL, the Working Group was unable to draw any conclusions about this study.] (iv) Non-human mammalian systems in vitro Tetrabromobisphenol A (10-6 to 10-4 M) markedly inhibited the binding of T3 to the TR in isolated nuclei from the rat pituitary MtT/E-2 cell line, and also stimulated proliferation and growth hormone production of rat pituitary GH3 cells. Tetrabromobisphenol A enhanced T3-induced GH3 proliferation (at 10-4 M) and growth hormone production (at both 10-5 and 10-4 M). These data were interpreted to indicate that tetrabromobisphenol A could act on the TR as an agonist (Kitamura et al., 2002). In contrast, tetrabromobisphenol A was antagonistic to the human TRα1 receptor in a transient transfection assay using CHO cells, and inhibited the effect of 10-8 M T3 on luciferase activity in the 4-50 µM concentration range, at which it was not cytotoxic. However, tetrabromobisphenol A did not antagonize the TRβ1 receptor at concentrations that were not cytotoxic and did not exhibit agonistic action on TRα1 or TRβ1 (Kitamura et al., 2005a). This group later confirmed their original observation that tetrabromobisphenol A could stimulate growth hormone production in GH3 cells (Kitamura et al., 2005b). Sun et al. (2009) reported that tetrabromobisphenol A did not exhibit TR agonist action, but suppressed transactivation by 10 nM T3 at 10-4M in CV-1 cells (African green monkey kidney cells). As CV-1 cells do not express TRs, this transient transfection system employed a GAL4/hTRβ1 fusion protein with a 4×UAS/luciferase construct. Tetrabromobisphenol A inhibited T3-induced luciferase expression at concentrations above 10 µM in rat pituitary GH3 cells stably transfected with a 2×DR4/luciferase construct, a system that is highly sensitive and can detect picomolar concentrations of T3. Extensive validation was carried out and tetrabromobisphenol A did not induce an agonistic effect in this system (Freitas et al., 2011). Tetrabromobisphenol A produced a TR agonist effect in the 10-5 to 10-4 M range in a yeast two-hybrid assay, an effect enhanced by prior incubation with a microsomal metabolic activation system. To detect chemical effects on the TR, this assay employed yeast cells transfected with human TRα and co-factor TIF2. The reporter gene was β-galactosidase (Terasaki et al., 2011). Tetrabromobisphenol A 269 Lévy-Bimbot et al. (2012) evaluated the effect of tetrabromobisphenol A on structural changes within the TRα receptor using a co-regulator recruitment assay. Tetrabromobisphenol A decreased the affinity of the TR ligand-binding domain for the NCoR-binding peptide, but did not simultaneously increase the affinity of the TR for the SRC2-binding peptide. The effective concentration of tetrabromobisphenol A was in the 1 µM range. Grasselli et al. (2014) evaluated tetrabromobisphenol A in a rat hepatoma cell line (FaO) that does not express TRs but accumulates lipid droplets. Treatment with T3 can cause a depletion of the lipids, which was mimicked by 10-6 M tetrabromobisphenol A. However, tetrabromobisphenol A induced the expression of genes related to lipid accumulation. [The Working Group noted that, in the absence of an antagonist to block T3-dependent processes (that are also TR-independent), this study was difficult to interpret.] (v) Non-mammalian experimental systems Tetrabromobisphenol A inhibited T3-induced tail resorption in Rana rugosa tadpoles at a concentration of 10-6 M, a similar range to that used in TR-binding studies, but exerted no effect on tail length in the absence of T3 (Kitamura et al., 2005a). This observation was confirmed by Goto et al. (2006), who reported that both 10-7 and 10-6 M tetrabromobisphenol A inhibited T3-induced tail resorption in Rana rugosa tadpoles, but again had no effect in the absence of T3. During T3-induced tail resorption, DNA becomes highly fragmented; Goto et al. (2006) also demonstrated that 10-6 M tetrabromobisphenol A could inhibit this fragmentation and block T3-induced hind limb growth. Finally, they demonstrated in transgenic Xenopus laevis carrying a TRE-linked green fluorescent protein that T3-induced fluorescence was blocked by tetrabromobisphenol A at 10-7 M. [The Working Group noted that, taken together, these data consistently demonstrated the antagonist action of tetrabromobisphenol A in amphibians and in the range of its binding to TR.] In the tree frog, tetrabromobisphenol A was antagonistic to the TR. Veldhoen et al. (2006) reported that it was agonistic to metamorphic changes in Pseudacris regilla. At 10 nmol/L, tetrabromobisphenol A suppressed T3-induced TRβ expression in the frog Pelophylax nigromaculatu, coincident with a suppression of several thyroid hormone-regulated genes (Zhang et al., 2015b). (b) Other pathways (i) Nuclear receptors and steroidogenesis Several studies have addressed the possible agonistic or antagonistic properties of tetrabromobisphenol A on relevant nuclear receptors in various human cell lines, such as human mammary carcinoma MCF-7 and human cervical carcinoma HeLa cells. For the estrogen and progesterone receptors, no significant agonistic or antagonistic properties of tetrabromobisphenol A were detected (Samuelsen et al., 2001; Hamers et al., 2006; Molina-Molina et al., 2013). This lack of direct estrogenicity of tetrabromobisphenol A has also been shown in vivo in the mouse uterotrophic assay (Ohta et al., 2012). The androgen receptor antagonistic activity of tetrabromobisphenol A was detected at the lower micromolar levels in MDA-kb2 cells (Christen et al., 2010). Tetrabromobisphenol A does not have any significant agonistic activity on the aryl hydrocarbon receptor (AhR), and several studies in vitro and in vivo showed that it does not induce AhR-mediated cytochrome P450 (CYP) A1 enzymes (Behnisch et al., 2003; Germer et al., 2006; Hamers et al., 2006). In addition to the data mentioned above, ToxCast identified interactions between tetrabromobisphenol A and the glucocorticoid receptor, the farnesyl X receptor, and the xenobiotic receptor PXR. IARC MONOGRAPHS – 115 270 In stably transfected human HeLa cells and monkey Cos-7 kidney cells, significant agonistic activity for human peroxisome proliferator-activated receptor-γ1 and -γ2 was found below 1 μM (Christen et al., 2010; Watt & Schlezinger, 2015). In human choriocarcinoma JEG-3 cells, low nanomolar levels of tetrabromobisphenol A also increased peroxisome proliferator-activated receptor-γ, as well as increasing progesterone and β-human chorionic gonadotrophin (Honkisz & Wójtowicz, 2015). Furthermore, tetrabromobisphenol A (0.1 and 1 μM) induced aromatase (CYP19) in these JEG-3 cells (Honkisz & Wójtowicz, 2015), but not in human adenocarcinoma H295R cells (Song et al., 2008). (ii) Neurotoxicity The possible neurotoxic mechanisms of action of tetrabromobisphenol A were studied in SH-SY5Y human neuroblastoma cells in vitro. It was both neurotoxic and amyloidogenic, as demonstrated by increased intracellular calcium levels and a release of β-amyloid peptide (Aβ-42) at micromolar levels (Al-Mousa & Michelangeli, 2012). As further evidence of its potential neurotoxicity, tetrabromobisphenol A inhibited the plasma membrane uptake of the neurotransmitters dopamine, glutamate, and gammaamino butyric acid in rat brain synaptosomes (Mariussen & Fonnum, 2003). However, in spite of the interactions of tetrabromobisphenol A in vitro with various neurotransmitters, neonatal exposure of mice did not induce any neurobehavioural changes (Eriksson et al., 2001; Viberg & Eriksson, 2011). (iii) Other effects Several studies in vitro have addressed the direct interaction of tetrabromobisphenol A with estrogen sulfotransferase (e.g. SULT1E1) and concluded that it strongly inhibits the estradiol binding process with half-maximal inhibitory concentrations between 12 and 33 nM (Kester et al., 2002; Hamers et al., 2006; Gosavi et al., 2013). In addition, many authors hypothesized that, at high concentrations, the conjugation of tetrabromobisphenol A to form tetrabromobisphenol A sulfate could possibly saturate the sulfation pathway (Kester et al., 2002; Hamers et al., 2006; Gosavi et al., 2013; Dunnick et al., 2015 Lai et al., 2015; Wikoff et al., 2016). [This competitive inhibition of estrogen sulfotransferases could lead to an increase in systemic and target tissue levels of estrogens.] A follow-up 28-day study of tetrabromobisphenol A in rats was carried out by Borghoff et al. (2016) using the same dose levels as those in the 2-year NTP carcinogenicity bioassay (NTP, 2014). At the highest dose levels (250, 500, and 1000 mg/kg bw per day), a decrease in the ratio of tetrabromobisphenol A sulfates to tetrabromobisphenol A glucuronides occurred. These results demonstrated that the saturation of tetrabromobisphenol A sulfation also occurs in vivo at these dose levels, which were associated with uterine tumours in the 2-year NTP study. [The Working Group noted that neither the NTP (2014) nor Borghoff et al. (2016) studies took measurements that provided information on estrogen homeostasis.] In addition, several other mechanistic explanations have been postulated to explain the uterine tumours in the 2-year NTP study (Dunnick et al., 2015; Lai et al., 2015), one of which is the interaction of tetrabromobisphenol A with dopamine and a subsequent decrease in prolactin levels that is considered to be a rat-specific mechanism (Neumann, 1991; Harleman et al., 2012). Tetrabromobisphenol A inhibited the cellular uptake of dopamine with a half-maximal inhibitory concentration of 9 μM (Mariussen & Fonnum, 2003). [At present, insufficient data were available to evaluate its relevance to the tetrabromobisphenol A-induced uterine tumours in the NTP (2014) study.] Tetrabromobisphenol A 271 4.2.2 Oxidative stress (a) Humans Treatment of isolated human neutrophil granulocytes with tetrabromobisphenol A at 1-12 µM for 60 minutes induced significant dose-dependent increases in the production of reactive oxygen species (ROS) and increased intracellular calcium concentrations (Reistad et al., 2005). ROS production was determined using the fluorescent probe 2,7-dichlorofluorescein diacetate or by lucigenin-amplified chemiluminescence. Production of ROS was inhibited by pretreatment with diphenyleneiodonium (a nicotinamide adenine dinucleotide phosphate oxidase inhibitor), U0126 (an inhibitor of mitogen-activated protein kinase kinases MEK1 and MEK2, i.e. MAPK/ERK kinase), bisindolylmaleimide (a protein kinase C inhibitor), erbstatin A (a tyrosine kinase inhibitor), or verapamil (a Ca2+ channel blocker), or by incubation in calcium-free media. A decrease in tetrabromobisphenol A-induced ROS by diethyldithiocarbamate, an inhibitor of superoxide dismutase (SOD), confirmed the involvement of the superoxide anion in the production of ROS by tetrabromobisphenol A (Reistad et al., 2005). (b) Experimental systems (i) Non-human mammalian systems in vivo Chignell et al. (2008) administered tetrabromobisphenol A (100 or 600 mg/kg bw) to SpragueDawley rats together with the spin-trapping agent α-(4-pyridyl-1-oxide)-N-t-butylnitrone and detected the α-(4-pyridyl-1-oxide)-N-t-butylnitrone/• CH3 spin adduct by electron paramagnetic resonance in the bile. Also measured in the bile was the 2,6-dibromobenzosemiquinone radical; reaction of the latter compound with oxygen could generate the superoxide anion. Daily treatment of male Sprague-Dawley rats with tetrabromobisphenol A (500 mg/kg bw for 30 days, beginning on postnatal day 18), induced a significant increase in the levels of 8-hydroxy-2′-deoxyguanosine (a biomarker of oxidative DNA damage) in the testis and kidney. No increase in the levels of malondialdehyde was observed in the liver of exposed rats compared with controls (Choi et al., 2011). Daily administration of tetrabromobisphenol A (750 or 1125 mg/kg bw) for 7 days to Wistar rats decreased the levels of reduced glutathione in females at both doses and increased the levels of malondialdehyde in male rats at the higher dose (Szymańska et al., 2000). A single oral dose of tetrabromobisphenol A in Sprague-Dawley rats produced increases in kidney levels of thiobarbituric acid reactive substances (TBARS) at 1000 mg/kg bw and in SOD activity at 250-1000 mg/kg bw, but no significant changes in urine analysis parameters. These parameters were not increased in a 14-day repeated-dose experiment with the same doses of tetrabromobisphenol A (Kang et al., 2009). (ii) Non-human mammalian systems in vitro Exposure of hepatocytes isolated from Fischer 344/Jcl rats to tetrabromobisphenol A at 0.25-1.0 mM for up to 3 hours decreased the reduced glutathione content with concomitant increases in oxidized glutathione (GSSG), and increased malondialdehyde levels (TBARS). Treatment with tetrabromobisphenol A also reduced the mitochondrial membrane potential and had an uncoupling effect on mitochondrial oxidative phosphorylation (Nakagawa et al., 2007). [Based on the longer time needed to induce lipid peroxidation compared with the rapid reduction in cellular adenosine triphosphate levels, the results suggested that lipid peroxidation induced by tetrabromobisphenol A was due to impaired mitochondrial function.] Incubation of primary cultures of cerebellar granule cells from Wistar rats with tetrabromobisphenol A at 2.5-7.5 µM produced significant increases in ROS production, with reductions in 45Ca uptake, increases in IARC MONOGRAPHS – 115 272 intracellular concentrations of 45Ca, and a slight decrease in the mitochondrial membrane potential. The production of ROS was reduced by co-treatment with 0.1 mM ascorbic acid or 1 mM glutathione (Ziemińska et al., 2012). Reistad et al. (2007) also observed concentration-dependent increases in ROS, phosphorylation of ERK1/2 and intracellular calcium in primary cultures of rat cerebellar granule cells exposed to tetrabromobisphenol A. ROS formation was inhibited by pretreatment with the MAPK/ERK kinase inhibitor U0126, the tyrosine kinase inhibitor erbstatin A, the SOD inhibitor diethyldithiocarbamate or by eliminating calcium from the culture medium. (iii) Fish and other species In goldfish (Carassius auratus) given a single intraperitoneal injection of tetrabromobisphenol A (100 mg/kg bw), ROS were increased in the liver and bile, an effect inhibited by the hydroxyl radical scavenger mannitol. Lipid peroxidation products (TBARS) and protein carbonyl levels, indicators of oxidative damage, were significantly increased in the liver at 1-3 days after treatment with tetrabromobisphenol A (Shi et al., 2005). Tetrabromobisphenol A in aquarium water (3 mg/L for 7 days) significantly decreased reduced glutathione levels and antioxidant enzyme activites (SOD and catalase) in fish livers (He et al., 2015). In Carassius auratus, intraperitoneal injections of tetrabromobisphenol A (10 or 100 mg/kg bw for 14 days) decreased the activities of antioxidant enzymes (SOD, catalase, and glutathione peroxidase), decreased reduced glutathione levels and increased the levels of malondialdehyde (a marker of lipid peroxidation) in the liver (Feng et al., 2013). In zebrafish embryos, tetrabromobisphenol A (0.05, 0.25, or 0.75 mg/mL for 96 hours) increased SOD activity, lipid peroxidation (TBARS), and the expression of heat-shock protein 70 (Hsp70) (Hu et al., 2009). Significant decreases in the activities of the antioxidant enzymes SOD, catalase, and glutathione peroxidase were observed in embryos and zebrafish larvae exposed to tetrabromobisphenol A at 0.4-1.0 mg/L in holding tanks for 3, 5, or 8 days post-fertilization (Wu et al., 2015). Similarly, increases in ROS production were observed in zebrafish embryos and larvae exposed to tetrabromobisphenol A at 0.1, 0.5, or 1.0 mg/L for 96 hours; the increases in ROS production were inhibited by co-incubation with puerarin (1 mg/L), an antioxidant free-radical scavenger. ROS production was measured with a fish ROS enzyme-linked immunosorbent assay kit using a horseradish peroxidase-labelled fish ROS antibody (Yang et al., 2015). Hepatic oxidative stress and general stress was induced in zebrafish exposed to tetrabromobisphenol A (0.75 or 1.5 µM) for 14 days and evaluated for hepatic changes in gene and protein expression (De Wit et al., 2008). [The Working Group noted that tetrabromobisphenol A induced oxidative stress, based on antioxidant-related responses, and general stress responses, based on stimulation of Hsp70 protein in the liver of zebrafish.] Tetrabromobisphenol A also induced hydroxyl radical formation and oxidative stress in earthworms (Eisenia fetida). Lipid peroxidation was increased while the reduced glutathione/ GSSG ratio was decreased (Xue et al., 2009). Exposure of earthworms to tetrabromobisphenol A at 50-400 mg/kg dry soil for 14 days resulted in an increased expression of genes encoding SOD and Hsp70 (Shi et al., 2015). In scallops (Chlamys farreri), exposure to tetrabromobisphenol A in seawater tanks (0.2, 0.4, and 0.8 mg/L for up to 10 days) increased SOD activity, the reduced glutathione levels, and malondialdehyde levels in the gill and digestive gland (Hu et al., 2015a). (iv) Plant systems Tetrabromobisphenol A increased total free radical generation and enhanced lipid peroxidation in plants (Ceratophyllum demersum L.) exposed at 0.05-1.0 mg/L in growth solution. Tetrabromobisphenol A 273 In addition, levels of GSH were decreased (Sun et al., 2008). ROS were also induced in green alga (Chlorella pyrenoidosa) cultures exposed to tetrabromobisphenol A at 2.7-13.5 mg/L for 4-216 hours (Liu et al., 2008). [The Working Group noted that the induction of oxidative stress by tetrabromobisphenol A has been well established on studies in human cells and in numerous experimental systems.] 4.2.3 Inflammation and immunosuppression Studies in human cells and in several experimental systems have demonstrated immunosuppressive effects caused by exposures to tetrabromobisphenol A. (a) Humans No data in exposed humans were available to the Working Group. The lytic and binding functions of isolated human natural killer (NK) cells were decreased when they were incubated with tetrabromobisphenol A at 0.1-5 µM for 1, 2, or 6 days. The effects of treatment with tetrabromobisphenol A on NK cells were dependent on both the concentration and duration of exposure. Exposure of NK cells to tetrabromobisphenol A at 1-10 µM for 1 hour resulted in a decrease in lytic function that persisted for at least 6 days. The loss of lytic function was more sensitive than the decrease in binding function to the treatment with tetrabromobisphenol A (Kibakaya et al., 2009). Exposure of human NK cells to tetrabromobisphenol A (2.5 µM for 24 or 48 hours) caused significant decreases in the expression of cell surface proteins that are involved in NK cell binding and/or the lysis of target cells. The analysis was done by flow cytometry after reactions with anti-CD2, anti-CD11a, anti-CD16, anti-CD18, or anti-CD56 antibodies (Hurd & Whalen, 2011). Phospho-p44/42 and phospho-p38 MAPKs were activated in isolated human NK cells exposed to tetrabromobisphenol A at 0.5-10 µM for 10 minutes, but not after exposures of 1 or 6 hours. Phosphorylation of MEK1/2 and MKK3/6, upstream activators of p44/42 and p38, respectively, was also increased in NK cells exposed to tetrabromobisphenol A at 5 or 10 µM for 10 minutes (Cato et al., 2014). This group had shown previously (Kibakaya et al., 2009) that tetrabromobisphenol A decreased the ability of human NK cells to lyse tumour cells, and that the activation of p44/42 can decrease the lytic function of NK cells. Thus, the aberrant activation of MAPKs by tetrabromobisphenol A may result in NK cells becoming unresponsive to subsequent encounters with tumour cells or virally infected cells. Tetrabromobisphenol A also activates inflammatory pathways in the human first trimester placental cell line HTR-8/SVneo (Park et al., 2014). Trophoblast cells were cultured for 8, 16, or 24 hours in media containing tetrabromobisphenol A at 5, 10, 20, or 50 µM and analysed for cytokine release (interleukin-(IL)-6, IL-8 and tumour growth factor-β) and prostaglandin E2 (PGE2) production by enzyme-linked immunosorbent assay. Exposure to tetrabromobisphenol A increased the release of PGE2 and the proinflammatory cytokines IL-6 and IL-8, and reduced the release of the anti-inflammatory cytokine tumour growth factor-β. Treatment with NS-398, a cyclooxygenase-2 (COX-2)-specific inhibitor, suppressed the tetrabromobisphenol A-stimulated release of PGE2. Quantitative mRNA analyses by the reverse transcriptase polymerase chain reaction showed that exposure to tetrabromobisphenol A at 10 µM increased the expression of genes encoding prostaglandinendo-peroxide synthase 2, COX-2, and IL-6 and IL-8. Thus, exposure to tetrabromobisphenol A activates inflammatory pathways in human placental cells (Park et al., 2014). IARC MONOGRAPHS – 115 274 (b) Experimental systems The pulmonary viral titer was significantly increased in BALB/c mice fed diets containing 1% tetrabromobisphenol A for 28 days and then intranasally infected with the A2 strain of respiratory syncytial virus. The viral titres were increased two- to threefold in tetrabromobisphenol A-treated mice compared with controls on day 5 after infection. Bronchoalveolar fluid from respiratory syncytial virus-infected mice treated with tetrabromobisphenol A showed enhanced production of tumour necrosis factor-α, IL-6 and interferon-γ, and reduced production of IL-4 and IL-10 (Watanabe et al., 2010). In a study of immune/allergic responses in vitro to brominated flame retardants, exposure of splenocytes from NC/Nga mice to tetrabromobisphenol A at 1 or 10 µg/mL for 24 hours increased the expression of surface proteins on antigen presenting cells (major histocompatibility complex class II and CD86), and increased the expression of the T-cell receptor and the production of cytokine IL-4 in splenic T-cells. Exposure of isolated mouse bone marrow cells to tetrabromobisphenol A at 1 µM for 6 days did not affect bone marrow-derived dendritic cell activation or differentiation (Koike et al., 2013). In splenocytes isolated from C57Bl/6 mice that had been incubated with tetrabromobisphenol A at 3 µM and concanavalin A (2 µg/mL) for 48 hours, the expression of the IL-2 receptor α chain (CD25), essential for proliferation of activated T-cells during the immune response, was suppressed (Pullen et al., 2003). Exposure of the mouse macrophage cell line RAW 264.7 to tetrabromobisphenol A at 1-50 µM increased the mRNA expression and protein levels of COX-2, enhanced the production of PGE2 (a major metabolite of COX-2), and increased the mRNA expression and production of proinflammatory cytokines including tumour necrosis factor-α, IL-6 and IL-1β. Pretreatment of the cells with tetrabromobisphenol A and NS-398, a COX-2-specific inhibitor, inhibited the tetrabromobisphenol A-induced increase in PGE2 production, indicating that the effect of tetrabromobisphenol A is mediated by COX-2 activity. Thus, exposure to tetrabromobisphenol A may promote inflammation by transcriptionally activating the macrophage COX-2 gene and protein expression and increasing the expression and secretion of proinflammatory cytokines (Han et al., 2009). Tetrabromobisphenol A activated MAPKs and protein kinase C in mussel haemocytes. The observed increase in extracellular superoxide production was reduced by pretreatment with kinase inhibitors specific for protein kinase C and MAPKs (Canesi et al., 2005). 4.2.4 Altered cell proliferation or death The studies reviewed below indicated neither enhanced cell proliferation nor suppression of apoptosis after exposure to tetrabromobisphenol A, which was associated with an increase in apoptosis in several experimental systems. (a) Humans No data in exposed humans were available to the Working Group. In human A549 epithelial alveolar lung cells and the human thyroid cell line Cal-62, tetrabromobisphenol A decreased the rates of DNA synthesis. A549 cells tended to arrest in the G1 phase, while Cal-62 cells tended to arrest in the G2 phase. MAPK cascades were also affected, but not in association with an increase in cell proliferation (Strack et al., 2007; see also Cagnol & Chambard, 2010). (b) Experimental systems (i) Non-human mammalian systems in vivo Apoptosis was induced in the testes of CD-1 mice exposed to drinking-water containing tetrabromobisphenol A at a concentration of 200 µg/L during gestation, lactation, and up to Tetrabromobisphenol A 275 age 70 days. In addition, expression of the proapoptotic Bax gene was increased, while expression of the anti-apoptotic Bcl-2 gene was decreased in tetrabromobisphenol A-exposed mice compared with controls (Zatecka et al., 2013). Although increased incidences of atypical endometrial hyperplasia were observed in the uterus of female Wistar Han rats exposed to tetrabromobisphenol A (250 mg/kg bw per day) in a 2-year study of carcinogenicity (NTP, 2014; Dunnick et al., 2015), this effect was considered to be a preneoplastic lesion rather than an early event in the development of uterine cancer. [The Working Group noted that, in the 3-month study at doses (5 times per week) of up to 1000 mg/kg bw (NTP, 2014), no treatment-related lesions were observed in the uterus of Wistar Han rats, Fischer 344/NTac rats, or B6C3F1/N mice treated with tetrabromobisphenol A.] (ii) Non-human mammalian systems in vitro In a non-transformed rat kidney (NRK) cell line, tetrabromobisphenol A decreased rates of DNA synthesis. NRK cells tended to arrest in the G1 phase. MAPK cascades were also affected, but not in association with an increase in cell proliferation (Strack et al., 2007; see also Cagnol & Chambard, 2010). Tetrabromobisphenol A induced cell death in mouse TM4 cells, a cell line derived from mouse testicular Sertoli cells, via apoptosis involving mitochondrial depolarization due to increases in cytosolic Ca2+ levels. Intracellular levels of Ca2+ were elevated in TM4 cells within 1-3 minutes of incubation with tetrabromobisphenol A at 30 µM; after 18 hours, cell viability was < 50%. Tetrabromobisphenol A also caused rapid mitochondrial membrane depolarization. The loss of cell viability by tetrabromobisphenol A was suppressed by the caspase inhibitor Ac-DEVD-CMK, indicating that this loss was due in part to apoptosis. Tetrabromobisphenol A also inhibited Ca2+-adenosine triphosphatase activity in rabbit muscle sarcoplasmic reticulum vesicles and in pig cerebellar microsomes at concentrations as low as 0.5 µM (Ogunbayo et al., 2008). The treatment of primary cultured neurons from rat cerebellum with tetrabromobisphenol A at 5 µM for 24 hours induced apoptosis-like nuclear changes, characterized by condensed chromatin and DNA fragmentation; however, other hallmarks of apoptosis, including activation of caspase-3, were not observed. Tetrabromobisphenol A induced a concentration-dependent increase in the phosphorylation of ERK1/2 (Reistad et al., 2007). (iii) Other experimental systems Apoptotic cells were detected in the brain, heart, and tail of zebrafish embryos and larvae exposed to tetrabromobisphenol A at 1.0 mg/L in holding tanks for 96 hours (Wu et al., 2015); exposures to tetrabromobisphenol A at 0.1-1.0 mg/L induced the expression of three proapoptotic genes – Tp53, Bax, and caspase 9 – and decreased the expression of the anti-apoptotic gene Bcl2 (Yang et al., 2015). 4.2.5 Genetic and related effects (a) Humans No data were available to the Working Group. (b) Experimental systems (i) Non-human mammalian systems in vivo See Table 4.1 No increase in DNA damage in the alkaline comet assay was observed in the testicular cells of CD-1 mice given tetrabromobisphenol A in corn oil twice (24 hours apart) at doses of 500, 1000, or 2000 mg/kg bw (Hansen et al., 2014). Tetrabromobisphenol A did not increase the frequency of micronucleated erythrocytes in the peripheral blood of male and female B6C3F1 mice exposed by gavage (10-1000 mg/kg bw in corn oil on 5 days per week for 14 weeks) (NTP, 2014).
E Anlamllar:
TETRABROMOBISPHENOL A CARBONATE OLIGOMER;3,5,3′,5′-Tetrabromobisphenol A;3,5,3′,5′-tetrabromobisphenola;4,4′-(1-methylethylidene)bis(2,6-dibromo-pheno;4,4′-(1-methylethylidene)bis(2,6-dibromophenol);4,4′-(1-methylethylidene)bis[2,6-dibromo-pheno;4,4′-(1-methylethylidene)bis[2,6-dibromo-Phenol;Great lakes BA-59P; Tetrabromobisphenol A; 79-94-7; 3,3′,5,5′-Tetrabromobisphenol A; Bromdian; bromdiyan; 4,4′-(propane-2,2-diyl)bis(2,6-dibromophenol); 2,2-Bis(3,5-dibromo-4-hydroxyphenyl)propane; 4,4′-Isopropylidenebis(2,6-dibromophenol); Firemaster BP 4A; Tetrabromodian; tetrabromodiyan; TBBPA; Fire Guard 2000; Great Lakes BA-59P; 2,2′,6,6′-TETRABROMOBISPHENOL A; Saytex RB 100PC; Phenol, 4,4′-(1-methylethylidene)bis[2,6-dibromo-; Tetrabromodiphenylopropane; Firemaster BP4A; tetrabromodifenilopropan; difenil propan; FG 2000; 4,4′-propane-2,2-diylbis(2,6-dibromophenol); UNII-FQI02RFC3A; 4,4′-(1-Methylethylidene)bis(2,6-dibromophenol); BA 59; dibromofenol, tetra bromo bisfenol A; bis fenol A; 3,5,3′,5′-Tetrabromobisphenol A; NSC 59775; CCRIS 6274; HSDB 5232; Saytex RB-100; 4,4′-Isopropylylidenebis(2,6-dibromophenol); 2,2-Bis(4-hydroxy-3,5-dibromophenyl)propane; EINECS 201-236-9; FQI02RFC3A; 2,2′,6,6′-Tetrabromo-4,4′-isopropylidenediphenol;2,6-dibromo-4-[2-(3,5-dibromo-4-hydroxyphenyl)propan-2-yl]phenol; 4,4′-(2,2-PROPANEDIYL)BIS(2,6-DIBROMOPHENOL); CHEMBL184450; DTXSID1026081; CHEBI:33217; Phenol, 4,4′-isopropylidenebis(2,6-dibromo-; Phenol, 4,4′-isopropylidenebis[2,6-dibromo-; 4,4′-(2,2-propanediyl) bis[2,6-dibromo]phenol; MFCD00013962; Phenol, 4,4′-(1-methylethylidene)bis(2,6-dibromo-; FR-1524; DSSTox_CID_6081; 4,4′-(1-Methylethylidene)bis(2,6-dibromophenol)2,2-bis(3,5-dibromo-4-hydroxyphenyl)propane; DSSTox_RID_78008; DSSTox_GSID_26081; W-104257; 2,6-dibromo-4-[1-(3,5-dibromo-4-hydroxyphenyl)-1-methylethyl]phenol; CAS-79-94-7; TetrabromobisphenolA; 25639-54-7; Tetrabromo bisphenol A; 4,4′-(1-methylethylidene)bis[2,6-dibromophenol]; 3,3′,5,5′-Tetrabromo bisphenol A; FLAME CUT 120G; 33’55’-Tetrabromobisphenol A; 3osw; XDI; 4,6-dibromophenol); Saytex RB-100 ABS; 2,5-dibromophenyl)propane; TETRABROMO-4,4′-ISOPROPYLIDENEDIPHENOL; bmse000567; Tetrabromobisphenol ”A”; EC 201-236-9; Oprea1_822733; SCHEMBL18647; MLS002152878; BIDD:ER0631; C15H12Br4O2; 330396_ALDRICH; ARONIS002155; 2,6,6′-Tetrabromobisphenol A; CTK4F6165; KS-00003VGG; 3,3′,5′-Tetrabromobisphenol A; BBC/271; 2,5-dibromo-4-hydroxyphenyl)propane; BDBM50150793; c0763; NSC-59775; SBB080626; STK048486; ZINC01689786; 2,6-dibromo-4-[1-(3,5-dibromo-4-hydroxy-phenyl)-1-methyl-ethyl]phenol; AKOS000491577; 2,2”,6,6”-Tetrabromobisphenol A; 3,3”,5,5”-tetrabromobisphenol A; 3,3′,5,5′-tetrabromobisphenol A; LS-1786; MCULE-8578472069; NCGC00091463-01; NCGC00091463-02; NCGC00091463-03; NCGC00091463-04; NCGC00091463-05; NCGC00091463-06; NCGC00254356-01; NCGC00258734-01; NCGC00259530-01; 30496-13-0; AC-11719; AK113742; AS-12834; SMR001224492; Phenol,4′-isopropylidenebis[2,6-dibromo-; 3,3′,5,5′-Tetrabromobisphenol A, 97%; AX8153220; phenol, 4,4′-isopropylidenebis (dibromo-); 2,2-bis(3,5dibromo-4-hydroxyphenyl)propane; 4,4”-Isopropylidenebis(2,6-dibromophenol); 4,4′-isopropylidene-bis(2,6-dibromophenol); FT-0617111; FT-0682679; 2,2-bis(3,5-dibromo-4-hydroxyphenyl)-propane; 2,2-bis-(3,5-dibromo-4-hydroxyphenyl)propane; C13620; Z-0813; 2,2-bis-(3,5-dibromo-4-hydroxyphenyl)-propane; tetrabromobisphenol A 100 microg/mL in Methanol; Phenol,4′-(1-methylethylidene)bis[2,6-dibromo-; Q425246; SR-01000596914; Tetrabromodian: tetrabromodihydroxy diphenylpropane; 4,4”-(1-Methylethylidene)bis(2,6-dibromophenol); 4,4”-(2,2-propanediyl) bis[2,6-dibromo]phenol; 4,4”-(propane-2,2-diyl)bis(2,6-dibromophenol); SR-01000596914-1; 2,2′,6,6′-Tetrabromo-4,4′-isopropylidene bisphenol; 2,2-bis-(4′-hydroxy-3′,5′-dibromophenyl)-propane; 3,3′,5,5′-Tetrabromobisphenol A, analytical standard; phenol, 4,4′-isopropylidenebis(2,6-dibromo- (8CI); 3,3′,5,5′-Tetrabromo-4,4-dihydroxy-2,2-diphenylpropane; 3,3′,5,5′-Tetrabromo-4,4′-dihydroxy-diphenyl-dimethyl-methane; 4-[1-(3,5-dibromo-4-hydroxyphenyl)-isopropyl]-2,6-dibromophenol; 3,3′,5,5′-Tetrabromobisphenol A, certified reference material, TraceCERT(R)

Tetrabromobisfenol A ( TBBPA ), bromlu bir alev geciktiricidir . Ticari örnekler sar görünmesine ramen bileik beyaz bir katdr (renksiz deildir). En yaygn yangn geciktiricilerden biridir .
Üretim ve kullanm
TBBPA, bromun bisfenol A ile reaksiyonu sonucu üretilir . Ticari TBBPA ürünlerinin çou , x = 1 ila 4 olan C 15 H 16 – x Br x O 2 formülüyle bromlama derecesi açsndan farkllk gösteren bir karmdan oluur. Alev geciktirme özellikleri,% Br ile ilikilidir. Avrupa’daki yllk tüketim. 2004 ylnda 6.200 ton olarak tahmin edilmitir. [3]

TBBPA, esas olarak polimerlerin reaktif bir bileeni olarak kullanlr, yani polimer omurgasna dahil edilir. Baz bisfenol A’y deitirerek yangna dayankl polikarbonatlar hazrlamak için kullanlr. Baskl devre kartlarnda kullanlan epoksi reçineleri hazrlamak için daha düük bir TBBPA snf kullanlr . [2]
Tetrabromlu monomer içeren polikarbonat kopolimerinin yaps
Toksisite
Aralk 2011’de Avrupa Gda Güvenlii Otoritesi (EFSA) tarafndan TBBPA ve türevlerinin gdalardaki maruziyetine ilikin bir çalma yaynland. Balk ve dier deniz ürünleri gda grubundan alnan 344 gda örneinde incelenen çalma, “Avrupa Birlii’nde TBBPA’ya u anda diyetle maruz kalmann bir salk sorunu yaratmad” sonucuna varmtr. EFSA ayrca, “özellikle küçük çocuklarn ev tozundan TBBPA’ya ilave maruz kalmasnn bir salk sorunu yaratmayacan” belirledi. [4]

Baz çalmalar TBBPA’nn bir endokrin bozucu ve immünotoksik olabileceini düündürmektedir . Bir endokrin bozucu olarak TBBPA hem engel olabilir östrojenlerin ve androjenlerin . [5] Daha fazla, TBBPA yapsal taklitleri tiroid hormonu tiroksin (T 4 ) ve tayc protein için daha güçlü bir ekilde balanabilen transtiretin T’den 4 muhtemelen normal T müdahale yapar 4 aktivitesi. TBBPA muhtemelen T hücreleri üzerindeki CD25 reseptörlerinin ekspresyonunu inhibe ederek, bunlarn aktivasyonunu önleyerek ve doal öldürücü hücre aktivitesini azaltarak baklk tepkilerini de bastrr .[6] [7]
TBBPA ile ilgili 2013 literatür taramas, TBBPA’nn “endokrin sistemdeki bozukluklarla ilikili olduu düünülebilecek yan etkiler” üretmedii sonucuna varmtr. [8] Bu nedenle, uluslararas kabul görmü tanmlara göre TBBPA, bir “endokrin bozucu” olarak deerlendirilmemelidir. Ayrca TBBPA memelilerde hzla atlr ve bu nedenle biyolojik birikim potansiyeline sahip deildir. Ev tozu, insan diyeti ve insan serum örneklerinde ölçülen TBBPA konsantrasyonlar çok düüktür. nsanlarda günlük TBBPA almlarnn birkaç ng / kg vücut arl / gün’ü geçmedii tahmin edilmektedir. Genel popülasyonun maruziyetleri, REACH’te potansiyel endie son noktalar için türetilmi etkisiz seviyelerin (DNEL’ler) oldukça altndadr.
TBBPA, bisfenol A’ya ve TBBPA dimetil etere parçalanr ve zebra bal ( Danio rerio ) üzerinde yaplan deneyler, gelitirme srasnda TBBPA’nn BPA veya TBBPA dimetil eterden daha toksik olabileceini göstermektedir. [9]
Olu
TBBPA emisyonlar hidrosfer , toprak ve tortulardaki eser konsantrasyonda bulunabilir . Ayrca lam çamurunda ve ev tozunda da oluur . [10] TBBPA, 460’n üzerinde çalmay gözden geçiren AB Risk Deerlendirme prosedürü kapsamnda sekiz yllk bir deerlendirmeye tabi tutuldu. Risk Deerlendirmesi Haziran 2008’de AB Resmi Gazetesinde yaynland. [11] Risk Deerlendirmesinin sonuçlar, Avrupa Komisyonu SCHER Komitesi (Salk ve Çevresel Riskler Bilimsel Komitesi [12] ) tarafndan onayland . TBBPA, REACH kapsamnda tescil edilmitir.
Morfolin bir bir organik kimyasal bileik olan kimyasal formüle O ( C- lH 2 CH 2 ) 2 , N Bu durum, H. heterosikl hem de özellikleri amin ve eter fonksiyonel gruplar . Çünkü amin, morfolin a, baz ; onun e asidi morfolinyum olarak adlandrlr. Örnein, ile morfolin tedavi hidroklorik asit yapan bir tuzu morfolinyum klorür.
Endüstriyel uygulamalar
Morfolin milyon bana ksm olarak yaygn kullanlan bir katk, bir konsantrasyon için, pH deeri hem de ayar fosil yakt ve nükleer santral buhar sistemleri. Onun için Morfolin kullanlan oynaklk ile hemen hemen ayndr , su su eklendikten sonra bu nedenle younluu hem su ve buhar oldukça eit bir ekilde datlm olur, fazlar . Bu pH-ayarlayc yetenekler bundan sonra da buhar bitki boyunca dalabilir korozyon korumas. Morfolin genellikle düük konsantrasyonlar ile balantl olarak kullanldnda, hidrazin ya da amonyak gibi bitkilerin buhar sistemleri için korozyon korumas için kapsaml tüm uçucu muamele kimyasn temin edecek ekilde. Morfolin yokluunda uygun yavaça parçalanr oksijen yüksek de scaklklar ve basnçlar , bu buhar sistemlerinde.
Organik sentez
Morfolin en maruz kimyasal reaksiyonlar dier ikincil için tipik aminler eter oksijen varl ileme, azot elektron younluu çeker olsa da, bu tür yapsal olarak benzer sekonder aminler daha az nükleofilik (ve daha az temel) piperidin . Bu nedenle, bu istikrarl kloramini (CAS # 23328-69-0) oluturur.
Genellikle oluturmak için kullanlr enaminleri .
Morfolin yaygn olarak kullanlan organik sentez . Örnein, antibiyotik hazrlanmasnda bir yap tadr linezolid , anti-kanser madde, gefitinib (Iressa) ve analjezik dekstromoramid .
Aratrmada ve sanayi, düük maliyet ve polarite bir olarak yaygn kullanm morfolin kurun çözücü kimyasal reaksiyonlar için.
Tarm
bir meyve kaplama olarak
Morfolin kimyasal olarak kullanlan emülsiyonlatrc meyve ada sürecinde. Doal olarak, meyveler böcekler ve mantar kirlenmeye kar korumak için mumlar yapmak, ancak meyve temizlenir olarak bu kaybolabilir. Yeni balmumu az miktarda yerine uygulanr. Morfolin için bir emülsiyon yapc ve çözünme yardmc maddesi olarak kullanldnda gomalak meyve kaplama için bir mum olarak kullanlr. Avrupa Birlii meyve kaplama morfolin kullanmn yasaklamtr.
fungisitler bir bileeni olarak
Tahllarda tarm fungisitleri olarak kullanlan morfolin türevleri ekilde bilinmektedir ergosterol biyosentezi inhibitörleri .

amorolfin
fenpropimorf
tridemorf
Çevresel Kader Fizikokimyasal özellikleri, tüm bölmelere (yani su, tortu ve toprak), bir partikül maddenin organik fraksiyonuna balanarak arlkl olarak tortu ve topraa bölüneceini göstermektedir. Mevcut çevresel kader çalmalar, TBBPA’nn suda (yar ömür [t1 / 2] 182 gün), toprakta (t1 / 2 182 gün) ve tortuda (t1 / 2 365 gün) (Kanada, 2013) kalc olduunu göstermitir. hidrolize uramas beklenen fonksiyonel gruplar (Kanada, 2013). Bir dizi laboratuvar çalmas (ECHA, 2013) aerobik koullar altnda bisfenol A’ya parçalanabileceini göstermitir (Kanada, 2013).
Trofoblast hücreleri, 5, 10, 20 veya 50 uM’de tetrabromobisfenol A içeren ortamda 8, 16 veya 24 saat kültürlendi ve sitokin salnm için analiz edildi (interlökin- (IL) -6, IL-8 ve tümör büyüme faktörü-β ) ve enzime bal immünosorbent analizi ile prostaglandin E2 (PGE2) üretimi. Tetrabromobisfenol A’ya maruz kalma, PGE2 salmn ve proinflamatuar sitokinler IL-6 ve IL-8’i arttrd ve anti-enflamatuar sitokin tümör büyüme faktörü-β’nn salmn azaltt. Bir siklooksijenaz-2 (COX-2) -spesifik inhibitörü olan NS-398 ile tedavi, tetrabromobisfenol A ile uyarlan PGE2 salmn bastrd. Ters transkriptaz polimeraz zincir reaksiyonu ile kantitatif mRNA analizleri, 10 uM’de tetrabromobisfenol A’ya maruz kalmann prostaglandinendo-peroksit sentaz 2, COX-2 ve IL-6 ve IL-8’i kodlayan genlerin ekspresyonunu arttrdn gösterdi. Bu nedenle, tetrabromobisfenol A’ya maruz kalma, insan plasental hücrelerindeki enflamatuar yollar aktive eder (Park ve dierleri, 2014). IARC MONOGRAPHS – 115 274 (b) Deneysel sistemler Pulmoner viral titresi, 28 gün boyunca% 1 tetrabromobisfenol A içeren diyetlerle beslenen BALB / c farelerinde ve ardndan A2 suu solunum sinsityal virüsü ile intranazal olarak enfekte edildi. Viral titreler, enfeksiyondan sonraki 5. günde kontrollere kyasla tetrabromobisfenol A ile tedavi edilen farelerde iki ila üç kat artt. Tetrabromobisfenol A ile tedavi edilen solunum sinsityal virüsü ile enfekte farelerden elde edilen bronkoalveolar sv, tümör nekroz faktörü-α, IL-6 ve interferon-‘nn artm üretimini ve azalm IL-4 ve IL-10 üretimini gösterdi (Watanabe ve dierleri, 2010) . Bromlu alev geciktiricilere in vitro olarak immün / alerjik yantlar üzerine yaplan bir çalmada, NC / Nga farelerinden alnan splenositlerin 24 saat boyunca 1 veya 10 µg / mL’de tetrabromobisfenol A’ya maruz kalmas, antijen sunan hücrelerdeki yüzey proteinlerinin ekspresyonunu artrd (majör histo-uyumluluk kompleksi snf II ve CD86) ve dalak T hücrelerinde T-hücresi reseptörünün ekspresyonunu ve sitokin IL-4 üretimini arttrd. zole edilmi fare kemik ilii hücrelerinin tetrabromobisfenol A’ya 6 gün süreyle 1 uM’de maruz kalmas, kemik iliinden türetilen dendritik hücre aktivasyonunu veya farkllamasn etkilemedi (Koike ve dierleri, 2013). 48 saat boyunca tetrabromobisfenol A ile 3 µM’de ve konkanavalin A (2 µg / mL) ile inkübe edilmi C57Bl / 6 farelerinden izole edilen splenositlerde, IL-2 reseptör α zincirinin (CD25) ekspresyonu, aktive edilmi proliferasyon için gereklidir. Baklk tepkisi srasnda T hücreleri basklanmtr (Pullen ve dierleri, 2003). Fare makrofaj hücre hatt RAW 264.7’nin 1-50 µM’de tetrabromobisfenol A’ya maruz kalmas, COX-2’nin mRNA ekspresyonunu ve protein seviyelerini artrd, PGE2 (COX-2’nin ana metaboliti) üretimini artrd ve mRNA ekspresyonunu artrd ve tümör nekroz faktörü-a, IL-6 ve IL-1β dahil olmak üzere proinflamatuar sitokinlerin üretimi. Hücrelerin tetrabromobisfenol A ve COX-2’ye özgü bir inhibitör olan NS-398 ile ön muamelesi, PGE2 üretiminde tetrabromobisfenol A ile indüklenen art inhibe etti, bu da tetrabromobisfenol A’nn etkisine COX-2 aktivitesinin araclk ettiini gösterdi. Bu nedenle, tetrabromobisfenol A’ya maruz kalma, makrofaj COX-2 geni ve protein ekspresyonunu transkripsiyonel olarak aktive ederek ve proinflamatuar sitokinlerin ekspresyonunu ve salglanmasn artrarak enflamasyonu tevik edebilir (Han ve dierleri, 2009). Tetrabromobisfenol A midye hemositlerinde aktive edilmi MAPK’lar ve protein kinaz C. Hücre d süperoksit üretiminde gözlenen art, protein kinaz C ve MAPK’lara özgü kinaz inhibitörleri ile ön ilemle azaltlmtr (Canesi ve dierleri, 2005). 4.2.4 Deimi hücre proliferasyonu veya ölümü Aada gözden geçirilen çalmalar, çeitli deneysel sistemlerde apoptozda bir artla ilikili olan tetrabromobisfenol A’ya maruz kaldktan sonra ne artm hücre proliferasyonunu ne de apoptozun basklanmasn göstermitir. (a) nsanlar Çalma Grubu’na maruz kalan insanlarla ilgili hiçbir veri mevcut deildi. nsan A549 epitelyal alveolar akcier hücrelerinde ve insan tiroid hücre hatt Cal-62’de tetrabromobisfenol A, DNA sentezi oranlarn düürmütür. A549 hücreleri G1 faznda tutuklanma eilimindeyken, Cal-62 hücreleri G2 faznda tutuklanma eilimindeydi. MAPK kaskadlar da etkilendi, ancak hücre proliferasyonundaki artla balantl deildi (Strack ve dierleri, 2007; ayrca bkz. Cagnol & Chambard, 2010). (b) Deneysel sistemler (i) nsan d memeli sistemleri in vivo Apoptoz, gebelik, laktasyon srasnda 200 ug / L’lik bir konsantrasyonda tetrabromobisfenol A içeren içme suyuna maruz braklan CD-1 farelerinin testislerinde indüklenmitir. Tetrabromobisphenol A 275 ya 70 gün. Ek olarak, proapoptotik Bax geninin ekspresyonu artarken, anti-apoptotik Bcl-2 geninin ekspresyonu, kontrollere kyasla tetrabromobisfenol A’ya maruz kalan farelerde azalmtr (Zatecka ve ark., 2013). Tetrabro’ya maruz kalan dii Wistar Han sçanlarnn uterusunda artm atipik endometriyal hiperplazi görülmesine ramen Mobisphenol A (günde 250 mg / kg vücut arl) 2 yllk bir kanserojenlik çalmasnda (NTP, 2014; Dunnick ve dierleri, 2015), bu etkinin erken bir olaydan ziyade preneoplastik bir lezyon olduu düünülmütür. rahim kanseri. [Çalma Grubu, 1000 mg / kg canl arla (NTP, 2014) kadar olan dozlarda (haftada 5 kez) 3 aylk çalmada, Wistar Han sçanlarnn uterusunda tedavi ile ilgili hiçbir lezyon gözlemlenmediini kaydetti, Fischer 344 / NTac sçanlar veya tetrabromobisfenol A ile tedavi edilen B6C3F1 / N fareleri] (ii) n vitro insan d memeli sistemleri Dönütürülmemi sçan böbrei (NRK) hücre hattnda, tetrabromobisfenol A, DNA sentezi oranlarn düürdü. NRK hücreleri G1 faznda tutuklanma eilimindeydi. MAPK kaskadlar da etkilendi, ancak hücre proliferasyonundaki artla balantl deildi (Strack ve dierleri, 2007; ayrca bkz. Cagnol & Chambard, 2010). Tetrabromobisfenol A, sitozolik Ca2 + seviyelerindeki artlara bal mitokondriyal depolarizasyonu içeren apoptoz yoluyla fare testiküler Sertoli hücrelerinden türetilen bir hücre hatt olan fare TM4 hücrelerinde hücre ölümünü indükledi. Hücre içi Ca2 + seviyeleri, 30 µM’de tetrabromobisfenol A ile inkübasyondan 1-3 dakika sonra TM4 hücrelerinde yükseldi; 18 saat sonra hücre canll <% 50 idi. Tetrabromobisfenol A ayrca hzl mitokondriyal membran depolarizasyonuna neden oldu. Tetrabromobisfenol A tarafndan hücre canll kayb, kaspaz inhibitörü Ac-DEVD-CMK tarafndan bastrld, bu da bu kaybn ksmen apoptoza bal olduunu gösterdi. Tetrabromobisfenol A ayrca, tavan kas sarkoplazmik retikulum veziküllerinde ve domuz serebellar mikrozomlarnda 0.5 uM kadar düük konsantrasyonlarda Ca2 + -adenozin trifosfataz aktivitesini de inhibe etti (Ogunbayo ve dierleri, 2008). Sçan serebellumundan gelen birincil kültürlenmi nöronlarn 24 saat boyunca 5 uM’de tetrabromobisfenol A ile muamelesi, youn kromatin ve DNA fragmantasyonu ile karakterize edilen apoptoz benzeri nükleer deiiklikleri indükledi; bununla birlikte, kaspaz-3’ün aktivasyonu dahil olmak üzere apoptozun dier ayrt edici özellikleri gözlenmedi. Tetrabromobisfenol A, ERK1 / 2’nin fosforilasyonunda konsantrasyona bal bir arta neden oldu (Reistad ve dierleri, 2007). (iii) Dier deneysel sistemler Apoptotik hücreler, bekletme tanklarnda 96 saat boyunca 1.0 mg / L’de tetrabromobisfenol A’ya maruz braklan zebra bal embriyolar ve larvalarnn beyin, kalp ve kuyruunda tespit edildi (Wu ve dierleri, 2015); 0.1-1.0 mg / L’de tetrabromobisfenol A’ya maruz kalma, üç proapoptotik genin (Tp53, Bax ve kaspaz 9) ekspresyonunu indükledi ve anti-apoptotik gen Bcl2 ekspresyonunu azaltt (Yang ve dierleri, 2015). 4.2.5 Genetik ve ilgili etkiler (a) nsanlar Çalma Grubuna ait veri bulunmamaktadr. (b) Deneysel sistemler (i) n vivo insan d memeli sistemler Tablo 4.1’e baknz. Msr yanda iki kez tetrabromobisfenol A verilen CD-1 farelerinin testis hücrelerinde alkalin kuyruklu yldz testinde DNA hasarnda art gözlenmedi (24 saat arayla) ) 500, 1000 veya 2000 mg / kg canl arlk dozlarnda (Hansen ve dierleri, 2014). Tetrabromobisfenol A, gavajla (14 hafta boyunca haftada 5 gün msr yanda 10-1000 mg / kg vücut arl) maruz kalan erkek ve dii B6C3F1 farelerinin periferal kanndaki mikronükleer eritrositlerin skln artrmad (NTP, 2014).
Tetrabromobisfenol A, ABD Çevre Koruma Ajans’nn Toksik Salnm Envanteri (EPA, 2013) kapsamnda kalc, biyoakümülatif ve toksik (PBT) bir bileik olarak tanmlanmtr. Ayrca, Washington Eyaleti Ekoloji Departman nn PBT Listesi’ne de yerletirildi (DOC, 2013). Bununla birlikte, Environment Canada ve Health Canada, TBBPA’nn biyoakümülasyon için kriterlerini karlamad sonucuna varmtr (yani biyoakümülasyon faktörü> 5000) (Kanada, 2013). Bu sonuç, TBBPA’nn fizikokimyasal özelliklerinden (örn. Maksimum 1.3 1,4 nm çap, çevresel olarak ilgili pH’ta iyonizasyon ve deiken logKOW) düük biyoakümülasyon potansiyeline ve ayrca TBBPA’nn suda hzla metabolize edildiini ve atldn gösteren çalmalara dayanyordu. ve karasal organizmalar (Kanada, 2013).
) Deneysel sistemler (i) nsan d memeli sistemler in vivo Chignell ve ark. (2008), SpragueDawley sçanlarna spin yakalama ajan α- (4-piridil-1-oksit) -Nt-butilnitron ile birlikte tetrabromobisfenol A (100 veya 600 mg / kg canl arlk) uygulad ve α- (4-piridil- 1-oksit) -Nt-butilnitron / • Safrada elektron paramanyetik rezonans ile CH3 spin eklentisi. Safrada 2,6-dibromobenzosemikinon radikali de ölçüldü; son bileiin oksijen ile reaksiyonu süperoksit anyonu oluturabilir. Erkek Sprague-Dawley sçanlarnn tetrabromobisfenol A (doum sonras 18. günden balayarak 30 gün süreyle 500 mg / kg vücut arl) ile günlük tedavisi, 8-hidroksi-2′-deoksiguanozin (oksidatif DNA’nn bir biyobelirteci) düzeylerinde önemli bir arta neden olmutur. hasar) testis ve böbrekte. Kontrollere kyasla maruz kalan sçanlarn karacierinde malondialdehit seviyelerinde art gözlenmedi (Choi ve dierleri, 2011). Wistar sçanlarna 7 gün boyunca günlük tetrabromobisfenol A (750 veya 1125 mg / kg vücut arl) uygulanmas, diilerde her iki dozda azalm glutatyon seviyelerini düürdü ve daha yüksek dozda erkek sçanlarda malondialdehit seviyelerini arttrd (Szymańska ve ark., 2000). Sprague-Dawley sçanlarnda tek bir oral tetrabromobisfenol A dozu, 1000 mg / kg canl arlkta böbrek seviyelerinde tiyobarbitürik asit reaktif madde (TBARS) ve 250-1000 mg / kg vücut arl düzeyinde SOD aktivitesinde artlara neden oldu, ancak idrarda önemli bir deiiklik olmad analiz parametreleri. Bu parametreler, ayn tetrabromobisfenol A dozlar ile 14 günlük tekrarlanan doz deneyinde artrlmad (Kang ve dierleri, 2009). (ii) n vitro insan d memeli sistemleri Fischer 344 / Jcl sçanlarndan izole edilen hepatositlerin 0.25-1.0 mM’de tetrabromobisfenol A’ya 3 saate kadar maruz kalmas, oksitlenmi glutatyonda (GSSG) elik eden artlarla birlikte azalm glutatyon içeriini düürdü ve artt malondialdehit seviyeleri (TBARS). Tetrabromobisfenol A ile tedavi ayrca mitokondriyal membran potansiyelini azaltt ve mitokondriyal oksidatif fosforilasyon üzerinde ayrtrc bir etkiye sahipti (Nakagawa ve dierleri, 2007). [Hücresel adenozin trifosfat seviyelerindeki hzl düüe kyasla lipit peroksidasyonunu indüklemek için gereken daha uzun süreye dayanarak, sonuçlar, tetrabromobisfenol A’nn neden olduu lipid peroksidasyonunun, bozulmu mitokondriyal fonksiyondan kaynaklandn ileri sürdü.] Wistar’dan serebellar granül hücrelerinin birincil kültürlerinin inkübasyonu 2.5-7.5 µM’de tetrabromobisfenol A içeren sçanlar, 45Ca almnda azalma, IARC MONOGRAPHS – 115 272 hücre içi 45Ca konsantrasyonunda art ve mitokondriyal membran potansiyelinde hafif bir azalma ile ROS üretiminde önemli artlar yaratt. ROS üretimi 0.1 mM askorbik asit veya 1 mM glutatyon ile birlikte muamele edilerek azaltld (Ziemińska ve dierleri, 2012). Reistad vd. (2007) ayrca, tetrabromobisfenol A’ya maruz braklan sçan serebellar granül hücrelerinin birincil kültürlerinde ROS, ERK1 / 2’nin fosforilasyonunda ve hücre içi kalsiyumda konsantrasyona bal artlar gözlemledi.ROS oluumu, MAPK / ERK kinaz inhibitörü U0126, tirozin ile ön muamele ile inhibe edildi. kinaz inhibitörü erbstatin A, SOD inhibitörü dietilditiokarbamat veya kültür ortamndan kalsiyumu elimine ederek. (iii) Balklar ve dier türler Tek bir intraperitoneal tetrabromobisfenol A enjeksiyonu (100 mg / kg canl arlk) verilen Japon balklarnda (Carassius auratus), hidroksil radikal süpürücü manitol tarafndan inhibe edilen bir etki olan karacier ve safrada ROS artmtr. Oksidatif hasarn göstergeleri olan lipid peroksidasyon ürünleri (TBARS) ve protein karbonil seviyeleri, tetrabromobisfenol A ile tedaviden 1-3 gün sonra karacierde önemli ölçüde artmtr (Shi ve ark., 2005). Akvaryum suyundaki tetrabromobisfenol A (7 gün boyunca 3 mg / L), balk karacierlerinde azalm glutatyon seviyelerini ve antioksidan enzim aktivitelerini (SOD ve katalaz) önemli ölçüde azaltmtr (He ve dierleri, 2015). Carassius auratus’ta, tetrabromobisfenol A’nn intraperitoneal enjeksiyonlar (14 gün boyunca 10 veya 100 mg / kg vücut arl) antioksidan enzimlerin (SOD, katalaz ve glutatyon peroksidaz) aktivitelerini azaltt, glutatyon seviyelerini düürdü ve malondialdehit seviyelerini yükseltti. karacierde lipid peroksidasyonu) (Feng ve dierleri, 2013). Zebra bal embriyolarnda, tetrabromobisfenol A (96 saat boyunca 0.05, 0.25 veya 0.75 mg / mL) SOD aktivitesini, lipid peroksidasyonunu (TBARS) ve s ok proteini 70 (Hsp70) ekspresyonunu artrd (Hu ve dierleri, 2009) . SOD, katalaz ve glutatyon peroksidaz antioksidan enzimlerinin aktivitelerinde önemli düüler, döllenmeden sonra 3, 5 veya 8 gün bekletme tanklarnda 0,4-1,0 mg / L’de tetrabromobisfenol A’ya maruz kalan embriyo ve zebra bal larvalarnda gözlenmitir (Wu vd., 2015). Benzer ekilde, 96 saat boyunca 0.1, 0.5 veya 1.0 mg / L’de tetrabromobisfenol A’ya maruz braklan zebra bal embriyolar ve larvalarnda ROS üretiminde artlar gözlendi; ROS üretimindeki artlar, bir antioksidan olan puerarin (1 mg / L) ile birlikte inkübasyonla engellendi.
serbest radikal süpürücü. ROS üretimi, bir yaban turpu peroksidaz etiketli balk ROS antikoru kullanlarak bir balk ROS enzimine bal immünosorbent test kiti ile ölçüldü (Yang ve dierleri, 2015). Hepatik oksidatif stres ve genel stres, 14 gün boyunca tetrabromobisfenol A’ya (0.75 veya 1.5 µM) maruz kalan zebra balklarnda indüklendi ve gen ve protein ekspresyonundaki hepatik deiiklikler için deerlendirildi (De Wit ve dierleri, 2008). [Çalma Grubu, tetrabromobisfenol A’nn, zebra bal karacierindeki Hsp70 proteininin uyarlmasna dayanan, antioksidanla ilgili tepkilere ve genel stres tepkilerine dayanan oksidatif strese neden olduunu kaydetti.] Tetrabromobisfenol A ayrca solucanlarda hidroksil radikal oluumunu ve oksidatif stresi indükledi ( Eisenia fetida). Azalan glutatyon / GSSG oran azalrken lipid peroksidasyonu artmtr (Xue ve ark., 2009). Solucanlarn tetrabromobisfenol A’ya 50-400 mg / kg kuru toprakta 14 gün boyunca maruz kalmas, SOD ve Hsp70’i kodlayan genlerin ekspresyonunda arta neden oldu (Shi ve dierleri, 2015). Deniz taranda (Chlamys farreri), deniz suyu tanklarnda (10 güne kadar 0.2, 0.4 ve 0.8 mg / L) tetrabromobisfenol A’ya maruz kalma, SOD aktivitesini, azalm glutatyon seviyelerini ve solungaç ve sindirim bezindeki malondialdehit seviyelerini artrmtr (Hu vd., 2015a). (iv) Bitki sistemleri Tetrabromobisphenol A, büyüme solüsyonunda 0.05-1.0 mg / L’ye maruz kalan bitkilerde (Ceratophyllum demersum L.) toplam serbest radikal oluumunu ve lipit peroksidasyonunu artrd. Tetrabromobisphenol A 273 Ek olarak, GSH seviyeleri azalmtr (Sun ve dierleri, 2008). ROS ayrca, 4-216 saat süreyle 2,7-13,5 mg / L’de tetrabromobisfenol A’ya maruz braklan yeil alg (Chlorella pyrenoidosa) kültürlerinde de indüklendi (Liu ve dierleri, 2008). [Çalma Grubu, oksidatif stresin tetrabromobisfenol A tarafndan indüksiyonunun insan hücrelerinde ve çok sayda deneysel sistemde yaplan çalmalarda iyi bir ekilde oluturulduunu kaydetti.] 4.2.3 nflamasyon ve immünosupresyon çalmalar, insan hücrelerinde ve birkaç deneysel sistemde immünosupresif etkilere neden olduunu göstermitir. Tetrabromobisfenol A’ya maruz kalma ile (a) nsanlar Çalma Grubuna maruz kalan insanlarla ilgili veri mevcut deildi. zole edilmi insan doal öldürücü (NK) hücrelerinin litik ve balanma fonksiyonlar, tetrabromobisfenol A ile 0.1-5 µM’de 1, 2 veya 6 gün inkübe edildiklerinde azald. Tetrabromobisfenol A ile tedavinin NK hücreleri üzerindeki etkileri maruziyetin hem konsantrasyonuna hem de süresine baldr. NK hücrelerinin 1-10 µM’de 1 saat süreyle tetrabromobisfenol A’ya maruz braklmas, litik fonksiyonda en az 6 gün devam eden bir azalmaya neden oldu. Litik ilev kayb, tetrabromobisfenol A ile tedaviye balanma ilevindeki azalmadan daha duyarlyd (Kibakaya ve dierleri, 2009). nsan NK hücrelerinin tetrabromobisfenol A’ya (24 veya 48 saat süreyle 2.5 uM) maruz braklmas, NK hücre balanmasnda ve / veya hedef hücrelerin lizizinde rol oynayan hücre yüzeyi proteinlerinin ekspresyonunda önemli düülere neden oldu. Analiz, anti-CD2, anti-CD11a, anti-CD16, anti-CD18 veya anti-CD56 antikorlar ile reaksiyondan sonra ak sitometrisi ile yaplmtr (Hurd & Whalen, 2011). Fosfo-p44 / 42 ve fosfo-p38 MAPK’lar, 0.5-10 µM’de 10 dakika süreyle tetrabromobisfenol A’ya maruz braklan izole insan NK hücrelerinde aktive edildi, ancak 1 veya 6 saatlik maruziyetlerden sonra deil. Srasyla p44 / 42 ve p38’in yukar ak aktivatörleri olan MEK1 / 2 ve MKK3 / 6’nn fosforilasyonu, 10 dakika boyunca 5 veya 10 uM’de tetrabromobisfenol A’ya maruz braklan NK hücrelerinde de artmtr (Cato ve dierleri, 2014). Bu grup daha önce (Kibakaya ve dierleri, 2009) tetrabromobisfenol A’nn insan NK hücrelerinin tümör hücrelerini lize etme kabiliyetini azalttn ve p44 / 42’nin aktivasyonunun NK hücrelerinin litik fonksiyonunu azaltabileceini göstermiti. Bu nedenle, MAPK’lerin tetrabromobisfenol A tarafndan anormal aktivasyonu, NK hücrelerinin, tümör hücreleri veya viral olarak enfekte olmu hücreler ile daha sonraki karlamalara yant vermemesine neden olabilir.