*2.1.3 Tetrabromobisphenol A (TBBPA)*

TBBPA is a reactive FR and one of the most prevalent FRs in the world. It is mainly applied in the epoxy resin used to produce printed circuit boards. It forms a covalent bond with the polymer structure, so it is less likely to be released into the environment. It is highly lipophilic (log *K*ow = 4.75) and has low solubility in water (0.718 mg/l) [17, 37].

Although TBBPA release into the environment is more difficult, it may be released during production, processing, and final usage and disposal of the product it is incorporated into [49]. TBBPA is currently found in many kinds of abiotic and biotic matrixes, and it has been detected in air, water, soil, indoor dust sewage sludge, and sediments [37, 50, 51]. TBBPA may also accumulate in the food chain [52]. Indoor dust is the environmental matrix where TBBPA accumulates the most. This is a concern because human beings spend a considerable time indoors, which increases the risk of adverse effects [37].

Long exposure to TBBPA used to be considered harmless because it was believed to lie below levels that would produce a toxic effect [37, 53, 54]. However, several research studies have demonstrated that even low TBBPA doses disrupt the

endocrine system, thyroid hormones, and neurobehavioral functions [37, 55]. Studies on animals have shown some toxic effects. Even at low doses, TBBPA induces toxicity in zebrafish, fathead minnow, and rainbow trout after exposure for 96 h (LC50 = 1.3 mg/l) [56]. In rodents, TBBPA induces nephrotoxicity, oxidative stress in the kidney, increased liver volume, hepatocyte necrosis, and endocrine disruption, but no neurological effects have been found in rats exposed to TBBA [37, 54].

The impacts of TBBPA on human health remain unclear. In vitro studies on human cells have suggested that TBBPA has the toxic potential [37, 55]. TBBPA increases caspase-3 activities and ROS generation; damages mitochondria; induces pathogenesis of several lung diseases in airway epithelial cells (A549) [57]; interferes with immune cell action [58]; induces liver cancer disorder promoting metastasis of liver cancer cells; promotes lysosome exocytosis; and decreases intracellular levels of hexosaminidase (HEXB), cathepsin B (CTSB), cathepsin D (CTSD), and lysosomal enzymes in HepG2 cells [59].

#### *2.1.4 Novel brominated flame retardants (NBFRs)*

The ban on some of the most widely used BFRs (PBDEs, HBCD, and TBBPA) has caused novel (or new) brominated flame retardants (NBFRs) to emerge. NBFR production and use have increased in the last decade [60]. Although NBFRs is applied as an alternative to replace traditional BFRs, they share a similar chemical structure with halogenic substitution in a cyclic hydrocarbon/aromatic hydrocarbon, so their physicochemical properties are generally analog. Some NBFRs are hydrophobic, semivolatile, relatively highly lipophilic, and little water-soluble [61, 62]. **Table 2** summarizes the NBFR chemical structure and physicochemical properties.

Information on NBFR toxicity and ecotoxicity is lacking, causing concern and increasing the number of studies about them. Like restricted and banned traditional BFRs, NBFRs are present in various environmental sources, including air, dust, sewage sludge, and sediments, and they also appear in biotic matrixes (human serum, fish, and birds) [62]. For example, BTBPE is usually measured in sediments associated with others BFRs, at a lower concentration than BDE-209, but higher concentrations than other PBDE congeners. Some studies have detected BTPE in household dust [60, 61, 63, 64].

Due to their physicochemical properties, NBFRs bioaccumulate and biomagnify. DBDPE has Bioaccumulation Factor (BAF) between 6.1 and 7.1 in three fish species (*Cirrhina molitorella*,*Tilapia nilotica*, and *Hypostomus Plecostomus*) from a Chinese river [65]. In southern China, the HBB trophic magnification in an aquatic food chain (invertebrates and fish) is about 2.1 [66], whereas PBT and PBEB biomagnify in waterbirds in the same region [67]. Metabolic rates in the organism influence NBFR bioaccumulation and biomagnification [62].

In vitro studies have reported that NBFRs are hepatotoxic. For instance, 0.1 and 0.2 μM DBDPE up-regulates CYP1A4/5 expression [68], modifying rainbow trout hepatocyte activity [69]. Additionally, it interferes in thyroid hormone deiodinase activity in human liver microsomes; its inhibitory concentration (IC50) is 0.16 μM [70]. As for HBB, it activates the aryl hydrocarbon receptor (AhR), but to a lesser extent than 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Furthermore, 100 μM HBB cannot activate the human androgen receptor (AR) in human hepatocarcinoma cells [71]. On the basis of the AMES test, PBEB and PBT have no mutagenic activity [72].
