**2. Brominated flame retardants**

Despite laws discouraging or even banning BRF use, their global production continues to grow because new BFRs are being introduced to replace the banned or phased-out ones. About 75 different BFRs are marketed today, and most of them are found in the environment [12, 14]. The main classes of BFRs are polybrominated biphenyls (PBBs), tetrabromobisphenol A (TBBPA), HBCD, and PBDEs. PBDEs and HBCD are the most employed BFRs worldwide [12, 17]. **Table 1** shows the BFR chemical structures and physicochemical properties.

After some poisoning episodes and toxicity evidence involving BFRs, some countries started regulating their use in the same way they regulate the use of PBBs and the commercial PBDE mixture. In the early 1970s, accidental poisoning with PBBs occurred on Michigan Farms—animal feed contamination during production resulted in about 5 million eggs and 15.5 tons of milk products being contaminated and 1.5 million chicken, 30,000 cattle, 6000 hogs, and 1500 sheep dying. After this episode, PBBs were removed from the U.S. market, and this class was banned in the U.S. in 1973 [14, 17]. In the late 1980s, the development of analytical methods helped scientists to begin gathering data about FRs in Europe, North America, and Japan, and environmental and human health concerns started to increase when PBDE presence was reported in human milk [18] and marine animals [19] and rising PBDE levels were identified in environmental compartments including sediments, sewage sludge, the aquatic environment, and biological samples (fish, aquatic birds, and human tissues) [20].

Given the toxicological concern and the fact that POPs represent (some BFRs are included as POP) a growing threat to human health and the environment, in 1995, the council of the United Nations Environment Program (UNEP) requested an international process for evaluating an initial list of 12 POPs, and UNEP asked the Intergovernmental Forum on Chemical Safety (IFSC) to recommend international action on

 *Chemical structure of the main classes BFRs and their physicochemical properties [12,*

 *17].*

### *Flame Retardants: New and Old Environmental Contaminants DOI: http://dx.doi.org/10.5772/intechopen.104886*

these pollutants. Thereafter, a negotiation process began; the Stockholm Convention on Persistent Organic Pollutants was created and adopted in 2001; and the Convention came into force three years later when 50 countries ratified it. Annex A lists PBDEs, PBBs, and HBCD as POPs to be eliminated [11]. In 2002, the European Union (E.U.) banned PBDEs and HBCD production, followed by the development of framework and directives such as the creation of the Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH), the Restriction of Hazardous Substances, and the Waste Electrical and Electronic Equipment directives [14]. Other initiatives that aimed to reduce and eliminate the two main commercial PBDE mixtures (Penta- and Octa-diphenyl ether – Penta/OctaBDE) were also undertaken in North America (the U.S. and Canada). In 2004, several U.S. states prohibited the use of these two PBDE mixtures in some products. Canada also supported the virtual DecaBDE voluntary elimination by 2013. In 2017, the U.S. Consumer Product Safety Commission (CPSC) petitioned to restrict HFR use as additives and nonpolymeric constituents in electronics, furniture, and children's products [9, 14]. China added DecaBDE and HBCD to the priority list of substances, which implied restricted production or limited discharges. Taiwan and Japan follow similar examples: they have restrictions on PBDEs and HBCD. On the other hand, although Brazil and India are signatories of the Stockholm Convention on Persistent Organic Pollutants, no comprehensive legislation for FRs exists in these countries [14]. **Figure 2** shows a schematic timeline of the regulation of halogenated flame retardants.

BFRs are divided into three subgroups—additive, reactive, and polymeric depending on how they are incorporated into manufactured materials. The incorporation mode directly influences BRF presence in the environment. Additive BFRs, such as PBDEs and HBCD, are just mixed at the time of manufacture, so they interact weakly with materials and easily leak into the environment. In contrast, reactive and polymeric BFRs establish a chemical interaction with materials, giving rise to a more stable interaction that results in less BRF bioavailability. Nevertheless, these BFRs

#### **Figure 2.**

*Schematic timeline of regulation of halogenated flame retardant (HFRs). PCBs = polychlorinated biphenyls; PBBs = polybrominated biphenyls; POPs = persistent organic pollutants; HBCD = hexabromocyclododecane; U.S. = United States; E.U. = European Union.*

should not be neglected because they may be lost to the environment during production or transport [21].

BFRs are ubiquitous in the environment. During the last decades, they have been detected in environmental samples even in places located far away from where they are produced or used (e.g., in the Artic) [22–24]. Once BFRs are released, they tend to persist, bioaccumulate, and biomagnify, and their physicochemical properties, mainly lipophilicity, may underlie potential toxic effects on the environment [24, 25].

#### **2.1 Environmental occurrence and (eco)toxicological effects**

#### *2.1.1 Polybrominated diphenyl ethers (PBDEs)*

PBDEs are sold as a mixture of congeners and have three commercial presentations: PentaBDE (pentabromodiphenyl ether), OctaBDE (octabromodiphenyl ether), and DecaBDE (decabromodiphenyl ether). The mixture name refers to the main congeners that compose it. Each PBDE congener varies in the number of bromine atoms and the arrangement of these substituted atoms in the aromatic ring. This gives 209 possible congeners, divided into ten groups: mono-, di-, tri-, tetra-, penta-, hexa-, hepta, octa-, nona-, and decabromo diphenyl ether. The number of isomers in these groups may be 3, 12, 24, 42, 46, 42, 24, 12, 3, and 1, respectively [26, 27]. Depending on the type of material, each mixture has a specific application. For example, DecaBDE is used in diverse polymeric materials, while Penta and OctaBDE are applied mainly in the textile and polyurethane foam industries [26].

PBDEs are released into the environment in different ways. First, they may be released during their industrial production. Second, materials containing PBDEs may release them. Third, goods with PBDEs in their composition may be inappropriately discharged. The latter situation is one of the main sources of environmental contamination with PBDEs. Other sources of exposure to PBDE congeners include use and recycling of products containing PBDEs, such as computers, household appliances in general, upholstery, and furniture [12, 27]. The PBDE physicochemical characteristics, including their high lipophilicity, hydrophobicity, low vapor pressure, and high affinity for particles, contribute to their presence in sediments in ambient compartments, particulate matter in the air, and foods. PBDEs are absorbed by inhalation of domestic and industrial dust, via the dermal route, and even by ingestion of contaminated food, which is aggravated by their ability to biomagnify in the food chain [17, 28].

Regarding the PBDE toxicological aspects, several studies have shown their high toxic potential. Their main effects include hepatotoxicity, neurotoxicity, immunological and endocrine alterations, and carcinogenicity. However, the mechanisms through which PBDEs exert their toxic action are not understood [17, 28]. PBDEs have been detected in human samples, especially blood and breast milk. The latter presentation is particularly alarming. Numerous studies involving human breast milk samples have reported different PBDE concentrations in all the analyzed samples, with the congeners BDE-47, -99, -100, and -153 being the most abundant and frequent [29–31].

PBDEs, mainly those with lower molecular weight, are structurally similar to thyroid hormones. Therefore, they may disrupt the endocrine system by interfering with hypothalamicpituitary-thyroid axis homeostasis [12, 32]. BDE-71 and -79 decrease thyroid hormone serum levels and induce liver enzyme biotransformation, as shown in studies carried out with mice and rats [33]. Moreover, many PBDE congeners damage mitochondria, increasing reactive oxygen species (ROS) production and

oxidative stress, exerting genotoxicity, and inducing apoptotic cell death in isolated rat mitochondrial and hepatocarcinoma cells (HepG2) [34–36].

### *2.1.2 Hexabromocyclododecane (HBCD)*

HBCD is a high-molecular-weight nonaromatic brominated cyclic alkane with six pairs of enantiomers. It is mainly used as an additive FR in thermoplastics for final application in styrene resins. Being an additive FR, HBCD is easily released into the environment. It has high lipophilicity (log *K*ow = 5.6) and low solubility in water (0.0034 mg/l) [12, 37]. Due to these characteristics, HBCD is persistent, with a halflife of 3 days in the air and 2025 days in water. It bioaccumulates with a bioconcentration factor of approximately 18,100 in fathead minnows [38, 39]. Its commercial formulation consists of three isoforms: γ-HBCD (75–89%), α-HBCD (10– 13%), and β-HBCD (1–12%) [37]. Enantiomers may behave differently in the environment; for example, γ-HBCD tends to be more toxic than α-HBCD, but α-HBCD is the enantiomer that occurs more often in environmental samples [40, 41].

HBCD has been measured in several environmental compartments, including air and dust, sediments, soil, and sewage sludge, and biological samples (aquatic organisms, marine mammals, birds, plants, and even human samples). In animals, HBCD tends to accumulate in lipid-rich organs, such as the liver, gonads, muscle, and adipose tissue [17, 37, 41].

HBCD presents high toxic potential. HBCD increases catalase transcription because this FR raises ROS concentration. Exposure to HBCD alters a protein involved in the mollusk immune system [42]. HBCD may lead to cellular apoptosis near the heart area, and zebrafish exposure to this compound induces cardiac hypertrophy and arrhythmia [43]. HBCD disrupts the endocrine system in Wistar rats and causes neuro- and hepatotoxicity in mice [44, 45]. HBCD induces cytotoxicity in human hepatocarcinoma cells (HepG2) and human neuroblastoma cells (SH-SY5Y), reducing cell viability. HBCD interferes with T4 metabolism in HepG2 cells and affects the estrogenic activity in breast cancer cells (MCF-7) [46–48], suggesting that it is hepatotoxic and neurotoxic and that it acts as an endocrine disruptor.
