Academic journal article Environmental Health Perspectives

Rodent Thyroid, Liver, and Fetal Testis Toxicity of the Monoester Metabolite of Bis-(2-Ethylhexyl) Tetrabromophthalate (TBPH), a Novel Brominated Flame Retardant Present in Indoor Dust

Academic journal article Environmental Health Perspectives

Rodent Thyroid, Liver, and Fetal Testis Toxicity of the Monoester Metabolite of Bis-(2-Ethylhexyl) Tetrabromophthalate (TBPH), a Novel Brominated Flame Retardant Present in Indoor Dust

Article excerpt

Brominated flame retardants (BFRs) have been routinely added to a wide range of consumer products to reduce their inherent flammability and thus lower potential fire-related injuries and property damage. However, there is growing concern regarding their toxic effects (Birnbaum and Staskal 2004) because of their environmental persistence and measurably elevated levels in humans (Meneses et al. 1999; Sjodin et al. 1999).

Until recently, polybrominated diphenyl ethers (PBDEs) were the most commonly used class of flame retardants (de Wit 2002). PBDEs have high structural similarity to the endogenous thyroid hormones 3,5,3',5'-tetraiodo-l-thyronine [thyroxine, (T4)] and 3,3',5-triiodo-l-thyronine [triiodothyronine (T3)] (Schriks et al. 2007) resulting in the potential to disrupt thyroid hormone homeostasis (Butt et al. 2011; Darnerud et al. 2001). Rodents acutely exposed to PBDE (Hallgren and Darnerud 2002; Zhou et al. 2001) and environmentally exposed human populations (Bloom et al. 2008; Hagmar et al. 2001; Julander et al. 2005; Turyk et al. 2008; Yuan et al. 2008) have disrupted thyroid activity and function. Concerns over environmental persistence, neurotoxicity, and endocrine-disrupting effects have led to legislative restrictions on PBDE use (Costa et al. 2008). By 2010, the U.S. Environmental Protection Agency (EPA) instituted phase-out programs for all types of PBDE flame retardants (U.S. EPA 2009b).

With a continuing demand for flame retardants, various PBDE replacements have been introduced into commerce. Firemaster 550 (Chemtura Corp., Middlebury, CT) is a new flame retardant mixture; although its composition remains proprietary, bis-(2-ethylhexyl) tetrabromophthalate (TBPH) has been identified as a component (Stapleton et al. 2008). TBPH, an ingredient in several other Chemtura flame retardant mixtures, is used in PVC (polyvinyl chloride), neoprene, wire insulation, carpet backing, coated fabrics, and wall coverings (Covaci et al. 2011). TBPH is a high production volume chemical with 450-4,500 tons produced in 2006 (Covaci et al. 2011). Its widespread use is clearly evident in the detectable levels of TBPH found in household dust (Stapleton et al. 2008) and rapidly rising atmospheric levels in the North American Great Lakes region (Ma et al. 2011). Furthermore, TBPH has been discovered in the fatty tissue of higher-order species, including porpoises and dolphins in the South China Sea, indicating its ability to enter the environment (Lam et al. 2009).

The U.S. EPA's High Production Volume Information System (U.S. EPA 2009a) is the sole source of information on the toxicity of TBPH. TBPH has a half-life of approximately 29 days in water (25[degrees]C, pH 7). Studies of acute toxicity in rats showed that a single dose of 5,000 mg/kg did not produce lethality, outwardly observable effects, or gross changes at necropsy after 15 days. Toxicity following chronic exposure was tested by food-borne exposure for 28 days in a rat model (U.S. EPA 2009a). The reported no observed adverse effect level was 2,000 ppm (223 mg/kg/day). High-dose exposure to 20,000 ppm TBPH (2,331 mg/kg/day) significantly decreased serum alanine amino transferase, calcium, and phosphorus levels and decreased body weight. In vivo studies in mice failed to identify genotoxic effects in the form of micronucleated erythrocytes in the bone marrow after either dermal exposure or intraperitoneal injection. In vitro studies using isolated human lymphocytes also did not exhibit any elicited chromosomal aberrations (U.S. EPA 2009a).

TBPH is a structural analog of di(2-ethylhexyl) phthalate (DEHP), a known peroxisome proliferator and male reproductive toxicant in rodents. DEHP is metabolized by esterases to mono(2-ethylhexyl) phthalate (MEHP), its toxicologically active monoester metabolite (Figure 1). DEHP induces hepatotoxicity in rodents, most likely as a result of MEHP-induced activation of peroxisome proliferator activated receptor [alpha] (PPAR[alpha]) (Ward et al. …

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