Nicholas School of the Environment, Duke University, Durham, NC 27708, USA.
Chem Res Toxicol. 2012 Jul 16;25(7):1435-41. doi: 10.1021/tx300086x. Epub 2012 May 23.
Due to the phaseout of polybrominated diphenyl ether (PBDE) flame retardants, new chemicals, such as 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB) and bis(2-ethylhexyl) 2,3,4,5-tetrabromophthalate (TBPH), have been used as replacements in some commercial flame retardant mixtures. Both chemicals have been detected in indoor dust at concentrations approaching the concentrations of PBDEs; however, little is known about their fate, metabolism, or toxicity. The goal of this study was to investigate the potential metabolism of these two brominated flame retardants in human and rat tissues by conducting in vitro experiments with liver and intestinal subcellular fractions. In all the experiments, TBB was consistently metabolized to 2,3,4,5-tetrabromobenzoic acid (TBBA) via cleavage of the 2-ethylhexyl chain without requiring any added cofactors. TBBA was also formed in purified porcine carboxylesterase but at a much faster rate of 6.29 ± 0.58 nmol min(-1) mg protein(-1). The estimated K(m) and V(max) values for TBB metabolism in human microsomes were 11.1 ± 3.9 μM and 0.644 ± 0.144 nmol min(-1) mg protein(-1), respectively. A similar K(m) of 9.3 ± 2.2 μM was calculated for porcine carboxylesterase, indicating similar enzyme specificity. While the rapid formation of TBBA may reduce the bioaccumulation potential of TBB in mammals and may be useful as a biomarker of TBB exposure, the toxicity of this brominated benzoic acid is unknown and may be a concern based on its structural similarity to other toxic pollutants. In contrast to TBB, no metabolites of TBPH were detected in human or rat subcellular fractions. However, a metabolic product of TBPH, mono(2-ethylhexyl) tetrabromophthalate (TBMEHP), was formed in purified porcine carboxylesterase at an approximate rate of 1.08 pmol min(-1) mg protein(-1). No phase II metabolites of TBBA or TBMEHP were observed. More research is needed to understand the in vivo toxicokinetics and health effects of these compounds given their current ubiquitous presence in most US households and the resulting probability of chronic exposure, particularly to young children.
由于多溴联苯醚 (PBDE) 阻燃剂的逐步淘汰，一些商用阻燃剂混合物中已开始使用 2-乙基己基-2,3,4,5-四溴苯甲酸酯 (TBB) 和双(2-乙基己基) 2,3,4,5-四溴邻苯二甲酸酯 (TBPH) 等新型化学物质作为替代品。这两种化学物质在室内灰尘中的浓度都接近 PBDEs 的浓度，但它们的命运、代谢和毒性知之甚少。本研究的目的是通过对肝和肠亚细胞部分进行体外实验，研究这两种溴化阻燃剂在人和大鼠组织中的潜在代谢情况。在所有实验中，TBB 均通过 2-乙基己基链的断裂而一致地代谢为 2,3,4,5-四溴苯甲酸 (TBBA)，而无需任何添加的辅助因子。TBBA 也在纯化的猪羧基酯酶中形成，但速度要快得多，为 6.29 ± 0.58 nmol min(-1) mg 蛋白(-1)。人微粒体中 TBB 代谢的估计 K(m) 和 V(max) 值分别为 11.1 ± 3.9 μM 和 0.644 ± 0.144 nmol min(-1) mg 蛋白(-1)。猪羧基酯酶的 K(m) 相似，为 9.3 ± 2.2 μM，表明酶的特异性相似。虽然 TBBA 的快速形成可能会降低 TBB 在哺乳动物中的生物累积潜力，并可能作为 TBB 暴露的生物标志物，但这种溴化苯甲酸的毒性尚不清楚，而且基于其与其他有毒污染物的结构相似性，可能会令人担忧。与 TBB 不同，在人和大鼠亚细胞部分均未检测到 TBPH 的代谢物。然而，在纯化的猪羧基酯酶中形成了 TBPH 的代谢产物，即单(2-乙基己基)四溴邻苯二甲酸酯 (TBMEHP)，其形成速度约为 1.08 pmol min(-1) mg 蛋白(-1)。未观察到 TBBA 或 TBMEHP 的任何相 II 代谢物。鉴于这些化合物目前在大多数美国家庭中普遍存在，并且由此导致慢性暴露的可能性，特别是对幼儿的暴露，因此需要更多的研究来了解这些化合物的体内毒代动力学和健康影响。
