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

Cecilia Springer,¹ Edward Dere,^1,2 Susan J. Hall,¹ Elizabeth V. McDonnell,¹ Simon C. Roberts,³ Craig M. Butt,³ Heather M. Stapleton,³ Deborah J. Watkins,^4,5 Michael D. McClean,⁴ Thomas F. Webster,⁴ Jennifer J. Schlezinger,⁴ and Kim Boekelheide¹

¹Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, USA; ²Division of Urology, Rhode Island Hospital, Providence, Rhode Island, USA; ³Nicholas School of the Environment, Duke University, Durham, North Carolina, USA; ⁴Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts, USA; ⁵Center for Environmental Health and Technology, Brown University, Providence, Rhode Island, USA

Abstract

Background: Bis-(2-ethylhexyl) tetrabromophthalate (TBPH) is widely used as a replacement for polybrominated diphenyl ethers (PBDEs) in commercial flame retardant mixtures such as Firemaster 550. It is also used in a commercial mixture called DP 45. Mono-(2-ethyhexyl) tetrabromophthalate (TBMEHP) is a potentially toxic metabolite.

Objectives: We used in vitro and rodent in vivo models to evaluate human exposure and the potential metabolism and toxicity of TBPH.

Methods: Dust collected from homes, offices, and cars was measured for TBPH by gas chromatography followed by mass spectrometry. Pregnant rats were gavaged with TBMEHP (200 or 500 mg/kg) or corn oil on gestational days 18 and 19, and dams and fetuses were evaluated histologically for toxicity. We also assessed TBMEHP for deiodinase inhibition using rat liver microsomes and for peroxisome proliferator-activated receptor (PPAR) α and γ activation using murine FAO cells and NIH 3T3 L1 cells.

Results: TBPH concentrations in dust from office buildings (median, 410 ng/g) were higher than in main living areas in homes (median, 150 ng/g). TBPH was metabolized by purified porcine esterases to TBMEHP. Two days of TBMEHP exposure in the rat produced maternal hypothyroidism with markedly decreased serum T3 (3,3´,5-triiodo-L-thyronine), maternal hepatotoxicity, and increased multinucleated germ cells (MNGs) in fetal testes without antiandrogenic effects. In vitro, TBMEHP inhibited deiodinase activity, induced adipocyte differentiation in NIH 3T3 L1 cells, and activated PPARα- and PPARγ-mediated gene transcription in NIH 3T3 L1 cells and FAO cells, respectively.

Conclusions: TBPH a) is present in dust from indoor environments (implying human exposure) and b) can be metabolized by porcine esterases to TBMEHP, which c) elicited maternal thyrotoxic and hepatotoxic effects and d) induced MNGs in the fetal testes in a rat model. In mouse NIH 3T3 L1 preadipocyte cells, TBMEHP inhibited rat hepatic microsome deiodinase activity and was an agonist for PPARs in murine FAO and NIH 3T3 L1 cells.

Key words: brominated, exposure, flame retardant, hepatotoxicity, hypothyroidism, metabolism, phthalate, PPAR, toxicity. 

Environ Health Perspect 120:1711–1719 (2012). http://dx.doi.org/10.1289/ehp.1204932 [Online 26 September 2012]

Address correspondence to K. Boekelheide, Department of Pathology and Laboratory Medicine, Brown University, Box G-E5, Providence, RI 02912 USA. Telephone: (401) 863-1783. Fax: (401) 863-9008. E-mail: kim_boekelheide@brown.edu

This research was supported in part by Superfund Research Program grants P42 ES013660 (K.B.) and P42 ES007381(J.S.), R01 ES015829 (T.F.W., M.D.M.), R01 ES016099 (S.C.R., C.M.B., H.M.S.), and T32 ES014562 (D.J.W.) from the National Institutes of Health/National Institute of Environmental Health Sciences; and pilot funding from the Boston University School of Public Health and the Voss Environmental Fellows Program, Brown University.

K.B. is an occasional expert consultant for chemical and pharmaceutical companies. The other authors declare that they have no actual or potential competing financial interests.

Received 6 January 2012; Accepted 26 September 2012; Online 26 September 2012.