Publications : 2016

Wikoff D, Borghoff SJ, Rager JE, Haws LC. 2016. Human relevance assessment of tetrabromobisphenol-A (TBBPA) induced uterine adenocarcinomas: Mode of action dependent on high dose molecular initiating event (MIE). Presented in the “Flame Retardants” session at the Society of Toxicology’s 55th Annual Meeting, March 13-17, New Orleans, LA.


TBBPA is a nongenotoxic flame retardant used to improve fire safety in a wide variety of consumer products. Estimated human exposures to TBBPA are very low (<0.00008 mg/kg-day), relative to the doses (500 and 1000 mg/kg-day of TBBPA) administered in a recent bioassay that resulted in uterine tumors in Wistar Han rats following chronic exposure. As part of an effort to characterize the relevance of the uterine tumors to humans, data and biological knowledge relevant to the progression of events associated with TBBPA-induced uterine tumors were organized in an adverse outcome pathway (AOP) framework. Based on a review of possible MOAs for chemically induced uterine tumors and available TBBPA data sets, it was determined that the most plausible MIE was the ability of TBBPA to inhibit SULT1E1, the enzyme responsible for sulfation of estradiol. Subsequent key events, including increased concentration of estradiol in uterine tissue, would occur with decreased sulfation, leading to a disruption in estrogen homeostasis, increased expression of estrogen responsive genes, cell proliferation, and hyperplasia. Additional key events considered as contributors to the AOP include generation of reactive quinones from the metabolism of estradiol, followed by DNA damage that could contribute to the development of uterine tumors. Uncertainties associated with human relevance are highlighted by potential strain/species and tissue sensitivities as well as the characterization of a dose-dependent MIE. At high doses (such as those used in the cancer bioassay), the TBBPA metabolic profile is altered, suggesting saturation of sulfation, decreased estradiol sulfation and increased tissue estradiol bioavailability. The MIE and subsequent key events for the development of TBBPA induced uterine tumors were determined to be plausible in humans however, are unlikely to occur based on differences in the kinetic and dynamic factors between rats and humans when the current human exposure levels of TBBPA are considered.