A high dose mode of action for tetrabromobisphenol A-induced uterine adenocarcinomas in Wistar Han rats: A critical evaluation of key events in an adverse outcome pathway framework

• Published in: Regulatory toxicology and pharmacology Vol. 77; pp. 143 - 159
• Main Authors: Wikoff, D.S., Rager, J.E., Haws, L.C., Borghoff, S.J.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.06.2016
• Subjects: Adenocarcinoma - chemically induced; Adenocarcinoma - enzymology; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Animals; AOP; Carcinogenicity Tests - methods; Carcinogens - administration & dosage; Carcinogens - toxicity; Cell Proliferation - drug effects; Cell Transformation, Neoplastic - chemically induced; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; DNA Damage; Dose-Response Relationship, Drug; Endocrine Disruptors - administration & dosage; Endocrine Disruptors - toxicity; Estradiol - metabolism; Estrogen; Female; Flame Retardants - administration & dosage; Flame Retardants - toxicity; Humans; Hyperplasia; Mode of action; Polybrominated Biphenyls - administration & dosage; Polybrominated Biphenyls - toxicity; Rats, Wistar; Risk Assessment; Species Specificity; Sulfotransferase; Sulfotransferases - antagonists & inhibitors; Sulfotransferases - metabolism; TBBPA; Time Factors; Uterine Neoplasms - chemically induced; Uterine Neoplasms - enzymology; Uterine Neoplasms - genetics; Uterine Neoplasms - pathology; Uterine tumor; Uterus - drug effects; Uterus - enzymology; Uterus - pathology; Uterine tumor; AOP; TBBPA; Sulfotransferase; Estrogen; Mode of action
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2016.01.018

TBBPA is a non-genotoxic flame retardant used to improve fire safety in a wide variety of consumer products. Estimated human exposures to TBBPA are very low (<0.000084 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 in female rats 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, a plausible molecular initiating event (MIE) was the ability of TBBPA to bind to and inhibit estrogen sulfotransferases, the enzymes responsible for sulfation of estradiol. Subsequent key events in the AOP, including increased bioavailability of unconjugated estrogens in uterine tissue, would occur as a result of decreased sulfation, leading to a disruption in estrogen homeostasis, increased expression of estrogen responsive genes, cell proliferation, and hyperplasia. Available data support subsequent key events, including generation of reactive quinones from the metabolism of estrogens, followed by DNA damage that could contribute to the development of uterine tumors. Uncertainties associated with human relevance are highlighted by potential strain/species sensitivities to development of uterine tumors, as well as the characterization of a dose-dependent MIE. For the latter, it was determined that the TBBPA metabolic profile is altered at high doses (such as those used in the cancer bioassay), and thus an MIE that is only operative under repeated high dose, administration. The MIE and subsequent key events for the development of TBBPA-induced uterine tumors are not feasible in humans given differences in the kinetic and dynamic factors associated with high dose exposures in rats relative to human exposure levels to TBBPA. [Display omitted] •TBBPA-induced uterine tumors in female rats were organized in an adverse outcome pathway (AOP) framework.•The MIE was determined to be binding inhibition of estrogen sulfotransferases.•Evidence demonstrates that the MIE that is only operative under repeated high dose, administration.•TBBPA-induced uterine tumors are not feasible in humans when considering current exposure levels.