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

Abstract

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.

Derivation of a no‐significant‐risk‐level for tetrabromobisphenol A based on a threshold non‐mutagenic cancer mode of action

“…A human relevance and concordance analysis of the postulated MOA was conducted by Wikoff et al (), and suggests that given the available data, the proposed MOA is plausible for the development of uterine tumors. Wikoff et al () conclude this is a plausible mechanism in humans qualitatively, but may be quantitatively excluded based on kinetic/dynamic factors between humans and rats. Given some of the data gaps associated with this MOA, we have given the greatest weight to the non‐mutagenic threshold MOA, as multiple lines of evidence support that the MOA identified is non‐mutagenic.…”

“…Thus, while we conclude that the Wikoff et al (2016) the most appropriate cancer endpoint, and they were therefore chosen as the critical effect for derivation of the NSRL (Table 3). However, it is worth noting that high doses were needed to induce tumor formation, and the available evidence before the NTP assay suggested TBBPA was not carcinogenic.…”

“…The literature search identified a carcinogenicity study of TBBPA by the US NTP (NTP, 2014), and associated published studies that evaluated these NTP (2014) tumor findings and the TBBPA cancer MOA (Dunnick et al, 2015;Hall, Coulter, Knudsen, Sanders, & Birnbaum, 2017;Harvey et al, 2015;Lai, Kacew, & Dekant, 2015;Sanders et al, 2016;Wikoff et al, 2015;Wikoff et al, 2016). These data are pertinent because the lack of cancer data was identified as a data gap precluding the development of a cancer potency value by regulatory agencies (EFSA, 2011;Health Canada, 2013 However, we did not request this information.)…”

“…In the NTP 2-year TBBPA bioassay, and as evaluated by Wikoff et al (2015), uterine tumors in rats were identified as the most appropriate endpoint for use in derivation of a cancer toxicity value. Based on the considerable amount of evidence that TBBPA is not mutagenic, a non-linear MOA was postulated for TBBPA-induced uterine tumors based on interference with estrogen metabolism, as discussed by several authors (Borghoff, Wikoff, Harvey, & Haws, 2016;Dunnick et al, 2015;Hall et al, 2017;Harvey et al, 2015;Lai et al, 2015;Sanders et al, 2016;Wikoff et al, 2015), most comprehensively by Wikoff et al (2016). The interference with estrogen is not thought to involve TBBPA binding directly to the estrogen receptor (ER).…”

“…(4) increases in estrogen-responsive genes contribute to cellular proliferation of cells, which may have increased DNA damage and p53 mutations; and (5) increased proliferation leads to hyperplasia of cells causing the adverse outcome (uterine tumors). These key events and supporting data are extensively discussed in Wikoff et al (2016), and so are only briefly described below.…”