Table E2.

Studies on mode of action of carcinogenicity/genotoxicity.

Reference	Comments
Song et al. (2013). Investigation of tetrabromobisphenol A interacting with DNA nitrogen bases using experimental and density functional theory methods	As studied by UV–Vis spectroscopy, TBBPA placed into a quartz cuvette interacted as an electrophile with guanine, adenine and cytosine; and as a nucleophile with thymine. The interactions of TBBPA with the nitrogen bases followed the order: guanine > adenine > thymine > cytosine. The TBBPA‐guanine complex exhibited the highest charge transfer, the largest bonding constant, and the most negative interaction energy. The authors concluded that TBBPA interacts directly with DNA nitrogen bases. The CONTAM Panel considered these data, based on chemical interaction rather than in a biological model, to be of limited relevance
Harvey et al. (2015). Uterine Carcinomas in Tetrabromobisphenol A‐exposed Wistar Han Rats Harbour Increased Tp53 Mutations and Mimic High‐grade Type I Endometrial Carcinomas in Women	Uterine carcinomas induced by TBBPA in the NTP (2014) study were found to have an increase in tumour protein 53 (Tp53 mutations), and overexpression of human epidermal growth factor receptor 2 compared to spontaneous uterine carcinomas. Tumours in TBBPA‐exposed rats were oestrogen receptor‐alpha positive and progesterone receptor negative by immunohistochemistry. The authors concluded that the morphologic and molecular features of uterine carcinomas in TBBPA‐exposed rats resemble those of high‐grade type I tumours in women, suggesting that exposure to TBBPA may pose an increased cancer risk
Lai et al. (2015). Tetrabromobisphenol A (TBBPA): Possible modes of action of toxicity and carcinogenicity in rodents	Review discussing possible MOAs for T4 changes and uterine tumours induced by TBBPA. MOA may increase circulating oestrogens by a competitive inhibition of oestrogen conjugation and produce uterine tumours by promoting pre‐existing Tp53‐mutations due to increased oestrogen levels resulting in increased cell proliferation
Hoffmann, Fiedor, et al. (2017). Bisphenol A and its derivatives tetrabromobisphenol A and tetrachlorobisphenol A induce apelin expression and secretion in ovarian cancer cells through a peroxisome proliferator‐activated receptor gamma‐dependent mechanism	TBBPA at low nM concentrations increased apelin (an adipokine) expression and secretion in the epithelial ovarian cancer cell line OVCAR‐3, which involved the peroxisome proliferator‐activated receptor gamma but not oestrogen receptors. Apelin stimulated proliferation of OVCAR‐3 cells. The authors suggested that TBBPA induce ovarian cancer cell progression by up‐regulating apelin, which acts as a mitogenic factor in these cells. The results depended on the specific ovarian cancer cell line used and relevance to uterine cancer is unclear
Hoffmann, Gogola, et al. (2017). Stimulation of ovarian cell proliferation by tetrabromobisphenol A but not tetrachlorobisphenol A through G protein‐coupled receptor 30	OVCAR‐3 and KGN cells were used as in vitro models to represent epithelial ovarian cancers and graulosa cell tumours, respectively. TBBPA, stimulated OVCAR‐3 and KGN cell proliferation. The stimulatory effects were reversed by pre‐treatment with a G protein‐coupled receptor 30 (GPR30) antagonist in both cell lines. GPR30 is a novel membrane receptor that promotes specific binding of endogenous and exogenous oestrogens The authors suggested that TBBPA stimulates ovarian cancer cell proliferation through the GPR30 pathway
Hoffmann et al. (2018). Bisphenol A and its derivatives decrease expression of chemerin, which reverses its stimulatory action in ovarian cancer cells	At low nM concentrations, TBBPA decreased chemerin expression and secretion in granulosa cell tumour COV434 cells by both peroxisome proliferator‐activated receptor γ and oestrogen receptor signalling pathways. Since chemerin inhibited TBBPA‐induced cell proliferation, the authors suggested that TBBPA down‐regulation of chemerin expression, may act as a mitogenic factor in ovarian cancer cells
Guyton et al. (2018). Application of the key characteristics of carcinogens in cancer hazard identification	Assessment of the key characteristics used by IARC in determining whether animal carcinogenicity is relevant for humans
Gorowska‐Wojtowicz et al. (2019). Leydig cell tumorigenesis – implication of G‐protein coupled membrane oestrogen receptor, peroxisome proliferator‐activated receptor and xenoestrogen exposure. In vivo and in vitro appraisal	Study primarily about possible aetiology of Leydig cell tumours, particularly with respect to involvement of PPAR. TBBPA affected PPARα expression
Lyu et al. (2020). TBBPA regulates calcium‐mediated lysosomal exocytosis and thereby promotes invasion and migration in hepatocellular carcinoma	TBBPA and TBBPA‐BDBPE at pM‐uM concentrations promoted migration and invasion of HepG2 cells in a transwell model system. Associated with changes in number and distribution of lysosomes and calcium ino‐mediated lysosomal exocytosis
Shockley et al. (2020b). Transcriptomic data from the rat liver after 5 days of exposure to legacy or emerging brominated flame retardants	This is accompanying data providing toxicogenomic data for others to use
Guan et al. (2021). The promotion of tetrabromobisphenol A exposure on Ishikawa cells proliferation and pivotal role of ubiquiti‘n‐mediated I kappa B ‘degradation	TBBPA at pM‐nM concentrations induced proliferation of Ishikawa cells, a human endometrial carcinoma cell line, associated with elevation on NF‐κB expression and ubiquitin‐mediated degradation of IκB. This was assumed to be analogous to progression of endometrial carcinoma
Xu, Su, et al. (2022). Constructing an MCF‐7 breast cancer cell‐based transient transfection assay for screening RAR? (Ant)agonistic activities of emerging phenolic compounds	TBBPA was found to have antagonistic activity on the retinoic acid receptor α (RARα) in MCF‐7 breast carcinoma cells were transiently transfected with a RARα expression vector (pEF1α‐RARα‐RFP) and a reporter vector containing a retinoic acid reaction element (pRARE‐TA‐Luc). Relevance for TBBPA carcinogenicity is unclear
Liu et al. (2022). Short‐term tetrabromobisphenol A exposure promotes fibrosis of human uterine fibroid cells in a 3D culture system through TGF‐beta signalling	TBBPA increased cell proliferation and promoted fibrosis, and upregulated expression of profibrotic genes in a 3D human uterine leiomyoma (ht‐UtLM) spheroid culture model. Relevance to carcinogenicity unclear
Cheng and Volz (2022). Halogenated bisphenol a analogues induce PPARγ‐independent toxicity within human hepatocellular carcinoma cells	TBBPA induces toxicity within HepG2 cells in a PPARγ‐independent manner