Table 3.

Summary of toxicity studies analyzed in this review.

	In Vitro	Animal Models	Human
Insulin receptors	Enhance glucose-stimulated insulin secretion in INS-1 832/13 pancreatic β-cells [28].	Increase in fasting blood glucose and reduced mRNA levels of Insr and Glut4 in mice fed with a normal diet [25]. Alteration of glucose and lipid metabolism in mice [26]. Increased expression of peptide hormone receptors in mice hypothalamus, affecting energy balance [27].
Thyroid hormone receptors	Agonistic activity of PBDEs on transcription factor TRβ in the human thyroid follicular cell line [31]. OH-PBDEs bind THs transport proteins such as TBG and TTR [32]. PBDE stronger binding capacity to TTR than thyroxine [33]. PBDE sulfates could disrupt THs signaling through the interaction with THs transport proteins or TRs [34].	Alteration of retinoic acid pathway in zebrafish larvae [35].
Other receptors	Directly bind steroid hormone receptors [36,37]. Interaction with estrogen receptors [38]. Inhibition of estradiol sulfotransferase [39]. Reduced PPARγ transactivational activity [40]. Antagonistic action towards glucocorticoid receptors [41].
Diabetes, insulin resistance, obesity and metabolic syndrome			U-shaped relationship between diabetes and metabolic syndrome and PBDE-153 [44]. Positive linear association between PBDE47 serum concentration and type 2 diabetes risk [45]. Potential association between dietary PBDE and risk of diabetes [46]. Increased risk of gestational diabetes mellitus (GDM) [47]. No association between PBDE exposure and diabetes risk [48,49,50].
Thyroid disease		Hypothyroxinemia in rodents [53,55,56].	No strong association between PBDE exposure and thyroid dysfunction [57,58,59,60]. Reduced TT4 levels [60]. Thyroid disease in women [61].
Pubertal effects, ovarian function and reproductive health		Diabetic offspring in mice [69]. Spermatogenic injuries in prenatally exposed mice [70].	Increased FSH, LH and testosterone in children [62]. Premature thelarche [63] Increased levels of PBDE in girls with precocious puberty [64]. Prenatal and childhood exposure to PBDE resulted in later age at menarche in females [65,66] and earlier pubarche in males [65]. Earlier menarche onset [67]. Increased risk of GDM [47]. Impaired semen quality [6]. Increase telomer length in newborns [71]. Lower head circumference and Apgar at 1 min [72].
Thyroid cancer	DNA single-stranded and double-stranded breaks [77].	Increased proliferation of normal human follicular epithelial cell line and papillary thyroid carcinoma (PTC)-derived cell lines (both in vivo and in vitro) [76]. Cell proliferation stimulus (both in vivo and in vitro) [76].	Effect on thyroid hormone levels in patients operated for thyroid cancer [75]. Case–control study showed increased thyroid cancer risk [78]. Case–control study did not show increased papillary thyroid cancer risk [79].
Breast cancer	Possible estrogenic effect and therefore proliferation stimulus [85,86,87,88].		No significant association with breast cancer [80,81,82,83]. Increased breast cancer risk [84].
Liver cancer		Liver toxicity in mice [89]. Potential causality for PBDE exposure in liver carcinomas from mice [90]. Liver cancer in mice [91].
Other cancers	Cancerogenesis in airway epithelial cells [98]. Activation of epithelial–mesenchymal transition (EMT) in colorectal cancer cells [99].		PBDE found in tissue samples from surgical cancer patients [97].
Inflammation	Altered innate immune response [100,101].