Bisphenol A Analogues: A Brief Review of their Occurrence in Food, Biological Samples and Endocrine Effects

Bisphenol A (BPA) is the most well-known compound from the bisphenol family. There is increasing evidence that bisphenol BPA used in plastics, receipts, food packaging, and other products might be harmful to human health due to its actions as an endocrine-disrupting chemical, therefore BPA is being replaced by compounds very similar in structure, but data on the occurrence and effects of these BPA analogs are limited. Therefore, there is increasing concern regarding human exposure to bisphenol analogs (BPs) due to their widespread use and potential adverse effects. The main objective of this work was to investigate human exposure to BPs and the associated endocrine activities. We performed a literature review of the available research made in humans, in in vivo and in vitro tests. The findings support the idea that exposure to BPs may have an impact on human health, especially in terms of endocrine disruption. Archives of Ecotoxicology, Vol. 2, No. 4, pp. 89-94, 2020


Introduction
Endocrine disruptors are compounds that alter normal functioning of the endocrine system, and their bioaccumulation in humans may cause adverse health effects (Andujar et al., 2019). Bisphenol A was first synthesized in 1905, with the condensation of phenol and acetone in the presence of acid as the catalyst (Rykowska and Wasiak, 2006), afterward, its production levels increased, and nowadays BPA is one of the most extensively used bisphenols, mostly as a monomer in the production of polycarbonate plastics and epoxy resins (Michałowicz, 2014). In recent years, there is increasing evidence of possible negative effects of bisphenol A (BPA) used in plastics, receipts, food packaging, and other products to human health due to its actions as an endocrine-disrupting chemical (EDC) ( Ideally, substitutes used to replace a chemical of concern should be inert, or at least far less toxic than the original chemical, but as seen in Figure 1, BPAF, BPB, BPF, and BPS are structural analogues to BPA, thus its effects in physiological systems may be similar (Rochester et

Material and methods
A review of the available literature was conducted in October 2020. PubMed/Medline and Scopus databases were searched using the keywords "Bisphenol A analogues", "Bisphenol A substitutes", "hormone effect", "endocrine disruption", and "endocrine activity". Data published between 2000 and 2020 were considered. We conducted a systematic review to identify the occurrence in food and biological samples, as well as adverse effects of bisphenols and their endocrine activities by focusing on animal models and in vitro mechanistic studies. After critical analysis of results, lines of evidence were built using a weightof-evidence approach to establish a biologically plausible link.

Occurrence of Bisphenols
Bisphenol A (BPA) is one of the highest-volume chemicals used widely in the production of diverse consumer products, and its use has resulted in ubiquitous existence in the environment and organisms (Zhang et al., 2018). The occurrence of BPA in more than 90% of 2,517 urine samples tested, with a geometric mean of 2. Little information is available on the occurrence of bisphenol analogues (BPs) in foods. In a study conducted in the United States, Liao and Kannan (2013) determined the prevalence of BPA, BPF, and BPS (N = 267) in nine food categories and found that 75% of the samples contained BPs, with total concentrations ranging from below the quantification limit to 1130 ng/g fresh weight (4.38 ng/g overall mean value). In preserved and ready-to-eat foods, the highest concentrations of BPF and bisphenol P (BPP) were 1130 ng/ g and 237 ng/g respectively. BPs in drinks and vegetables, by comparison, were detected at concentrations of 0.341 ng/g and 0.698 ng/g, respectively. In canned food, higher levels of individual and total BPs were found than in foods that came in containers of plastic, glass, or paper. In a study conducted in China, Liao and Kannan (2014) determined the presence of eight BPs (N = 289) in 13 food categories using high-performance liquid chromatographytandem mass spectrometry. BPA and BPF were the most commonly observed BPs, detected at mean value concentrations of 4.94 ng/g and 2.50 ng/g fresh weight, respectively. In canned goods (27.0 ng/g), the highest overall concentration (sum of eight BPs) was observed, followed by fish and meat (16.5 ng/g), and drinks (15.6 ng/g). By comparison, milk and dairy products, cooking oils, and eggs (2-3 ng/g) had the lowest overall concentration. In canned foods (56.9 ng/g), higher total concentrations were found than in foods containing glass (0.43 ng/g), paper (11.9 ng/g), or plastic (6.40 ng/g). The presence of BPA analogs in canned vegetables, fruits, and soft drinks Although BPA is the most studied BP, BPs are widely used in epoxy coatings applied in drinking water delivery systems and have also been found in drinking water. BPs from coatings may be exposed to chemical oxidants (disinfectants), which, in comparison to the parent compounds, have the potential to form by-products with increased or decreased estrogenic activity (Lane et al., 2015).
In babies under six months of age, breast milk is the primary source of nutrition and can also be used as a surrogate for internal exposure levels in mothers and fetuses. In breast milk samples, BPA, BPF, BPS, and BPAF were found by Niu et al.

Adverse Effects of Bisphenols
The presence of BPA analogues in food, environmental, and human biological samples indicates that it could affect the body. The most widely studied effect of BPA is estrogen activity, and its effects on other hormonal receptors have also been reported (Gramec-Skledar et Peterlin-Masic, 2016). However, limited studies have confirmed that BPs have related BPA-like endocrine-disrupting activities (Liao et al., 2012). The estrogenicity of BPs was first reported in 1998 in cultures of the human breast cancer cell line MCF7 using an E-SCREEN assay (Perez et al., 1998). Later, in 2002, by evaluating the induction of pS2 (mRNA and protein) and progesterone receptors as well as the expression of the luciferase reporter gene transfected into MVLN cells, the effects of these chemicals on the expression of estrogen-controlled genes were demonstrated (Rivas et al.,  2002). The estrogenic effect of certain BPs has also been reported to be higher than that of BPA (Cao et al., 2017). BPS, for example, has a higher hormonal activity, which can probably be due to its heavy polarity and the presence of the sulfonyl group Age-specific and dose-specific effects of BPS that were different from the effects of BPA were observed in the study. Furthermore, using L1 larvae of the Caenorhabditis elegans model animal, Zhou (2018) measured low-concentration BPS toxicity. Multiple indicators have been examined at physiological, biochemical, and molecular levels, the overall results showed that BPS was less noxious compared with the effects of BPA, indicating that individual bisphenols could have specific effects. Eladak et al. (2015) conducted research, which showed that 10 nmol/L BPS and BPF can minimize the secretion of basal testosterone by fetal human and mouse testicles. Desdoits-Lethimonier et al., (2017) showed that BPE, BPF, BPB, and BADGE exhibited antiandrogenic properties in adult human testes using an ex vivo culture system. In addition, BPA, BPAF, BPB, BPF, BPS, and bisphenol Z (BPZ) have been found to alter thyroid endocrine system function in a study conducted on the GH3 rat cell line, which appears to be increased by 17β-estradiol (Lee et al.,  2018). Serra et al., (2019) reported that existing information on BPB's estrogenic activity and inhibition of testosterone production is similar to BPA's endocrine activity.

Conclusion
There is increasing concern regarding human exposure to bisphenol analogues (BPs) due to their widespread use and potential adverse effects. It is not surprising that these replacements also pose a danger to wildlife and human health, considering the similarities between BPA and BPA analogues in terms of their metabolism and behavior, including hormonal effects beyond those of BPA. Regulations for the safety evaluation of consumer goods should be expanded to include all substances in the same category of chemicals. Futhermore, more work is required to find chemical alternatives without harmful health effects, as recommended by various researchers. The trend towards replacement of BPA analogs in consumer goods, especially food contact materials, should be exercised with caution and should include effective and frequent monitoring to assess their effects on human health. 4. Calafat, A.M., Ye, X., Wong, L.Y., Reidy, J.A., Needham, L.L., 2008. Exposure of the U.S. population to bisphenol A and 4tertiary-octylphenol: