Four scientific articles analyze and discuss exposure to bisphenol A (BPA, CAS 80-05-7) and its analogues as well as potential associated health risks, e.g., on the cardiovascular system.
In a review article published on March 31, 2022, in the journal Integrated Environmental Assessment and Management, John N. Hahladakis from Qatar University, Doha, Qatar, and co-authors summarized the exposure and health risk of long-term exposure to BPA used in plastic materials, components, and products (MCPs) with a focus on polycarbonates, which is synthesized using BPA as a monomer, and epoxy resins that are often used to produce coatings and sealers. The narrative review first provides an overview of BPA’s properties as well as how the compound is regulated in the US and Europe, continues with human exposure sources and pathways throughout the whole lifecycle as well as adverse health effects arising from that exposure and finally suggests future research topics. Hahladakis and co-authors summarized that the global BPA market is expected to grow “reaching a value of 20.63 USD billon by 2026” despite the fact “that BPA is a significant contributor to long-term human exposure to EDCs [endocrine-disrupting chemicals].” Furthermore, BPA may accumulate in the human body, but further assessment is needed to investigate the related mechanisms. Cars and electronics are the driving force behind the expected increase of BPA on the market.
Despite scientific evidence for BPA-associated health implications, the authors write that regulatory action would be limited since regulators would mainly rely on guideline studies, leading “to scientifically invalid decisions.” The research program Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA) compared and integrated the results of guideline and academic studies on BPA effects. CLARITY-BPA found that guideline and academic studies came to different results (e.g., due to differences in sample sizes, sensitivity) and that the lowest BPA doses assessed had effects across organs including increased mammary cancer cases (FPF reported and here).
Hahladakis et al. summarized that currently set BPA limits were based on “four misguided assumptions: (i) dose-response curves are monotonic; (ii) below a threshold limit no effects are induced; (iii) both sexes (female, male) respond similarly to BPA exposure; and (iv) only toxicological guideline studies […] are valid.” They warn that costs due to human health incidents associated with BPA could outweigh those of replacing or banning BPA. The scientists call for the increased collaboration of researchers, risk assessors, governments, and policy-makers “to explore the impacts of BPA in the long term and introduce restrictions to BPA-based MCPs.”
In an article published on April 5, 2022, in the Journal of Food Composition and Analysis, Heba Shaaban and colleagues from Abdulrahman Bin Faisal University, Dammam, Saudi Arabia, analyzed levels and associated health risks of BPA and its analogues bisphenol F (BPF, 620-92-8), bisphenol S (BPS, CAS 80-09-1), D8 (4-Hydroxy-4′-isopropoxydiphenylsulfone, CAS 95235-30-6), and pergafast 201 (CAS 232938-43-1) in commonly consumed foods in Saudi Arabia. To this aim, they purchased 140 food samples belonging to seven groups (e.g., beverages, milk products, vegetables) that were packaged in plastics, glass, paper, or cans from retailers and local markets in the Eastern province of Saudi Arabia. After extraction, they quantified the target analytes by liquid chromatography-mass spectrometry (UPLC-MS/MS). The limits of detection of the optimized methods were between 0.003 and 0.015 µg/kg depending on the analyte.
Shaaban and co-authors detected BPA, BPF, and BPS in 84.3% of the analyzed food samples with an overall mean concentration of 23 µg/kg food. BPA was the most frequently detected compound (82.9% of the samples), while pergafast 201 and D8 were not detected in any sample. Comparing the different packaging types, the scientists found that canned food contained the highest levels of total bisphenols (23.8 mg/kg) followed by foods packed in plastics (7.68 mg/kg) and paper (3.53 µg/kg). Glass packaged samples contained 1.14 mg/kg on average. Analyses performed in 2018 and 2017 on cans sold on the Danish and the US markets measured BPA in 2 out of 13 food can coatings (FPF reported) and in 71 out of 78 cans (FPF reported), respectively.
Based on measured concentration, Shaaban and co-authors also calculated the estimated dietary intake (EDI) for the adult Saudi Arabian population to be 286.7 and 307.8 ng/kg body weight/day for males and females, respectively. In December 2021, the European Food Safety Authority (EFSA) proposed to lower the tolerable daily intake (TDI) of BPA from 4 µg/kg body weight/day to 0.04 ng/kg body weight/day (FPF reported). Consequently, Shaaban et al. concluded that “the dietary exposure to total bisphenols investigated in this study exceeded the updated TDI value of BPA, thus periodic monitoring of bisphenol A and its analogues in food chain is highly necessary to ensure consumer safety.” Since they only included exposure via consumption of selected foods, they think that their EDI underestimates exposures.
In a review article published on April 8, 2022, in the journal Critical Reviews in Toxicology, Patrícia Dias and co-authors from Charles University, Hradec Králové, Czech Republic, provide an overview of the potential impacts of bisphenols on the cardiovascular system and the shortages in that research field. The scientists searched PubMed for literature using a set of keywords and identified 112 relevant articles published until February 2022 that cover animal models and human population studies. They reported that research mainly covered BPA while data for other bisphenols was limited.
Looking at total serum levels, Dias et al. summarized that BPA was detected in concentrations of up to 430 nM and BPS of 680 nM. Even in micromolar concentrations, in vitro studies have demonstrated effects on ion channels and thyroid, oestrogenic, and androgenic receptors. Both the interaction with ion channels playing a role in vessel and heart contractibility and the endocrine activities could lead to potentially harmful vascular effects. Furthermore, the authors summarized that “bisphenols are also claimed to have a negative effect on lipidic spectrum and coronary artery disease.” Generally, data was found to be “inconsistent and unsatisfactory” and in vitro and in vivo studies come to contradictory results, e.g., reporting vasodilation and increase in arterial blood pressure, respectively. According to the authors, one reason for the observed difference may be that the studies used different and sometimes very high concentrations. They recommended studying doses corresponding to actual human exposure and to consider both males and females to capture potential gender-specific differences.
Concerning human population studies, Dias and co-authors reported that most were relatively recent and estimated exposure based on urine or blood serum concentration. Almost all suggested “an association between bisphenol exposure and harmful cardiovascular and endocrine alterations.” For instance, an epidemiological analysis published in October 2020 used data from the US National Health and Nutrition Examination Survey from 2003 to 2016 and reported a significant association between BPA and cardiovascular disease (FPF reported). Dias et al. recommend performing further studies on humans since they are lacking and on less researched bisphenols than BPA. For non-human studies, they emphasize using species that have the same toxicokinetics for bisphenols as humans, e.g. avoid using rodents since they excrete bisphenol conjugates into the bile as opposed to humans who excrete it into the urine.
One pathway to how bisphenols and other EDCs present in food contact materials can lead to endocrine disruption is by interacting with peroxisome proliferator-activated receptors (PPARs). PPARs are nuclear receptors regulating the expression of genes involved in glucose and lipid metabolism. In a study published on March 13, 2022, in the International Journal of Food Sciences and Nutrition, Federica Agosta and Pietro Cozzini from the University of Parma, Italy, identified food contact chemicals (FCCs) that bind to the three PPAR isoforms α, β/δ, and γ and analyzed the binding mechanism. Using molecular modeling, the researchers elucidated the characteristics of the binding pocket, i.e., the location where receptors bind the ligand.
FCCs that represent potential ligands were identified based on the chemical characteristics of the compounds and molecular docking and consensus scoring analysis “to study the best adaptation of each compound into the binding pocket and to classify them into high, medium, and low-affinity ligands.” Screening 3522 FCCs included in the Food Packaging Forum’s (FPF’s) Food Contact Chemicals database (FCCdb), the authors reported that 627 could bind to PPARα, 136 to PPARβ, and 762 to PPARγ. Of these, 33%, 19%, and 27% showed a high binding affinity for the three receptors, respectively. While of the potential PPARα ligands many (16.45%) belonged to the FCC categories of dyes and fatty acids, of the PPARγ high-affinity ligands 15% belonged to dyes and 13% to plasticizers. Agosta and Cozzini emphasized that identifying EDCs’ mechanisms of action is essential to identify safer alternatives and that computational approaches, such as the one they performed, can help to address this.
References
Agosta, F. and Cozzini, P. (2022). “Food contact materials as possible endocrine disruptors for PPARs: a consensus scoring analysis.” International Journal of Food Sciences and Nutrition. DOI: 10.1080/09637486.2022.2050998
Dias, P. et al. (2022). “The effects of bisphenols on the cardiovascular system.” Critical Reviews in Toxicology. DOI: 10.1080/10408444.2022.2046690
Hahladakis, J., N. et al. (2022). “An overview on the occurrence, fate and human risks of Bisphenol-A (BPA) present in plastic materials, components and products (MCPs).” Integrated Environmental Assessment and Management. DOI: 10.1002/ieam.4611
Shaaban, H. et al. (2022). “Simultaneous determination of bisphenol A and its analogues in foodstuff using UPLC-MS/MS and assessment of their health risk in adult population.” Journal of Food Composition and Analysis. DOI: 10.1016/j.jfca.2022.104549
