Open access peer-reviewed chapter - ONLINE FIRST
Abstract
Bisphenol-A (BPA) is a widely used chemical compound in the production of consumer items and building materials. Over the years, concerns have been raised about its potential adverse effects on human health. This chapter aims to explore the existing evidence regarding the association between BPA exposure and the risk of non-communicable diseases (NCDs). NCDs, such as cardiovascular diseases, diabetes, obesity, and certain types of cancer, are the leading causes of morbidity and mortality worldwide. Multiple studies have investigated the potential role of BPA in the development and progression of these diseases. Epidemiological studies have also provided evidence suggesting a link between BPA exposure and NCDs in humans. Several potential mechanisms have been proposed to explain the effects of BPA on NCDs, including its ability to mimic estrogenic activity and alter hormone signaling. A broader knowledge of the association between BPA and NCDs can inform public health policies and strategies aimed at reducing BPA exposure towards mitigating the burden of NCDs. In general, while the evidence regarding the association between BPA exposure and NCDs is still evolving, the existing literature suggests a potential link between BPA exposure and an increased risk of developing various non-communicable diseases.
Keywords
- bisphenol A (BPA)
- non-communicable diseases (NCDs)
- human health
- epidemiology study
- endocrine disruptor
1. Introduction
1.1 History of BPA use
A class of chemicals known as bisphenols has been widely used in the production of consumer items and building materials. The molecular structure of bisphenol consists mainly of two phenol moieties joined by links provided by various functional groups. Bisphenol A (BPA), also known as 2,2-(4,4′-hydroxyphenyl) propane, is the most widely used bisphenol [1]. The manufacture of plastics and resins frequently uses the organic synthetic chemical BPA. However, BPA has been classified as an endocrine-disrupting chemical (EDC) since it can alter the hormonal balance of living things [1]. BPA was originally synthesized in 1891 [2], and it first saw widespread industrial use in the 1950s when it was used to make epoxy resins and polycarbonate. BPA is synthesized by the condensation reaction of phenol with acetone [3].
The potential impacts of BPA on humans were first announced in 1997 when it was reported that BPA at even extremely low concentrations can have negative consequences [4]. Low doses of BPA in the womb were proven to increase prostate weights in male mice and decrease daily sperm production (Figure 1) [5].
1.2 Current applications of BPA
The global production of BPA is reported as 8 million tons [6], and by the end of 2023, the market will continue to produce 7300 k tons of BPA [7]. Fifty percent volume of the BPA is produced in North East Asia with China being one of the major producers of the world’s BPA market [2, 7].
One of the primary uses of BPA is the production of polycarbonate (65%), and epoxy-based resins (30%), and a small amount (2–5%) is used as a stabilizer and an antioxidant in the production of PVC and as a precursor in the manufacturing of a brominated flame retardant, tetrabromobisphenol A (TBBPA)[8]. Because of this, bisphenol A is utilized in the production of a wide range of goods, such as thermal (fax) paper, safety helmets, laminate that is bulletproof, plastic windows, auto parts, adhesives, protective coatings, powder paints, as well as the sheathing of electrical and electronic components [9, 10]. BPA is also utilized in the manufacture and processing of PVC, where it can act as an antioxidant and a reaction inhibitor.
2. Sources of bisphenol A exposure in the environment
BPA is a widely used synthetic organic compound. It is ubiquitous in our daily lives having found its use in various consumer products [11], including food and beverage containers, thermal paper receipts, epoxy resins, and medical devices [12]. Several health issues have been linked to exposure to BPA, making it essential to understand the sources of exposure to this chemical in the environment.
BPA is commonly used in producing plastic containers to package foods and beverages, which can increase the risk of exposure. Several studies have reported high levels of BPA in baby/water bottles, and other containers for packing food, which are made of polycarbonate plastic [11, 13, 14, 15]. The leaching of BPA into the food can be exacerbated when these containers are heated or when they come into contact with acidic substances, such as tomato sauce or citrus juice [15].
Thermal paper receipts are another source of exposure to BPA which is commonly used as a color developer in carbon-less copy papers used as a receipt at points-of-sales, and to generate a print on faxes, bus tickets, Automated Teller Machine (ATM) receipts, and labels, fixed on retail goods [16, 17]. BPA can easily transfer to the skin when such thermal papers are touched [18]. People that handle thermal paper receipts frequently, such as cashiers, are therefore at risk of increased exposure to BPA.
BPA is also used to manufacture medical devices, including catheters and tubes, enteral feeding tubes, blood bags, dialysis equipment, nasogastric tubes, injectors, granule, medical pipes, injectors, bags, and infusion sets used in dialysis and parenteral nutrition, dental filling materials used in dentistry, extracorporeal oxygenation devices, film tablets used in the pharmaceutical industries and so on [19]. When these devices come into contact with bodily fluids or are heated, BPA can leach out, increasing the risk of exposure [20]. Medical professionals and patients who use medical devices frequently may be at risk of increased exposure to BPA. BPA can also be found in other consumer products, such as electronic devices, toys, and household appliances. BPA is also present in the environment, as it can be released from plastic waste and industrial runoff [17]. Additionally, BPA can be found in some canned foods, as the chemical is used in the lining of the cans [21].
Generally, BPA exposure can occur via several sources in the environment, and enter the human body via ingestion, inhalation, eye contact, materno-fetal transmission, and skin. In the body, it can deleteriously target numerous organs and tissues, such as adipose tissue, the thyroid, the heart, the liver, and the reproductive systems as in Figure 1 [12]. Reducing exposure to BPA may require avoiding products made with BPA or choosing BPA-free alternatives whenever possible (Figure 2).
Figure 1.
Chemical reaction for BPA synthesis.
3. Mechanisms of bisphenol A toxicity
The primary mechanism of BPA is its endocrine-disrupting properties. BPA possesses a high binding affinity to many of the receptors on the surface of body cells such as; estrogen receptors (ERα and ERβ), androgen receptors (AR), G protein-coupled receptors (GPCR), estrogen-related receptors (ERRs), and epidermal growth factor receptor (EGFR) [22]. BPA was earlier reported to mimic the effects of estrogen in the body, binding to and activating estrogen receptors (ERs) and disrupting the endocrine system as in Figure 2 [23]. BPA widely targets and modulates many other pathways that relate to metabolisms in endocrine, reproductive systems and steroid biosynthesis leading to a series of hostile health effects, such as developmental disorders, reproductive abnormalities, and cancer [23].
Figure 2.
Bodily exposure to BPA from the environment and targets.
Exposure to BPA has also been reported to in Exposure to BPA increases oxidative stress and inflammation in the body. Oxidative stress is the discrepancy between the generation of reactive oxygen species (ROS) in the body and the ability to offset them with antioxidants. BPA exposure has been reported to increase the production of ROS and decrease antioxidant activity, leading to oxidative stress and cellular damage; as well as inducing inflammation in the body that can result in tissue damage and disease [24, 25]. Another potential mechanism of BPA toxicity is its effects on epigenetic regulation. Epigenetic modifications, such as histone modification and DNA methylation, can alter the expression of certain genes without altering the sequence of DNA. BPA exposure has been shown to alter DNA methylation patterns and modify histone structure, resulting in changes in gene expression and potential health effects [12]. Other studies have also reported that exposure to BPA can induce cell death, disrupt mitochondrial function, and alter neurotransmitter signaling [25, 26, 27]. However, further research is necessary to fully elucidate the mechanisms behind these effects (Figure 3).
Figure 3.
Steps in the mechanism of endocrine disruption by BPA. ER is an endocrine receptor and HS is hormonal signaling.
4. Epidemiological evidence of bisphenol A link to non-communicable diseases
BPA is an endocrine-disrupting chemical that has been linked to several non-communicable diseases, including obesity, diabetes, cardiovascular disease, reproductive disorders, and cancer [28, 29, 30]. Epidemiological studies have examined the association between BPA exposure and these diseases, with some providing evidence of positive associations [31, 32]. The mechanisms underlying these associations are not fully understood but may involve BPA’s ability to interfere with the hormonal regulation of metabolism and other physiological processes [28, 32].
Human studies indicate a positive correlation between BPA exposure and the incidence of non-communicable diseases [33, 34]. For instance, a study analyzing data from NHANES discovered that individuals with higher levels of urinary BPA had higher rates of obesity, insulin resistance, and type 2 diabetes [35, 36]. Another study found that higher levels of BPA were associated with a greater likelihood of coronary artery disease in individuals with metabolic syndrome [37]. Multiple studies have demonstrated a connection between urinary BPA concentrations and obesity, type 2 diabetes, and coronary artery disease [37, 38]. Additionally, BPA exposure has been suggested to cause reproductive toxicity, including hormonal imbalances and alterations in sperm quality in both males and females [39, 40].
BPA exposure has been linked to non-communicable diseases in animal studies as well. For example, a study conducted on rats found that prenatal exposure to BPA resulted in decreased testicular weight and sperm production in male offspring [40, 41, 42]. Similarly, exposure to low doses of BPA during pregnancy and lactation led to an increased risk of developing obesity and diabetes in female offspring in a study conducted on mice [41, 43]. Studies on rodents have revealed that maternal exposure to BPA during pregnancy and lactation can lead to adverse effects on mammary gland development and reproductive function [43, 44, 45]. Additionally, BPA exposure has been associated with an increased risk of cancer in animal models, with evidence suggesting that it may promote tumor growth and increase cancer stem cell population [34].
Although evidence links BPA exposure to non-communicable diseases, there are limitations and inconsistencies in the studies [46]. While some have reported no significant associations between BPA exposure and disease outcomes, others have found varying strengths of association by disease [47]. A 2020 systematic review and meta-analysis did not identify a clear link between BPA exposure and cancer risk [46]. Furthermore, the existing evidence is primarily based on observational studies, which cannot establish causality and may be subject to confounding and reverse causation biases.
The mechanisms behind BPA-induced non-communicable diseases are not completely understood, although various hypotheses exist. BPA can bind to estrogen and androgen receptors, leading to changes in gene expression and epigenetic modifications [48, 49].
BPA disrupts hormonal regulation of metabolism, alters glucose metabolism, and causes inflammation and oxidative stress [29, 50, 51]. BPA can interfere with insulin signaling, causing increased insulin resistance and impaired glucose metabolism [52]. Furthermore, BPA binds to estrogen receptors and inhibits glucose transporter 4 (GLUT4) transport, leading to decreased glucose uptake and insulin resistance [53]. It also lowers adiponectin levels and promotes the accumulation of visceral fat, increasing the risk of metabolic disorders [54]. The development of cancer and cardiovascular disease is further aided by the pro-inflammatory and oxidative stress responses that BPA exposure triggers. It encourages the generation of reactive oxygen species (ROS), which leads to DNA damage and the emergence of cancer, and boosts the expression of pro-inflammatory cytokines including interleukin-6 (IL-6) and tumor necrosis factor-alpha [29, 51]. BPA exposure alters the expression of genes involved in lipid metabolism and adipogenesis, leads to insulin resistance, and impairs glucose tolerance [52, 55]. Additionally, it promotes the proliferation of breast cancer cells and increases tumor growth in animal models [56, 57]. In-vitro and animal studies have also shown that BPA disrupts hormone signaling pathways, alters glucose uptake, and promotes the development of adipocytes, inflammation, and oxidative stress [53, 54].
To stop the onset of these disorders, measures to minimize BPA exposure should be a top public health priority. More study is required to fully understand the processes behind this link. Potential modes of action for BPA include modifying glucose metabolism, upsetting hormonal control of metabolism, and inducing oxidative stress and inflammation, all of which may be harmful to human health.
5. Factors affecting BPA exposure and susceptibility to disease
Numerous non-communicable disorders have been associated with BPA. However, several variables may affect the extent of exposure and vulnerability to BPA-associated illnesses.
5.1 Factors affecting BPA exposure levels
5.1.1 Age
Age is an important factor to consider when assessing BPA exposure levels. Infants and young children are at higher risk of BPA exposure than adults because of their immature metabolic systems and higher food intake relative to their body weight [43]. Moreover, fetuses can also be exposed to BPA as it crosses the placenta and alters the development of organs and tissues [42]. Prenatal BPA exposure has been linked to adverse neurodevelopmental outcomes, including attention-deficit hyperactivity disorder and behavioral problems [58, 59].
5.1.2 Sex
Sex is another factor that could affect BPA exposure levels. Females were reported to have higher urinary BPA concentrations than males, which could be attributed to differences in the metabolism and elimination of the compound between the sexes [60]. Moreover, hormonal fluctuations during the menstrual cycle and pregnancy can affect BPA metabolism and excretion, leading to higher exposure levels in females [61].
5.1.3 Diet
Diet is a significant source of BPA exposure as it is present in food containers, particularly those made of polycarbonate plastics, epoxy resins, and thermal paper. Foods that are acidic or high in fat content are more likely to contain higher levels of BPA, as the compound can leach from the container and bind to fat molecules [62]. A study showed that canned food products had higher BPA content than freshly prepared meals, indicating the potential contribution of BPA exposure from canned foods [63].
5.1.4 Environmental factors
BPA can also be present in the environment, such as in the air, water, and soil, and people who live near industrial facilities or landfills may be at increased risk of exposure [28].
5.2 Factors affecting susceptibility to BPA-induced disease
5.2.1 Genetics
Genetic susceptibility to BPA-induced diseases is a critical factor to consider in understanding the health risks of BPA. Genetic polymorphisms in genes related to the metabolism and detoxification of BPA have been linked to an increased risk of developing diseases such as obesity, diabetes, and cardiovascular disease [64]. The metabolism of BPA is mediated by enzymes such as UDP-glucuronosyltransferases (UGTs) and cytochrome P450s (CYPs), which are encoded by polymorphic genes. Polymorphisms in these genes can affect the expression and activity of these enzymes, leading to a variation in BPA metabolism and susceptibility to diseases [65].
5.2.2 Pre-existing health conditions
Pre-existing health conditions such as obesity and diabetes can also increase the susceptibility to the adverse effects of BPA exposure. These conditions are associated with a higher risk of developing metabolic disorders and cardiovascular diseases and have been linked to changes in metabolism, inflammation, and oxidative stress [66]. BPA exposure can exacerbate these effects by triggering insulin resistance, oxidative stress, and inflammation and increasing the production of advanced glycation end products (AGEs), which are linked to diabetes and cardiovascular disease [67].
5.2.3 Hormone levels
BPA can interfere with hormone signaling in the body, and individuals with abnormal hormone levels or hormone-related disorders may be more susceptible to BPA-induced health effects [47]. Also, the effects of BPA exposure may be more severe in certain age groups, such as infants and the elderly, due to differences in hormone levels, metabolism, and immune function [41, 68].
5.2.4 Exposure level
Additionally, exposure to other environmental chemicals, such as phthalates, bisphenol S (BPS), and flame retardants, can enhance the effects of BPA and increase susceptibility to non-communicable diseases [68]. These compounds are present in food packaging, personal care products, and household items, and have been shown to have similar or synergistic effects to BPA, amplifying the health risks associated with their exposure.
Food intake is the commonest route of BPA in man and it predisposes man to various non-communicable diseases (NCDs) like cancer, infertility, type-2 diabetes mellitus, cardiovascular diseases, and obesity due to its endocrine-disrupting property [69]. NCDs account for the majority of deaths globally. BPA exposure contributes to the high incidence of NCDs. Despite numerous reported adverse effects of BPA, it is still being used in food packaging and other consumer products. In a nationally representative cohort of US adults, Bao et al. [70] reported that higher BPA exposure was significantly associated with an increased risk of all-cause mortality among US adults.
6. Areas for future research to improve our understanding of the relationship between BPA exposure and NCDs
6.1 BPA and mesenchymal stem cells (MSCs)
MSCs are multipotent cells present in mesenchymal tissues. Sources of MSCs are lungs, muscles, adipose tissue, placenta, umbilical cord, dermis, and dental tissue. However, they are more prominent in bone marrow [71]. Recently, MSCs have been discovered to represent potential target cells for BPA [72, 73]. The pro-adipogenic effect of BPA is widely reported. BPA enhances adipogenic signaling pathways in human mesenchymal stem cells [74, 75]. This may explain its role in the perpetuation of obesity. In an in vivo study of BPA-mediated action on MSCs using animal models, intrauterine exposure to BPA-induced obesity in the newborn [76]. Other studies on prenatal BPA-induced epigenetic changes in MSCs corroborate the enhancement of adipogenesis [77]. Therefore, current research is targeted on MSCs as a possible therapeutic tool for the treatment of BPA-induced tissue damage [78].
6.2 Use of human models
The fetus is the most vulnerable to BPA exposure as there are ample reports of increased risk of metabolic syndromes and other diseases later in life. There are reports of BPA influencing brain and behavioral changes in animal models and human studies. Gestational exposure to BPA during developmental stages affects emotional, cognitive social, and sexual behaviors in children [79]. However, most studies were carried out using animal models. Therefore, research using a human model is advocated to evaluate the impact of gestational exposure to BPA.
6.3 Epigenetic studies
According to Cariati et al. [80], exposure to BPA can induce epigenetic modifications in both animal and human cells. Such modifications could contribute to male reproductive disorders and cancer development which can also be transmitted to offspring. Understanding the mechanisms underlying BPA-related epigenetic changes in paternal sperm and offspring phenotype is key to finding appropriate therapies to reduce the impact of BPA-induced dysfunctions.
Research on genome regulatory impacts of environmental exposures and their relationship with the risk of NCDs could present some desirable health impacts. Development of polygenic risk scores (PRS) for NCDs, and assigning phenotypic impacts to BPA can help predict an individual’s genetic propensity with the BPA exposure risks associated with NCDs traits [81]. Hüls et al. [82] demonstrated associations between high PRS for obesity and sociodemographic and lifestyle factors in obese children. Similarly, Ye et al. [83] in a study of cardiovascular disease and type 2 diabetes reported a significant link between PRS and an improved disease status upon adherence to a modified lifestyle. Thus, PRS can be utilized to determine the phenotypic impact of BPA exposure and vulnerability to NCD.
6.4 Increase in prenatal screening for NCDs
Early detection of disease at the preclinical stage before clinical manifestation especially in newborns is necessary. This way, prevention, reduction in disease burden, improvement in population health and quality of life, and reduced health care costs would be achieved. The prenatal period is particularly vulnerable to environmental exposures because of rapid cellular differentiation and development. Thus, measurements of epigenetic marks in early life can be used as biomarkers to identify individuals who have experienced environmental perturbations like BPA exposure during development, and thus who are more likely to develop NCDs later in life [84]. More so, epigenetic markers like those involved in DNA methylation and histone modifications have been reported as possible molecular biomarkers of BPA-induced prostatic carcinoma progression [85].
6.5 Improved cohort studies
There is a scarcity of information on cohort studies. Cohort studies are important in identifying the relationship among early life exposure, genetics, and development of NCDs. Therefore, longitudinal studies like cohort studies are advocated to throw more light on epigenetic mechanisms by which BPA exposures and genetics predispose to the development of NCDs in later life and across generations [86].
7. Level of social awareness of BPA/BPA products toxicity/possible adverse effects on human health in developed and developing nations
Bisphenol A and its associated toxicity are known in most European countries and the United States of America but are still unknown to the public in most countries in Africa. Nigeria and Uganda for example have no existing regulations/laws on the use of BPA and BPA-related products. Boudalia and Oudir (2016) reported that there is a paucity of information on the sources and extent of BPA exposure in most of the developing countries in Africa, South East Asia, and South and Central America. The authors also observed that South Africa, Brazil, and Colombia have passed some legislation on BPA use in food contact materials. Also, Pouokam et al. (2014) reported that in Nigeria and Cameron, the meaning of the label BPA-free in some plastic containers such as plastic baby bottle is unknown to both vendors and customers, and the BPA toxicity is also largely unknown to policymakers, and media. Therefore, there are no regulations/existing laws on BPA toxicity in food contact materials. The wide availability of BPA-containing baby bottles, food packaging plastic materials, lack of information, and usage patterns (e.g. temperature and duration of heating) suggest a likely widespread exposure of the African population. Though a lot of scientific studies and publications on the possible toxicity of BPA using animal models have been carried out in Nigeria and Uganda. More scientific data and advocacy are needed from Africa to attract the attention of regulatory bodies in charge of the use of chemicals, policymakers, and the Government to come up with legislation on the exposure and use of BPA-made plastic materials in food packaging to avoid an outburst of possible non-communicable diseases associated to BPA exposure.
8. Governmental measures on BPA/BPA products in developed and developing nations
In industrialized nations like Europe, the United States of America, and part of Asian countries there are existing laws/regulations on BPA exposure. International regulatory bodies such as the US Food and Drug Administration (FDA), the European Food Safety Authority (EFSA), and the International scientific community had launched a broad program on the evaluation and investigation of the adverse potential effect of BPA, on human and animal endocrine pathways and health. And these efforts have resulted, in the ban of BPA-made plastic food and water containers/materials in countries like France, Canada, Belgium, Denmark, Sweden, Brazil, Colombia, most states in the United States of America, and even South Africa (Baluka and Rumbeiha, 2016). Apart from South Africa, there is no other country in sub-Saharan Africa that has laws/regulations on the exposure of BPA products to humans or animals.
9. Conclusion
NCDs kill 41 million people each year which is equivalent to 74% of all deaths globally and a majority of this death occur in low and middle-income countries. Among these deaths, cardiovascular diseases account for the highest followed by cancer, chronic respiratory diseases, and diabetes. These four diseases account for over 80% of NCD-related deaths. Evidence abounds suggesting BPA is a contributor to the incidence of these four diseases and a cause of adult mortality even in developed countries. Recently, BPA exposure is fingered to be associated with an increased risk of mortality among US adults. Thus, arresting BPA exposure could curb the prevalence of these diseases and enhance longevity.
10. Recommendations for reducing BPA exposure and mitigating its potential health risks
10.1 Global
There should be global policies and plans aimed at curbing the indiscriminate use of BPA and related compounds especially in food packaging since diet is the main entry route.
Research for NCDs prevention and control should be supported and encouraged by agencies like WHO, UN, UNICEF, etc.
Effective monitoring of NCDs trends and regular dissemination of information crucial to mitigating NCDs.
10.2 National level
Enhancement of funds budgeted for an effective healthcare system targeted towards prevention and control of NCDs.
Good policies and plans to minimize the unguided use and disposal of products that contain BPA like plastics should be enforced.
Collaborative engagements with partners like research organizations, schools, and other private bodies in the fight against NCDs and finding better alternatives to BPA.
10.3 Individuals
Adoption of a healthy lifestyle through good nutritional practice, regular exercise, and timely medical attention can minimize risks to NCDs.
Minimizing exposure to BPA can minimize risks to NCDs.
Conflict of interest
The authors declare no conflict of interest.
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