{"paper_id":"8811a197-fb70-4b5f-97a1-fcc6140a3594","body_text":"Every day, humans are exposed to natural and synthetic chemical compounds, including xenoestrogens, which are similar to female hormones. These exogenous compounds may interact with the human hormonal system, leading to homeostasis disorders by modulating both estrogenic activities and androgenic activity itself [ 1 ].\nThe presence of anthropogenic endocrine disruptors (ECDs) in various elements of the environment is a direct or indirect threat to humans, as indicated by biomonitoring studies on the systemic distribution of biomarkers of human exposure to this group of compounds. ECDs are present in tissues, human body fluids, and breast milk, as well as in food, despite the introduction of restrictions on their use. The biomonitoring of compounds that adversely affect human health is an indispensable tool for assessing the risks related to environmental pollution while providing a substantial basis for risk management. Tracking trends regarding the levels of these compounds in various elements of the environment, including humans, is particularly important due to the toxicological properties of ECDs. The results of biomonitoring are an important element used in risk assessment, along with toxicological data, to enable the determination of the point of departure (PoD) when determining hazard profiles (HQ), or for preparing statistical models that, based on population data (age and gender) and the levels of biomarkers for selected chemical groups, can be used to determine the total concentrations of specific environmental pollutants in the human body. For a biomonitoring-based risk assessment, PoD can be defined as an internal exposure–response point that marks the threshold above which the incidence begins to increase. This approach also considers the fact that the internal exposure, expressed as serum concentrations above PoD, as being of concern. This is especially important in the case of xenoestrogens, for which a diverse geographical distribution and tissue distribution and different rates of release of individual compounds from the human body depending on age and sex have been demonstrated. This direction of research, which uses a holistic approach to describe the relationship between simultaneous exposure to a multitude of different risk factors and the body’s response, is a major public health challenge [ 2 , 3 , 4 , 5 , 6 ].\nAn essential and main area of interest for various research centers is the monitoring of risk markers of substances that tend to accumulate in humans and to determine their impact on health in different human populations. However, researchers are less interested in those xenobiotics that do not exhibit bioaccumulation properties. Xenoestrogens, which are classified as endocrine-disrupting chemicals (EDCs), have been of special interest for many years and are a subject of growing concern, especially regarding their potential biological risks, including the internal risk that comes from releasing deposits formed in the human organism. According to the WHO Classification, EDCs include esters of phthalic acid, bisphenols, polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), perfluoroalkylated substances (PFASs), bromoorganic flame retardants (FRs, e.g., polybrominated diphenyl ethers (PBDEs)), tributyltin (TBT), and parabens [ 1 , 2 , 7 , 8 , 9 ]. Among them are both persistent and less-persistent compounds. There is a lot of information in scientific publications about the impacts of POPs, such as PCBs, PBDEs, and PFASs, on human health. However, there are fewer studies on less-persistent compounds. Therefore, in this study, special attention was paid to the less-persistent EDCs, such as bisphenol A (BPA), benzo-α-pyrene (a representative of PAHs), and parabens (PHBs), due to their frequent use in various areas of daily human life.\nXenoestrogens are absorbed by humans, mainly through the digestive system, since they can migrate to food from food packages and drinks as well as from plastic products used daily [ 1 , 10 ]. For humans, the main source of such chemicals is food, mainly processed and packaged food. Their absorption from cosmetics and household chemicals should also be noted through direct dermal contact. Humans can take up EDCs, or precursors of EDCs, also by inhaling them, e.g., with cosmetic products. Human exposure varies considerably and depends on individual habits (e.g., food choices) and the locations where people work and live [ 1 , 7 , 8 , 10 , 11 ]. We spend about 90% of our lives in enclosed spaces. Sources of human exposure to EDCs have also been identified in indoor environments, such as homes and the workplace. Materials for building construction, furnishings, carpets, textiles, etc., are present in indoor environments. These lead to common classes of chemicals, such as formaldehyde, pesticides, phthalates, PCBs, brominated flame retardants, and parabens, being found in indoor air and dust [ 12 , 13 , 14 , 15 , 16 , 17 ].\n\nThe material was prepared based on a meta-analysis of research on the impact of selected EDCs on the health of a specific group of people. The review was limited to research published in peer-reviewed journals or other peer-reviewed studies as per the checklist of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [ 18 ]. Data were collected by the manuscript author by systematically searching electronic databases of scientific publications, such as PubMed and Web of Science. Studies were included in this systematic review when the following criteria were met: (1) prospective cohort; (2) definitions of EDCs were in accordance with WHO definition; (3) concentration of chemicals was measured using biological specimens; (4) risk estimates including risk for described population (age, gender, place of residence). When selecting and rejecting publications, it was considered that the presented data were representative, i.e., the amount of data from individual continents was comparable. It was particularly important when selecting biomonitoring data.\n\nIt has been proven that the mechanism of EDCs’ toxicity is based on their mimicry of endogenous hormones. The structural similarity of xenoestrogens to steroid sex hormones results in their easy association with estrogen and androgen receptors through competitive binding (a ligand with a chemical structure similar to estradiol’s associates with an estrogen receptor and activates it). The mechanism by which a chemical disrupts hormone action has a very large impact on the pattern of effects one would expect to observe. Generally, there are two pathways by which a chemical could disrupt hormone action: a direct action on a hormone receptor protein complex, or a direct action on a specific protein that controls some aspect of controlling hormone delivery to the right place at the right time. This could be a protein that is involved in hormone production (e.g., aromatase), an important transporter (e.g., sodium/iodide symporter), or a carrier protein (e.g., cortisol binding protein). EDCs act as antagonists of hormones. They may block estrogen receptors or, via the receptor, inhibit the activity of endogenous hormones. Xenoestrogens have multiple mechanisms of action, interact with different receptors, and affect the entire hormonal system. These involve the aryl hydrocarbon receptor (AhR), which regulates the expression of several genes, including the cytochrome P450 (CYP-1) gene family members and glutathione S-transferase M, which mediates many of the responses to environmental toxic chemicals. They influence synthesis, decomposition, or elimination from the system as well as hormone bio-accessibility; for example, they may directly influence gene expression by limiting the concentrations of protein-binding sex hormones [ 19 , 20 , 21 , 22 ]. Due to their similar influence on humans—that is, their sex-hormone-imitative effects on estrogen receptors as well as their similar toxicological properties and wide uses in different areas of life, both as a group or individually—xenoestrogens are the subject of various research studies with the aims of explaining their range of impacts on the human organism, conducting risk assessments, and consequently, determining their influences on health [ 6 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ].  Table 1  presents the concentrations of selected EDCs in human biological materials. The data were selected to be representative both for a given geographic region and for a given country.\nThe presence of these chemicals in the human organism is considered a potential cause of some diseases, commonly referred to as ‘diseases of civilization’. The notion of ‘diseases of civilization’ is used to describe certain ailments whose etiology is difficult to explain based on knowledge about the functioning of the body and its metabolism. Only studies at the cellular level and biochemical changes have shed light on the causes of some diseases described as diseases of civilization (cancers, cardiovascular and respiratory diseases, obesity, psychomotor disorders in children, and malformations or neurodegenerative diseases that have increased in frequency). For example, over the past 20 years, the incidence of mental and behavioral disorders has increased by more than 37% (Parkinson’s disease has increased by 75%, Alzheimer’s disease has doubled, autism has increased by 30%, and attention deficit hyperactivity disorder (ADHD) has increased by 16%) [ 1 , 30 ]. Recent studies on the impact of EDC on the functioning of the human body focus on changes in physiology, behavior, and biochemical mechanisms in connection with the circadian cycle. Extensive bidirectional crosstalk exists between circadian and endocrine systems, and circadian rhythmicity is present at all levels of endocrine control, from synthesis and release of hormones to sensitivity of target tissues to hormone action. In mammals, a range of hormones directly alters clock gene expression and circadian physiology via nuclear receptor (NR) binding and subsequent genomic action, modulating physiological processes such as nutrient and energy metabolism, stress response, reproductive physiology, and circadian behavioral rhythms. Because EDCs mimic the action of hormones in the body and the potential of these compounds to disrupt the circadian rhythm is still insufficiently characterized, hence the new focus of research on this aspect. These studies concern: dysregulated core clock and circadian rhythm network gene expression in brain and peripheral organs, and altered circadian reproductive, behavioral, and metabolic rhythms. Circadian impacts occurred in parallel to endocrine and metabolic alterations such as impaired fertility and dysregulated metabolic and energetic homeostasis [ 32 , 33 ].\nNumerous research studies, as shown in  Table 2  and  Table 3 , have provided evidence that the main sources through which human beings come into contact with this type of chemical are processed and packaged foods as well as food contact materials (FCMs). This mainly concerns bisphenol A and PAHs [ 34 , 35 , 36 , 37 , 38 ].  Table 2  and  Table 3  present the concentrations of selected EDCs in foods, food contact materials, and selected daily use products.\nBy considering the occurrence of selected EDCs in the environment, their wide use in different areas, and the biomonitoring results, it was possible to link the roles of these chemicals to the process of the development of various diseases that have shown a growing incidence in recent years.\nThe aim of this paper was to review data on the impacts of selected anthropogenic chemicals from the group of endocrine disruptors on various diseases, including ‘diseases of civilization’. These chemicals may facilitate the prevention of these diseases and be used as tools in managing public healthcare.\n\nPhthalates are esters of phthalic acid that belong to a group of chemicals that are widely used as emollients in plastic production, e.g., in the production of polyvinyl chloride (PCV). They are present in medical equipment (e.g., intravenous tubes, blood bags, and masks), building materials (e.g., insulating cables, pipes, and wallpaper), car equipment, toys, and home equipment and are used as additives in the textile industry, as carriers in pesticide formulations, as coatings in time-release pharmaceuticals, as industrial solvents, and as lubricants. Phthalates are also added to cosmetics (perfumes, sprays, paints, and fragrances) and household chemicals [ 1 , 40 , 42 , 43 ]. The ones used most widely phthalates are benzylbutyl phthalate (BBP), di- n -butyl phthalate (DBP), di-2(2-ethylhexyl) phthalate (DEHP), and nonylphenol phthalate (NP). Their wide use in various areas results in humans being exposed to these chemicals through different sources throughout their lifetimes. The main sources of phthalates are foods, drinking water, and house dust [ 8 , 35 , 38 ]. The presence of phthalates in the human organism (see  Table 1 ) causes disorders of hormonal homeostasis, which negatively influences health. Based on numerous biomonitoring research studies, it has been proven that phthalates contribute to thyroid disorders, asthma, and allergies due to their presence in household dust. Phthalates may interfere with the thyroid gland, e.g., within the conduction of signals regarding the synthesis, transport, and level of TSH circulating in the serum. The presence of phthalates in the body can also negatively affect free and total T3 levels in children. These disorders may also affect the courses of biochemical processes, i.e., the proper working of various organs [ 26 , 44 , 45 ]. Moreover, phthalates influence the reproductive systems of both men and women. In men, exposure to phthalates results in disorders of cell differentiation and the development of androgen-dependent tissues and gonadal disorders. Furthermore, following risk exposure during the growth period, gonadal dysgenesis, and testicular and epididymis reduction as well as pathological and biochemical changes in the testicles, necrosis of the seminiferous tubule epithelium, lower sexual reproduction as a consequence of changes in the structure and functioning of the epididymis, and reductions in sperm quantity and quality can occur, which may lead to male infertility [ 1 , 46 ]. In women, phthalates may influence the development of endometriosis and fibroids. Exposure to phthalates during pregnancy and lactation may cause disorders of the reproductive system in offspring. Risk assessment for phthalate exposure presents an additional challenge because of the interactions between different pollutants and the complexity of interactions in the endocrine system [ 1 , 10 , 24 , 26 , 28 , 30 , 46 , 47 ]. Detailed information is provided in  Table 4 .\nThe most common is bisphenol A (BPA), which is used in the production of epoxy resins, polycarbonate plastic (PC), and other plastics and in the production of thermal paper (e.g., POS receipts). Plastics are used to produce food and drink packages, disposable products (e.g., plates and cups), microwave containers, children’s toys, plastic coatings (e.g., in food cans), water storage tools, and other daily use products. BPA may be detected in all these products and items. Bisphenol A is also used to produce food contact materials (FCMs), epoxy resin paints, printing ink, and flame retardants (FRs). Moreover, bisphenol A is used as an antioxidant in foodstuffs and cosmetics [ 1 , 8 , 10 , 35 , 36 , 41 ]. As shown in  Table 2 , the main sources through which humans come into contact with bisphenol A are foods and drinking water. Humans are also at risk of coming into contact with this compound through thermal paper, CDs, paints, glue, and electronic devices as well as through outdoor and indoor air in closed spaces due to the absorption of these chemicals in suspended dust. Bisphenol A enters the human organism through the digestive system, the breathing system, and the skin. It may be released from plastics and therefore may be present in foods, drinks, and baby food, especially if the packaging is warmed up, washed with detergent, or mechanically changed (pressed or extended). The main risk groups are infants and small children due to their low body weights and the ever more frequent use of plastic bottles, cups, plates, and spoons made from materials containing BPA. The European Food Safety Agency (EFSA) estimated that the total risk for infants and children of contacting BPA from food and non-food sources is slightly below the tolerable daily intake (TDI) of 4 μg × kg −1  bw × day −1 . The risk was found to be lower in adults [ 9 , 29 , 34 , 35 ]. Exposure to BPA can have many health consequences, especially during the prenatal period. Numerous studies have confirmed that the presence of a high amount of BPA in the mother’s urine is associated with a lower body birth weight in the child. Additionally, changes in the reproductive systems of boys, changes in behavior (anxiety, depression, and increased aggression), and dysfunctions in thyroid function are frequently observed. For example, the exposure of pregnant women to BPA was shown to cause a decrease in the T4 concentration in women and a reduced TSH concentration in newborns. However, the authors indicated that these results were not statistically significant, but similar results have been obtained in various research centers [ 36 , 50 ]. A positive correlation between the concentration of BPA and obesity, which starts with an aggressive increase in body weight in the first 6 months of a child’s life, has been identified in both sexes [ 1 , 8 , 10 , 24 , 34 , 46 , 50 ]. Detailed information is presented in  Table 5 .\nParabens are esters of para-hydroxybenzoic acid (PHBA) with different functional groups. They have fungistatic activity and weak antibacterial activity. The most widely used parabens are those with straight-chain alkyl groups, such as methylparaben (MP, E218), ethylparaben (EP, E214), propylparaben (PP, E216), butylparaben (BP), and heptylparaben (HP, E209). Less significant parabens are those with branched alkyl groups, such as isopropylparaben and isobutylparaben, as well as aryl groups, such as benzyl paraben. Sometimes, their salts are also used [ 1 , 38 ]. Due to their widespread use, humans are at risk from these chemicals through the consumption of foods whose production involves the use of preservatives from the paraben group. Risk also comes from skin contact, since parabens are commonly used in various cosmetics (e.g., soaps, shampoos, creams, etc.) [ 1 , 38 , 40 ]. Parabens do not bioaccumulate in the human organism; they are eliminated through the urine and feces [ 28 , 56 ]. Parabens are commonly considered to be chemicals that are ‘safe for human health and life’; however, the WHO classifies them as non-persistent EDCs, as they show agonistic activity towards estrogen receptors [ 1 ]. They may contribute to the development of breast cancer, inappropriate development of the male reproductive system during the fetal period, or unfavorable changes in the uterus [ 1 , 3 ]. They may also cause food and contact allergies as well as contact dermatitis [ 1 , 28 , 56 ].\nPolycyclic Aromatic Hydrocarbons develop as a result of incomplete thermal burning or through pyrolysis during the treatment of organic materials. They are complex chemicals that may consist of numerous combinations [ 1 , 11 ]. There are various sources through which people may be exposed to this group of chemicals. The main risk for non-smokers is processed foods, whereas for smokers, the risk from smoking is comparable to the risk from processed foods. Another health issue is exposure to PAHs while breathing, especially occupational exposure to PAHs (e.g., at waste incineration plants, crude oil refineries, and coke, asphalt, and aluminum production facilities) [ 1 , 39 , 57 , 58 , 59 ]. Foods may be contaminated by these chemicals by environmental sources as well as through food preservation methods (e.g., heating, drying, and smoking) and cooking processes (e.g., grilling and baking) [ 1 , 11 , 58 , 60 ]. Based on environmental monitoring studies, including those on foods, it was concluded that benzo-α-pyrene (BaP) may be used as a marker of exposure to the entire PAH group and to determine the margins of exposure (MOEs) for this group of compounds [ 11 ]. The WHO [ 1 ] classified benzo-α-pyrene as a chemical that has been proven to have endocrine-disrupting activities that affect human homeostasis (EDCs). The EFSA [ 11 ] found that the median risk for Europeans coming into contact with benzo-α-pyrene through food consumption is 235 ng × day −1  (3.9 ng × kg bw −1  × day −1 ). The main sources of PAHs are cereals, cereal products, and seafood (see  Table 2 ). Epidemiological tests have concluded that PAHs have cancerogenic activity, e.g., contributing to lung cancer, as well as genotoxic and mutagenic activity, while BaP is a major promotor of pancreatic cancer and colorectal adenoma. Due to its affinity for fat, BaP is also detected in female milk, which puts babies at risk from the first days of their lives [ 1 , 38 , 60 , 61 ]. This is particularly important because of the influence of these chemicals on human reproductive activities. Their presence in the human organism can lead to male infertility due to competition for aryl hydrocarbon receptors (AhRs) [ 1 , 62 ]. In women, it leads to malfunction of the ovaries, which may result in premature menopause [ 61 , 63 ]. Detailed information is provided in  Table 6 .\n\nThe biomonitoring of xenoestrogens, which are chemicals with an unfavorable impact on human health, is a crucial tool that can be used to assess the risk caused by anthropogenic pollution from the group of endocrine disruptors. It is also an essential element in risk assessment for diseases of civilization. This mainly applies to chemicals with real or potential effects on the homeostasis of the human endocrine system (EDCs). This includes the chemicals discussed here and others, e.g., those classified as persistent organic pollutants (POPs). Numerous studies on the risks associated with cumulative and/or aggregate toxicity and potential interactions between these chemicals at the human body level have allowed the above hypotheses regarding possible adverse health effects due to their presence in human life to be formed. These findings also suggest that more intensive human actions should be conducted to eliminate these chemicals from the environment in order to minimalize their unwanted health consequences. This is particularly essential since humans are surrounded by a cocktail of anthropogenic chemicals that directly impact human health. In the era of fighting environmental pollution, in order to prevent its complete degradation, conducting so many studies related to the impact of EDCs on human health is a great positive contribution of the world of science to the precise determination of threats. With regard to these studies, it can only be noted that they focus solely on individual problems. What is new is a holistic approach to issues related to public health, consumer safety, and/or the environment, as well as the wide dissemination of research results in a manner accessible to the general public.","source_license":"CC-BY-4.0","license_restricted":false}