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Review

Risk Assessment of Bisphenol A in the Korean General Population

by
Myungsil Hwang
1,2,
Seon-Joo Park
1,2,* and
Hae-Jeung Lee
1,2,3,*
1
Department of Food and Nutrition, College of Bionanotechnology, Gachon University, Seongnam-si 13120, Republic of Korea
2
Institute for Aging and Clinical Nutrition Research, Gachon University, Seongnam-si 13120, Republic of Korea
3
Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences & Technology, Gachon University, Incheon 21999, Republic of Korea
*
Authors to whom correspondence should be addressed.
Appl. Sci. 2023, 13(6), 3587; https://doi.org/10.3390/app13063587
Submission received: 31 January 2023 / Revised: 5 March 2023 / Accepted: 7 March 2023 / Published: 10 March 2023
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Abstract

:
Bisphenol A (BPA) is not a natural substance but is produced artificially during the manufacturing of various plastics. Exposure to (BPA) is a pervasive and growing concern. BPA has recently been classified as a substance of great concern by the European Union (EU). BPA is suspected to be associated with several chronic human health effects. In this study, the estimated total BPA exposure levels were based on biomonitoring of the general population, and exposure levels ranged from a mean of 0.031 to 0.042 µg/kg body weight (bw)/day, reaching up to 0.104 µg/kg bw/day in the high-exposure population. When comparing the exposure levels of BPA to some toxicological effects, such as immunotoxicity and thyroid function, a sufficient exposure margin was not secured in the high-exposure group. Food is considered the main source of exposure for the general population, but other sources of exposure may exist in the high-exposure group. As humans are primarily exposed to BPA through food, water, house dust, skin contact, and air, integrated risk management is required to reduce BPA exposure. In addition, it is considered necessary to develop a new methodology for human health evaluation in response to low-dose exposure to BPA.

1. Introduction

Some industrial chemicals, such as bisphenol A (BPA) and phthalates, may be considered harmful to human health if the cumulative intake remains above the safety level expressed by a Health-based Guidance Value (HbGV) such as the tolerable daily intake (TDI) [1,2]. BPA is a synthetic chemical that is used in the manufacturing of various consumer products [3]. In the United States, production of BPA in 2019 amounted to a total of approximately 1.03 million metric tons, and a similar quantity has been produced every year since 2000 [4,5]. BPA poses a potential risk as an environmental endocrine disruptor [6,7], causing various adverse effects such as cardiovascular disease, metabolic disease, reproductive system disorders, and effects on the immune system [8,9,10]. Because of these health effects, the usage of BPA is restricted in infant items such as baby bottles, synthetic resin for children’s products, food contact and packaging materials, cosmetics, and thermal paper [11,12]. In Republic of Korea, the use of BPA is regulated in baby bottles, tableware, and toys for children. Risk assessment for BPA has been conducted repeatedly since 2010. Research has focused on the survey of total exposure in the body through biomonitoring and dietary exposure assessment, which is the main source of BPA exposure. Since 2014, epidemiological studies have been conducted on the human health effects, such as obesity, diabetes, and thyroid disease [13,14,15]. However, these studies have not found significant health effects from the levels of BPA typically found in food. When certain types of food come into contact with materials, including plastic containers and metal cans with a protective lining, small amounts of BPA can leach out and contaminate the food. In food monitoring for BPA, it is typically undetectable in most food. Recently, an integrated risk assessment was conducted which comprehensively considered not only food, but also consumer products such as cosmetics and children’s toys, as well as environmental media [16].
According to a risk assessment result conducted by the National Institute of Food and Drug Safety Evaluation (NIFDS) of Republic of Korea, BPA may be present in several food items at acceptable levels that do not pose considerable risks to human health [17,18]. However, risk managers are concerned about whether the current exposure levels of BPA in the general population are safe after the European Food Safety Authority (EFSA) published a new HbGV for BPA [19]. Recently, EFSA has suggested lowering the TDI by 0.04 ng/kg body weight (bw)/day, which is 100,000 times lower than the previous temporary TDI of 4 µg/kg bw/day [19,20].
Risk characterization can be evaluated using both exposure data and safety level. The safety level is determined from animal toxicological studies due to limited epidemiological evidence. Various safety levels for BPA have been proposed at different times by various risk assessment agencies, such as the United States Environmental Protection Agency (US EPA), Health Canada, Food and Agricultural Organization (FAO)/World Health Organization (WHO), EFSA, as well as in Republic of Korea. In early animal toxicity studies of BPA, liver toxicity and reproductive toxicity were reported as critical effects [21,22,23]. These effects have been found with high amounts of BPA [24]. Recently, BPA has been found to have estrogen-like and anti-androgen effects, causing damage to different tissues and organs such as the immune system and the neuroendocrine system [24,25,26]. Endocrine-disrupting effects of BPA have been reported at low doses, which are below the accepted no observed adverse effect level (NOAEL) for BPA in animal toxicity studies [27,28,29]. The BPA safety level proposed by EFSA was calculated based on the lowest reference point BMDL20 of 60 ng/kg bw/day (expressed as the human equivalent dose of 0.93 ng/kg bw/day), related to an increment of Th17 cell frequency in the spleen of offspring mice [19].
BPA can enter the human body through different routes, such as oral, respiratory, or dermal, from diverse sources, such as food, house dust, water, and various consumer products [27,30,31,32,33]. Since 2010, the NIFDS of Republic of Korea has assessed BPA exposure levels in the general population of Republic of Korea, and levels have gradually declined [16]. However, compared to the new safe level of BPA suggested by EFSA, the latest Korean BPA exposure level may be considered a potential risk to human health at all ages, although with the TDI in Republic of Korea and in agencies in other countries, the current risk remains low, and these evaluation results are confusing for risk managers.
The objective of the present study was to assess the potential risk of BPA exposure in the general population. We focused on the epidemiological evidence obtained from Koreans with regard to exposure levels in excess of the TDI of BPA proposed by the EFSA. In addition, this study aimed to determine whether the risk could be characterized by the margin of exposure (MOE) approach instead of the existing method of determining the risk based on TDI.

2. Literature Search for Safety Levels of BPA

In principle, epidemiological studies are considered first for dose–response assessment to establish a level of safety such as TDI. However, when these studies are insufficient, the results of animal tests are used to set a safety level. Therefore, it is important to determine whether the observed adverse effects in animals are relevant in humans. Because of the gap between the health effects observed from epidemiological evidence and the endpoint of animal testing, controversy still continues over the biological significance of many of the more sensitive endpoints in humans through exposure to BPA, and whether studies that have assessed only conventional endpoints are adequate for the detection of all potentially relevant effects. Over the past decades, many epidemiological studies have suggested associations between BPA exposure and human health effects [34,35,36,37,38,39]. However, no dose–response assessment has yet been attempted based on epidemiological studies. Many regulatory authorities around the world reviewing these low-dose studies have generally concluded that they are insufficient for use in risk assessment because of a variety of flaws in some of the study designs, scientific uncertainty concerning the relevance of the reported effects to health, and the inability of other researchers to reproduce the effects in standardized studies [16,40,41,42,43,44].
There is an extensive literature on the evaluation of the health effects of BPA in animal models [19]. BPA has consistently been found to cause several adverse effects in rats and mice at doses of 50 mg/kg bw per day and above. However, these amounts (3 g/day for 60 kg adult) are difficult to identify in humans. Over the past 20 years, many studies have provided evidence that considerably lower dose levels (range 0.002–0.2 mg/kg bw/day) of BPA induce some health effects in animals following exposure during gestation and/or lactation [40,45,46]. However, these studies have limitations in applying dose–response modeling because of experimental design, such as the use of only one or two dose levels, non-oral route of administration, and lack of data on internal dosimetry. In addition, the systematic review of these studies suggests many limitations, including the lack of independent confirmation of the findings and scientific consensus on whether the changes observed would result in impairment of functional capacity or the ability to compensate for additional stresses.
The safety levels of BPA for humans established by different risk assessment authorities show disparities with respect to the range of exposure. The BPA safety level for agencies other than EFSA fell within a range of similarly derived values (from a TDI of 0.005 µg/kg bw/day to a TDI of 0.5 µg/kg bw/day). Many agencies have accepted the study of Tyl et al. [47,48] as a good statistical and methodological study to establish safe levels of BPA. Table 1 summarizes the safety levels of BPA by international organizations. U.S. EPA and the National Sanitation Foundation (NSF International) have determined the appropriate NOAEL for BPA to be 5 mg/kg bw/day, and the two agencies have set the chronic oral safety level of BPA as 0.05 mg/kg bw/day [42,49] and 0.016 mg/kg bw/day [50], respectively. The U.S. Food and Drug Administration (US FDA) and Japan have proposed three safe levels for each critical endpoint [41,51]. A provisional tolerable daily intake (pTDI) of 25 µg/kg bw/day was established in 1996 and 2008 by the Food Directorate of Health Canada [43,44]. Meanwhile, the FAO/WHO did not establish the TDI of BPA due to a lack of toxicological data suitable for human risk assessment [40].
EFSA set a temporary TDI for BPA of 4 µg/kg bw/day [20] which was recently reduced to 0.04 ng/kg bw/day [19]. The process for the re-evaluation of BPA by EFSA is a reasonable approach and will be helpful for addressing various questions with the current risk assessment. In the benchmark dose (BMD) analysis, the benchmark dose lower confidence interval (BMDL)20 values for cellular immunity based on Th17 cells were the lowest BMDL20 (0.93 µg/kg bw/day) compared to other endpoints, such as metabolic effects, neurotoxicity, and reproductive and developmental toxicity [19].
In Republic of Korea, the TDI of BPA was assessed twice, in 2010 and 2016, by the NIFDS [17,18]. The last assessment set the TDI at 0.02 mg/kg bw/day, which was derived by applying an uncertainty factor of 500 to a BMDL10 10.5 mg/kg bw/day based on Tyl et al. [47,48].

3. Exposure Level of BPA in Korea General Population

In Republic of Korea, two approaches are used to assess the exposure level of BPA in the general population: a scenario-based exposure assessment approach and a biomonitoring-based extrapolation approach. According to the aggregated exposure assessment of BPA based on the scenario presented in 2020 by the NIFDS, the total exposure amount for the general population was 0.023 µg/kg bw/day for adults and 0.045 µg/kg bw/day for 3–6-year-olds (Table 2). With regard to the values in Table 2, a scenario-based exposure assessment was performed based on BPA concentration data sets in the literature of monitoring studies in Republic of Korea on various exposure sources, such as food, drinking water, consumer products (toys, cosmetics, detergent, etc.), and house dust. Dietary exposure was assessed using BPA content information of foods (1999–2012) and mean daily consumption data of foods that Koreans eat often and in large amounts. BPA was not detected in most foods except for some foods, such as canned food, and 1/2 limit of detection (LOD) was applied to the value for non-detection to calculate the mean BPA content of each food. The non-dietary sources that may lead to exposure of the general population were assessed based on source concentrations and intake amount. Scenario-based exposure assessment was calculated as the sum of the exposure to various exposure materials, such as food, drinking water, cosmetics, personal products (detergent and toothpaste), toys, and environmental sources (indoor dust, outdoor air). All sources were considered chronic exposure. Exposure assessment of each source was conducted according to the deterministic calculation, and exposures from all available sources were aggregated. All relevant consumer groups were included and were stratified according to age: toddlers (3–6 years), children (7–12 years), adolescents (13–18 years), and adults (19–79 years). In the scenario-based aggregated exposure assessment, food was the main exposure source for all age groups. BPA was positive in all of the canned food samples, while it was not detected in non-canned foods. Although dust is considered to be a minor exposure source for humans [53], indoor dust was considered one of the main exposures for the 3–6-year-old group of in this study. The scenario of Goetz et al. [54] was similar to that of the NIFDS’s aggregated exposure to BPA, and the total exposure amount was lower than the EU exposure range of 0.140 to 0.384 µg/kg bw/day for 3–45-year-olds.
Since 2009, numerous biomonitoring studies to quantify BPA exposure have been conducted in Republic of Korea. Biomonitoring data represent an integrated measure of BPA exposure from multiple sources and routes. More than 90% of Koreans have detectable levels of BPA in their urine, and the exposure level to BPA has been shown to have decreased in all age groups since 2015 [18,55]. However, total BPA concentrations in previous studies have been reported, and some differences exist. These differences may be related to differences in the study designs, analytical methods used, or study population. To assess exposure to BPA for the general population of all ages in Republic of Korea, this study used national biomonitoring survey data, which was conducted by the Ministry of Environment Korea (KME). Urinary BPA concentrations for the general population above three years of age were obtained from the Korean National Environmental Health Survey (KoNEHS) Cycle 3 (2015 to 2017). The mean urinary BPA concentration (1.32 ng/mL, 1.38 µg/g creatinine) of the adult subjects (Table 3) was lower than that reported in other studies conducted in Malaysia (mean urinary BPA, 1.89 ng/mL), India (mean urinary BPA, 1.97 ng/mL), Japan (mean urinary BPA, 1.98 ng/mL), China (mean urinary BPA, 3.86 ng/mL), Vietnam (mean urinary BPA, 3.32 ng/mL), and Kuwait (mean urinary BPA, 4.10 ng/mL) [56]. Using the biomonitoring data from the Korean National Environmental Health Survey (KoNEHS) Cycle 3 (2015 to 2017), we calculated the extrapolated exposure amount. The calculation equation was suggested by the NIFDS in 2012 [16]. The total urinary BPA concentrations (µg/g creatinine) were adjusted for urinary creatinine concentration, multiplied by the age-specific estimated 24 h urinary creatinine output volume and divided by body weight. The equation for exposure estimates (µg/kg bw/day) based on PBPK modeling is as follows.
E s t i m a t e d   d a i l y   i n t a k e   ( E D I   ( µ g / k g b w / d a y ) ) = u r i n a r y   B P A   c o n c e n t r a t i o n   µ g / g   creatinine + 0.000001 × U r i n a r y   c r e a t i n i n e   o u t p u t   ( g / day ) 0.993   x   B o d y   w e i g h t   ( kg )
Urine creatinine excretion volumes at each age were calculated according to Remer et al. [57] and Johner et al. [58]. The body weight of each age group used mean values from the data of the 2018–2020 Korea National Health and Nutrition Examination Survey (KNHANES). Using these assumptions, the biomonitoring-based mean exposure estimates are in the range of 0.017 µg/kg bw/day for adults and 0.042 µg/kg bw/day for children 3–6 years of age. The 95th percentile exposure estimates were in the range of 0.104~0.201 µg/kg bw/day for all ages (Table 3). This is higher than EFSA’s new TDI (0.04 ng/kg bw/day) but lower than Republic of Korea’s TDI (0.02 mg/kg bw/day).
Food is considered the main source of exposure in the general population (>95%), but in the adult group (19–79 years), food contributes 54.8%, and there may be other sources of exposure (Table 3). The results indicate that it is still necessary to evaluate additional exposure in the adult group. In the high-exposure biomonitoring group, with food contributing less than 20%, there may be additional sources of exposure (Table 3). One of the reasons for the low contribution of food in the high-exposure group may be the lack of information on the high intake of specific foods because the KHNANES is a dietary survey for the general population. BPA has been found primarily in canned foods and packaged foods and rarely or at very low concentrations in other foods. In the 2013–2016 KNHANES, the proportion of canned food consumers was very low at <18%. The KNHANES nutritional survey is conducted in one-day-24 h recall. Therefore, interpretation of the results is limited, and there were limitations in assessing the exact exposure for consumers who ate a lot of BPA-detected foods. In a probabilistic evaluation of canned food intake only, the total exposure level of the 75th population and the exposure through canned food were estimated to be almost the same (Figure 1). However, there was still a difference in the estimated intake in the high-exposure group, suggesting a contribution from other sources. In-depth study on high content sources of bisphenol A is needed.
With regard to children, the contribution of exposure to house dust was evaluated as an important factor [59,60]. Since the risk management of BPA has been strengthened, the average exposure to bisphenol A is gradually decreasing; however, efforts to reduce exposure in the high-exposure group are needed.
Applsci 13 03587 g001 550
Figure 1. Compared estimated daily intake of bisphenol A (µg/kg bw/day) from canned foods and exposure based on urinary BPA concentration (µg/g creatinine) in Korean general population (Source: Korean National Environmental Health Survey (KoNEHS), 2015–2017) [61].
Figure 1. Compared estimated daily intake of bisphenol A (µg/kg bw/day) from canned foods and exposure based on urinary BPA concentration (µg/g creatinine) in Korean general population (Source: Korean National Environmental Health Survey (KoNEHS), 2015–2017) [61].
Applsci 13 03587 g001

4. Risk Characterization of BPA

In a domestic epidemiological study using the Korean National Environmental Health Survey 2016, urinary BPA among 922 adolescents aged 12–17 years did not show a significant relationship with the lifetime prevalence of asthma and serum IgE levels [12]. The mean urinary BPA for these participants was 0.67~0.86 µg/g creatinine for 478 males and 1.37~1.03 µg/g creatinine for 422 females. Compared to the EFSA’s new TDI, exposure of these subjects translates into an immunological risk with adverse health effects. Therefore, determining the risk characterization of BPA using the current approach of comparing TDI and exposure levels to determine BPA safety is confusing. BPA does not show a typical classical dose–response relationship at low-dose exposure. However, assessment methods for this non-monotonic dose–response relationship, such as U-shape or inverted U-shape, have not yet been developed.
Since the health effects of BPA in humans are related to exposure in low doses, a new TDI could be established if a method for evaluating the dose–response relationship at low-dose exposure in human was proposed. Therefore, this study performed risk characterization using the margin of exposure (MOE) approach, which compared the exposure amount and point of departure (POD) of critical effects in this study. The MOE approach is a tool used to consider possible safety concerns arising from the substances in food which are both non-threshold genotoxic carcinogens or without TDI [62]. Generally, MOEs are not used to assess the safety of regulated substances such as food additives or food contact materials. Use of MOEs can help support risk managers in defining possible actions required to keep exposure to such substances as low as possible. BPA can be used in the manufacture of polycarbonate and other plastic products and epoxy resin-based food can liners that are not genotoxic and are regulated in various exposure sources [16,19]. Given the uncertainty in hazard characterization, the MOE approach was deemed appropriate for assessing the potential human health risks of low-dose exposure to BPA.
Firstly, three points of departure (PODs) from epidemiological and animal studies were selected for their critical effects. Previous sub-chronic and multigenerational studies using rodents first identified a no observed adverse effect level of toxicity (NOAEL) of 5 mg/kg bw/day for systemic toxicity [47,48]. Available pharmacokinetic data and comparisons between ages and species further support the use of this NOAEL as a very conservative tool in extrapolating data to humans. This NOAEL was also used as a POD in the establishment of current TDI by several agencies. Secondly, the lowest toxicity value was selected, which was one of 19 BMDL values for 10 endpoints by EFSA [19]. The lowest value was BMDL20 (60 ng/kg bw/day) for an immunotoxic effect, which was assigned a likelihood level of likely at a weight of evidence approach by EFSA. Finally, an estimated daily intake based on blood BPA level (cut point in blood 0.979 ng/mL) in a Korean case-control study was selected [63]. The relationship between urinary BPA concentration and thyroid function was not confirmed; however, a relationship between serum BPA and thyroid cancer was reported [63]. The T3 group had a higher prevalence of thyroid cancer compared to the T1 group. The urinary mean BPA value of the T3 group (1.38 µg/g creatinine) was close to the 75th percentile of urinary BPA levels (range: 1.29–3.21 µg/g creatinine) in the Korean general population (Figure 2). Although there are limitations of the case-control study, it was selected as a POD because it presented statistically significant results as a domestic epidemiological study. The estimated daily intake was calculated as 0.5 µg/kg bw/day using the blood BPA level that was not correlated with thyroid cancer [63]. In the case of the third POD, epidemiological causality has not been established, so further research is needed to determine the causality between BPA exposure and thyroid cancer.
The MOE approach uses a reference point, and judgment of the MOE is important for risk managers. For non-genotoxic substances, an MOE of >100 is routinely applied to the POD in animal studies [64]. When compared with PODs from epidemiological evidence, an MOE of >10 would be of low concern from a public health point of view, and it might be considered a low priority for risk management actions. The MOE for current levels of exposure to bisphenol A was calculated by dividing each POD value by the age-specific exposure level of the general population presented in Table 3. Table 4 shows the MOE calculated for each age group based on the POD values and exposure levels. The current BPA exposure level in the general population above 3 years of age in Republic of Korea is a sufficient margin of exposure when compared to animal toxicity levels. However, when compared to the 95th percentile exposures to the toxicological dose based on newly discovered health effects, immunotoxicity, and an epidemiological association with thyroid cancer, the MOE was calculated to be under 10 in all age groups. However, direct causality between exposure to BPA and health effects, such as immunological or thyroid dysfunction and thyroid cancer, has not been confirmed. In this study, the potential for these risks was evaluated by the MOE method, so a more accurate evaluation of causality with BPA will be required in the future.
Contrary to the results of domestic bisphenol risk assessments so far, our result, which was evaluated with the MOE approach, shows that exposure management of domestic bisphenol A is necessary. Specifically, efforts to reduce exposure to BPA are needed to obtain a sufficient margin of exposure for the potential risk of health effects in the high-exposure group. Diet is known to be the main source of BPA exposure, but in most food, BPA is either undetectable or at a very low level. In the biomonitoring-based exposure assessment, the high-exposure group had a relatively low contribution of food. Therefore, it will be necessary to not only continuously monitor exposure in the body, but to also to investigate in detail the sources of further exposure in high-exposure groups.

5. Further Study for BPA

BPA has been used in food packaging since the 1960s. Many studies on BPA have been reported to evaluate potential risks to human health. Although a wealth of data show that BPA is an endocrine-disrupting chemical, controversy on whether exposure poses a risk to human health remains. In Republic of Korea, risk assessment for BPA has been focused on relying on traditional toxicology animal studies rather than academic studies whose endpoints are more sensitive and considered appropriate. As mentioned above, traditional animal toxicity tests have limitations in identifying causality with human health, especially for low-dose exposure. The method for hazard identification and characterization is also evolving, and it will be necessary to incorporate this method in the risk assessment.
This study identified the need for further studies to reinforce BPA risk assessment. First, the biological hazard characterization of BPA is limited when applying the traditional risk assessment approach. Unlike safety management based on TDI for many hazardous chemicals, a new concept is required for BPA. If TDI continues to be lowered with an uncertainty factor without a new toxicity dose through animal testing, it will be difficult to judge whether it is safe. In the case of non-monotonic BPA, it is difficult to develop a new dose–response evaluation. It may be necessary to regulate the major exposure source with an MOE approach based on a non-threshold concept. In addition, human exposure to BPA occurs via various routes, primarily orally. It is possible that as mixtures are exposed to BPA analogs because of restrictions on the use of BPA in various consumer products, that they have been replaced with other bisphenol analogs such as bisphenol S (BPS) and bisphenol F (BPF). These analogs have similar chemical properties to BPA, and have high stability and long biological half-life in animals and humans [65,66]. Dose–response assessment for mixtures of chemical exposure requires further investigation.
Second, biomonitoring is an alternative approach for refining traditional risk assessment that will provide more information for understanding the low-dose health effects of BPA. A method to obtain repeated BPA measurements under real exposure conditions is needed in future studies. A single measurement of BPA in a spot urine sample may not be representative of overall BPA exposure. The measurement of BPA in 12 h collected urine samples from Koreans was higher than that of spot urine samples. Biomonitoring and extrapolation approaches for exposure assessment using the PBPK model or statistical approaches for epidemiological correlations are needed to understand the new low-dose health effects of BPA.
Third, epidemiologic dose–response analyses are useful for causal inference and risk assessment. The possibility of performing a dose–response assessment based on epidemiological data is considered, when available. If possible, a positive dose–response is more convincing than a simple excess of disease risk between the exposed and non-exposed groups. Therefore, appropriate biomarkers must be considered in epidemiological studies. BPA and its metabolites were detected at parts per billion (or less) concentrations in human urine, milk, saliva, serum, plasma, ovarian follicular fluid, and amniotic fluid [27,67]. Controlled ingestion trials in healthy adult volunteers with 5 mg d 16-BPA were unable to detect parent BPA in plasma, but by 96 h 100% of the administered dose was recovered in urine as the glucuronide [50]. In the liver and the intestines, BPA is mainly metabolized to glucuronides, to a lesser extent to sulfates, and to a minor extent to hydroxylated compounds and other metabolites [68]. Evidence suggests that only unconjugated BPA binds to estrogen receptors, and most BPA glucuronides have been found to lack estrogenic activity [68,69,70]. However, several studies have suggested other possible effects of BPA, such as the induction of adipocyte differentiation by BPA glucuronide and deconjugation of BPA glucuronide or BPA sulfate [71,72,73,74]. Moreover, this evidence may be even more relevant in sensitive age groups, for example, the fetus, since this may be relevant with a higher concentration of unconjugated BPA in fetal than in adult serum [75]. Therefore, it is important to select a human bio-sample to confirm the correlation between BPA exposure and its health effects. According to a review of various epidemiological studies, the correlation between health effects and BPA exposure showed differences in human samples. Generally, urinary BPA is a biomarker for exposure to BPA, and some indication of health effects, such as thyroid cancer, were correlated with serum BPA levels in a Korean cohort study [63].
Finally, additional studies [76,77,78] on the low-dose effects of BPA were updated to determine the relationship between BPA exposure and health effects, such as thyroid function and chronic disease, in a cohort study. The inconsistent results of animal experiments on BPA exposure and thyroid function may be due to experimental design with different doses, routes of exposure to BPA, exposure duration, or age at exposure.
In order to overcome the limitations of the current toxicological evaluation of low-dose exposure to BPA, studies for methodological improvement of traditional animal toxicological and epidemiological studies are needed.

6. Conclusions

There is no clear statistical significance of the relationship between BPA exposure and health effects in Republic of Korea. Typically, toxicity effects are studied at high doses, but we cannot ignore the potential low-dose effects of BPA. Although diet is thought to be the primary sources of human exposure to BPA, other potential sources may still exist.
At present, more than the 95th percentile of the general population is exposed to BPA in the general population of Republic of Korea. Therefore, management at a national level, based on an integrated approach and considering various exposure scenarios by different exposure routes, is needed to reduce the potential risk of BPA.
This study provides a scientific basis for determining the need for risk management for BPA. The study uses the margin of exposure (MOE) approach to evaluate the potential risk of BPA with its various toxic effects. However, it is possible that some potential confounding factors have not been taken into account when analyzing the association between human health effects and exposure to low doses of BPA. Further well-designed studies may be necessary to evaluate the low-dose toxicity of BPA, particularly with regard to immunotoxicity or other health effects based on epidemiological data.

Author Contributions

Conceptualization, H.-J.L. and M.H.; methodology, M.H. and S.-J.P.; writing—original draft preparation, M.H.; writing—review and editing, S.-J.P. and H.-J.L.; visualization, M.H.; funding acquisition, H.-J.L. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by a grant (21162MFDS076) from the Ministry of Food and Drug Safety in 2022.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

Korean National Environmental Health Survey (KoNEHS), 2015–2017 data can be downloaded from the KOSIS homepage (https://kosis.kr/statHtml/statHtml.do?orgId=106&tblId=DT_106N_99_1100051&conn_path=I2, accessed on 10 October 2022).

Conflicts of Interest

The authors declare no conflict of interest.

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Applsci 13 03587 g002 550
Figure 2. Distribution of urinary bisphenol A level (µg/g creatinine) in the general population from the 2009–2020 National Survey of Korea (upper figure) and the urinary BPA levels for the case-control study population (lower table). The percentile of urinary BPA levels in the general population is expressed as a range from cycle 1 to cycle 4 of the survey [63]. The red lines in the upper figure represent the 25th and 75th percentiles of BPA levels in the case-control study population, respectively.
Figure 2. Distribution of urinary bisphenol A level (µg/g creatinine) in the general population from the 2009–2020 National Survey of Korea (upper figure) and the urinary BPA levels for the case-control study population (lower table). The percentile of urinary BPA levels in the general population is expressed as a range from cycle 1 to cycle 4 of the survey [63]. The red lines in the upper figure represent the 25th and 75th percentiles of BPA levels in the case-control study population, respectively.
Applsci 13 03587 g002
Table
Table 1. Various international health-based guidance values of bisphenol A (BPA).
Table 1. Various international health-based guidance values of bisphenol A (BPA).
AgenciesEndpointPoint of Departure
(Uncertainty Factor)		Tolerable Daily
Intake
US EPA 1Reduced body weightNOAEL 5 mg/kg bw/day
(100)		0.05 mg/kg bw/day
US FDA 2Reduced body weight and liver effectsNOAEL 5 mg/kg bw/day
(1000)		0.005 mg/kg bw/day
Irreversible reproductive effectsNOAEL 50 mg/kg bw/day (1000)0.05 mg/kg bw/day
Reversible reproductive effectsNOAEL 50 mg/kg bw/day (100)0.5 mg/kg bw/day
Japan 3Body weightNOAEL 5 mg/kg bw/day
(100)		0.05 mg/kg bw/day
ReproductionNOAEL 50 mg/kg bw/day (100)0.5 mg/kg bw/day
Liver effectsNOAEL 23 mg/kg bw/day (500)0.046 mg/kg bw/day
Republic of Korea 4Relative kidney weight increaseBMDL10 10.5 mg/kg bw/day (500)0.02 mg/kg bw/day
NSF-Int 5Systemic toxicityNOAEL 5 mg/kg bw/day
(300)		0.016 mg/kg bw/day
EFSA 6ImmunotoxicityBMDL20 0.93 ng/kg bw/day (25)0.04 ng/kg bw/day
Canada 7Body weight reductionNOEL 25 mg/kg bw/day (1000)0.025 mg/kg bw/day
Development and reproduction effects NOAEL 5 mg/kg bw/day (200)0.025 mg/kg bw/day
FAO/WHO 8Reproductive toxicityNOAEL 5 mg/kg bw/day-
NOAEL: No observed adverse effect level, BMDL: Benchmark dose lower confidence interval. 1 National Toxicology Program (NTP) 1982 two years cancer study in both rats and mice. 2 Tyl et al., 2008 [48], 2-generation mouse study, and Tyl et al., 2002 [47], 3-generation rat study. 3 Tyl et al., 2002 [47], 2008 [48], and NTP 1985 continuous breeding study in mice. 4 Tyl et al., 2002 [47], 2008 [48]. 5 Willhite et al., 2008 [50], Tyl et al., 2002 [47], 2008 [48]. 6 Luo et al., 2016 [52] Increased number of Th17 cells was considered an endpoint for BPA, and EFSA considered a 20% BMR for an increase in Th17 cells. BMDL20-related increment of Th17 cells before conversion to human equivalent dose (HED) was 60 ng/kg bw/day. For the calculation of BMDL value expressed as HED, HED-factor of 0.0155 was used for mouse study. 7 Tyl et al., 2002 [47], 2008 [48] NTP 90-day preliminary study. 8 Tyl et al., 2002 [47], 2008 [48].
Table
Table 2. Bisphenol A exposure assessment in Korean general population by age in 2018–2020 (µg/kg bw/day).
Table 2. Bisphenol A exposure assessment in Korean general population by age in 2018–2020 (µg/kg bw/day).
Exposure MethodAge Group (Years)
3–67–1213–1819–79
Aggregated exposure amount0.0450.0280.0210.023
Dietary exposure amount0.0400.0300.0180.017
Source: National Institute of Food and Drug Safety Evaluation (NIFDS), 2019–2020.
Table
Table 3. Calculated exposure based on urinary bisphenol A concentration of Korean general population.
Table 3. Calculated exposure based on urinary bisphenol A concentration of Korean general population.
PopulationUrinary Concentration 1
(µg/g Creatinine)		Extrapolated Exposure Amount 2
(µg/kg bw/day)
(Contribution Rate of Foods)
Mean95th PercentileMean95th Percentile
3–6 years old2.8312.10.042
(95%) *		0.201
(19.9%) *
7–12 years old1.568.220.027
(100%) *		0.160
(18.8%) *
13–18 years old0.894.580.017
(100%) *		0.104
(17.3%) *
≥19 years old1.388.080.031
(54.8%) *		0.181
(9.39%) *
1 Biomonitoring data from the Korean National Environmental Health Survey (KoNEHS) Cycle 3 (2015 to 2017). 2 The extrapolated exposure was calculated based on biomonitoring data from the Korean National Environmental Health Survey (KoNEHS) Cycle 3 (2015 to 2017). * Numbers in parentheses indicate the contribution of food to the BPA total exposure based on biomonitoring. Dietary exposure amount is shown in Table 2.
Table
Table 4. Margin of exposure (MOE) of current exposure of bisphenol A by age in Korean general population.
Table 4. Margin of exposure (MOE) of current exposure of bisphenol A by age in Korean general population.
Point of Departure (POD)Margin of Exposure (MOE)
3–6 yrs7–12 yrs13–18 yrs19–79 yrs
MeanNOAEL 5000 µg/kg bw/day
(animal toxicity)		>119,000>185,100>294,100>161,200
BMDL20 60 ng/kg bw/day
(animal toxicity; immunotoxicity)		22345530
EDI 0.5 µg/kg bw/day
(epidemiological study; thyroid cancer)		12192916
95thNOAEL 5000 µg/kg bw/day
(animal toxicity)		>24,800>31,200>48,000>27,600
BMDL20 60 ng/kg bw/day
(animal toxicity; immunotoxicity)		5695
EDI 0.5 µg/kg bw/day
(epidemiological study; thyroid cancer)		2353
NOAEL: No observed adverse effect level, BMDL: Benchmark dose lower confidence interval, EDI: Estimated daily intake. MOE = POD/Extrapolated exposure amount from Table 3.
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Hwang M, Park S-J, Lee H-J. Risk Assessment of Bisphenol A in the Korean General Population. Applied Sciences. 2023; 13(6):3587. https://doi.org/10.3390/app13063587

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Hwang, Myungsil, Seon-Joo Park, and Hae-Jeung Lee. 2023. "Risk Assessment of Bisphenol A in the Korean General Population" Applied Sciences 13, no. 6: 3587. https://doi.org/10.3390/app13063587

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