Bisphenol-A and Female Fertility: An Update of Existing Epidemiological Studies

PubMed (Medline) was searched to identify observational studies published between May 2013 and May 2022 that were related to BPA and fertility. We focused on articles published between 2013 and 2022 to expand on previous reviews on the same topic [ 14 , 15 ]. The search was limited to English papers and human studies. The following search terms were combined: ‘Bisphenol-A’, ‘BPA’, ‘female fertility’, ‘female fecundity’, female reproduct*’, ‘ovary’, ‘oviduct’, ‘uterus’, ‘HPO’, ‘anti-Mullerian hormone (AMH), ‘FSH’, ‘estradiol’, ‘ovarian reserve’, ‘AFC’, ‘oocytes retrieved’, ‘fertilization rate’, ‘implantation rate’, ‘pregnancy rate’, ‘live birth’, ‘PCOS’, ‘Endometriosis’. We further hand-searched the citations of the retrieved eligible papers to identify additional publications that might have been missed during the initial search. Cohort, case-control and cross-sectional studies reporting the association of BPA with female fertility, PCOS and endometriosis were included. Studies reporting in vitro experiments, which may fail to replicate the conditions of cells in an organism or predict in vivo behavior, were excluded. From each study, the following information was abstracted: first author, publication year, study location, study period, sample size, female age, and type of study ( Table 1 ).

The urbanization and industrialization of modern societies have undoubtedly led to the degradation and pollution of the environment, posing further threats to human health [ 1 ]. Individuals are exposed to an extensive variety of modern chemical substances daily, such as phthalates, bisphenol-A (BPA), triclosan (TCS), parabens and many more, all identified as endocrine-disrupting chemicals (EDCs). EDCs are substances found in a variety of products used daily that interfere with endogenous hormonal systems at various levels, resulting in adverse health effects [ 2 ]. During the past decade, global health communities have succeeded in improving and protecting maternal and child health to a great extent, focusing primarily on reproductive health [ 3 , 4 ]. Nevertheless, infertility remains a major medical, psychosocial, and economic challenge of the present era. In a National Survey of Family Growth (NSFG) conducted between 2015 and 2019, the percentage of married women aged 15–49 who were infertile ranged between 12.6% and 26.8% [ 5 ]. The leading causes of female infertility seem to involve certain tubal and uterine disorders, as well as ovarian and endocrine diseases, such as polycystic ovarian syndrome (PCOS) and endometriosis [ 6 ]. Bisphenol-A (2,2-bis(4-hydroxyphenyl) propane, CAS No. 80-05-7) is one of the most extensively studied and debated EDCs. To date, several studies have been carried out, highlighting the role BPA plays in the reproductive capacity of women. This substance is mainly used in the plastic industry to manufacture numerous consumer products, including epoxy resins, food and drink containers, baby bottles, polycarbonate plastics, thermal receipt paper, personal care products, dental sealants, etc. Although the main source of exposure to BPA is assumed to be oral ingestion [ 7 ], lately, scientific interest has turned towards the transdermal route of exposure [ 8 ]. BPA seems to have a particularly high affinity for estrogen receptors (ERα and β), as it disposes of phenol group, such as estradiol (E2), and therefore exhibits estrogen-mimicking behavior [ 9 , 10 ]. This suggests that such a chemical compound could potentially arouse estrogen function and contribute to the pathogenesis of various diseases of the female reproductive system by disrupting the hypothalamic pituitary–gonadal axis. Moreover, BPA has the capacity to inhibit androgen function by binding androgen receptors (AR). Additionally, several studies have illustrated the ability of BPA to bind G-protein-coupled estrogen receptors (GPER30) and, therefore, interfere with estrogen-activated signaling pathways [ 11 , 12 , 13 ]. Due to its reproductive toxicity, BPA usage has been restricted globally over the past few years. Instead, certain BPA analogues were introduced in baby bottles, infant formula packaging and other plastic materials; bisphenol S (BPS; bis(4- hydroxyphenyl sulfone) and Bisphenol F (BPF; 4,4′-dihydroxydiphenyl methane) are two of the most commonly used analogues of BPA. Our study aims to critically review the current epidemiological studies evaluating the association of serum and/or urinary BPA levels and female fertility, mostly focusing on in vitro fertilization (IVF) outcomes and on infertility-related reproductive disorders, namely endometriosis and PCOS.

The association between BPA and fertility impairment constituted a matter of discussion in several studies ( Table 2 ). The researchers examined the effect of BPA either on ovarian reserve parameters or on IVF outcomes, both of which defined the success of an IVF cycle. Furthermore, some studies compared the levels of BPA between fertile and infertile women with the aim of finding a link between BPA levels and fertility, although in this category no causality could be established. In 2013, Souter et al. investigated the relationship between urinary BPA levels and ovarian response during IVF among women undergoing infertility treatments from the EARTH cohort. The researchers found a decrease in antral follicle count (AFC) with higher BPA levels ( p < 0.001). However, no association between BPA and FSH or ovarian volume (OV) was reported [ 19 ]. Similarly, Zhou et al. reported that a unit increase in BPA is associated with a statistically significant decrease in AFC. The researchers also noted that BPA is negatively associated with anti-Müllerian hormone (AMH) and day-3 FSH, but no statistical significance was found [ 27 ]. Two recent studies confirmed the aforementioned data [ 47 , 50 ]. Czubacka et al., in particular, found a negative association of high BPA levels with AFC and AMH [ 47 ]. Similarly, Lin et al. reported a lower AFC count in the group with high BPA levels, although no statistical significance was reached [ 49 ]. However, with regards to these associations, two studies reported different conclusions. A Korean cross-sectional study reported higher BPA levels in women with diminished ovarian reserve (DOR), although no significant correlation of EDCs with AFC or OV was shown [ 39 ]. Furthermore, Li et al. reported a positive association of BPA with LH and no association with AFC or FSH [ 44 ]. All of the above studies indicate that BPA could adversely affect oocyte viability. However, they are not designed to identify the exact mechanisms by which these alterations could be established. Regarding the association between BPA and E2 levels during IVF, most studies report no association [ 23 , 35 , 41 , 47 ]. However, some studies reported a possible negative correlation between BPA levels and peak E2 [ 49 , 51 ], whereas one study, in 2015, reported a positive association between BPA and E2 levels [ 24 ]. More specifically, Lin et al. analyzed BPA concentrations in normo-gonadotropic infertile patients who underwent their first IVF-ET cycle, reporting lower peak E2 levels in the high-BPA-exposure group, although this result was not statistically significant, possibly due to the small sample size of the study [ 49 ]. Yenigül et al. also observed lower E2 levels in women with higher BPA exposure; again, this association was not statistically significant [ 51 ]. On the other hand, in the study by Miao et al. a positive association between urine BPA and E2 was observed with borderline significance among women in the BPA-exposed group ( p = 0.05) [ 24 ]. These findings suggest that BPA exposure may interfere with E2 production during gonadotropic stimulation. Lastly, two research groups that examined the BPA levels in adolescents indicated an inverse association between BPA levels and E2 in young females [ 38 , 46 ], which clearly confirmed the aforementioned data regarding the interference of BPA with E2 production. Overall, seven studies have investigated the association between serum or urine BPA concentrations and various IVF outcomes [ 23 , 35 , 41 , 45 , 49 , 50 , 51 ]. Most of them reported the absence of a statistically significant association between high BPA concentrations in various human fluids and IVF outcome measures, namely fertilization, clinical pregnancy, and live birth rates [ 23 , 35 , 41 , 51 ]. However, Nazli Yenigul et al. found a lower clinical-pregnancy and live-birth probability, as well as decreased embryo quality, in women undergoing intra-cytoplasmic sperm injection (ICSI) with higher serum and follicular-fluid BPA levels [ 51 ]. Additionally, Aftabsavad et al. observed lower clinical pregnancy rates and total embryo and oocyte quality in the group of women with unhealthy lifestyle habits (group 2), among whom the BPA levels also appeared to be significantly higher in comparison to the group with healthy lifestyle habits (group 1) [ 50 ]. Lin et al. note a statistically significant association between high urinary BPA levels and decreased embryo implantation, oocyte retrieval and maturation rates [ 49 ]. Moreover, Radwan et al. report a statistically significant decrease in implantation rates and MII oocyte counts in women who present higher urine BPA concentrations [ 45 ]. In addition, several studies assessed the levels of BPA in populations with different infertility impairments. Pednekar et al. reported higher BPA levels in an infertile population compared to healthy individuals [ 32 ], whilst Özel et al. found that women with premature ovarian insufficiency had increased serum BPA concentration [ 33 ]. Arya et al. found that individual BPA levels are not associated with infertility, but a combination of BPA, benzophenone-3 (BP-3) and TCS exposure may be positively correlated with infertility [ 37 ]. Nevertheless, it should be highlighted that a major limitation of this study is the lack of a medical confirmation of impaired fecundity, as the study relied on self-reported infertility. Caserta et al. also found higher BPA levels in infertile women, as well as a positive association between BPA and Era-, ERb-, AR-, AhR- and PXR-gene expression [ 18 ]. Finally, in 2020, a research group evaluated the relationship between bisphenols and thyroid function, since hyperthyroidism is known to affect fertility. The researchers found that only urine BPC is associated with high TSH levels and may therefore interfere with normal fertility [ 40 ]. PCOS constitutes one of the most common endocrine diseases among women of reproductive age [ 53 ]. PCOS is associated with endocrine, metabolic and reproductive health implications, including anovulation, infertility, hyperandrogenism, obesity, hyperinsulinism, increased risk of type-2 diabetes and cardiovascular disease [ 54 , 55 , 56 ]. Although the exact etiology and pathophysiological mechanisms of this syndrome remain enigmatic, many studies have highlighted the potential role of ethnic origin, geographic location, lifestyle and environmental factors in the pathogenesis and/or clinical manifestation of PCOS [ 57 , 58 ]. Among environmental factors, BPA has raised great concern regarding its association with PCOS, mainly due to its estrogen-like actions. Between 2013 and 2022, ten human studies were identified which examined the association of bisphenols, particularly BPA, with PCOS ( Table 3 ). In 2013, Tarantino et al. concluded that high serum BPA levels in PCOS women are associated with higher grades of insulin resistance, hepatic steatosis, free-androgen index (FAI), inflammation and spleen size [ 16 ]. Two later studies, which measured serum BPA levels in healthy and PCOS women, found that the BPA levels were higher in women with PCOS compared to the control group [ 22 , 25 ]. In particular, Akin et al.’s study, which evaluated 173 female adolescents, reported statistically significantly higher mean BPA levels in PCOS women compared to healthy women (1.1 ng/mL vs. 0.8 ng/mL), as well as a statistically significant correlation between BPA and androgen levels [ 22 ]. More recent publications confirm the aforementioned association of high BPA levels and PCOS [ 29 , 31 , 36 , 48 , 52 ]. In particular, a research group from Poland reported significantly higher BPA levels in women with PCOS compared to the control group ( p = 0.035) and a positive correlation of BPA with FAI and serum total testosterone (TT) [ 31 ]. The correlation reported by previous studies between high BPA and androgen levels may suggest a potential contribution of BPA to the ovarian hyperandrogenism usually seen in women with PCOS. Lazúrová et al. found analogous results regarding high BPA levels and PCOS associations; however, the research group reported a negative association between U-BPA levels and TT, free testosterone (FT) and FAI, suggesting controversial results concerning BPA and androgen levels [ 52 ]. Akgul et al., in 2019, found that BPA is associated with polycystic morphology on ultrasound in adolescent females with PCOS, but no association with obesity, androgen levels or other metabolic parameters was reported [ 36 ]. Finally, a recent study by Jurewicz et al., who evaluated the association between PCOS and BPA and its analogues, namely BPS and BPF, found that, in women with PCOS, only BPS was significantly higher compared to the control group ( p = 0.023) [ 48 ]. However, in disagreement with the aforementioned studies, two research groups found no association between BPA levels and PCOS [ 21 , 30 ]. Vagi et al. reported no association of creatine-adjusted urine BPA levels with PCOS. However, this study had several limitations, particularly the small sample size and the inadequate confounding adjustment for BMI and age [ 21 ]. Similarly, Gu et al., in 2018, did not find a significant relationship between PCOS and urinary BPA either in an unadjusted binary logistic regression model or in a model adjusted for potential confounders [ 30 ]. All of the above data, although controversial, highlight that PCOS development may be strengthened by high BPA levels in female populations, mainly due to the potential contribution of BPA to ovarian hyperandrogenism. Endometriosis is commonly defined as the presence of endometrial glands and stroma outside the endometrial cavity, primarily on the pelvic peritoneum, ovaries, rectovaginal septum and, in rare cases, on the diaphragm, pleura and pericardium [ 59 ]. This is a common disease entity, as, according to epidemiological studies, it affects roughly 6–10% of reproductive-age women and girls globally [ 60 ]. Despite its high prevalence, endometriosis remains an enigmatic disease, as its pathogenesis has not yet been established. Many factors have been implicated at different times, including retrograde menstruation, genetics and immunity; however, in the past few decades, questions have arisen concerning the possible role of EDCs in the pathogenesis of endometriosis. It is generally considered a benign condition and can be asymptomatic; however, this perplexing disease is frequently responsible for symptoms such as chronic pelvic pain, dyspareunia, dysmenorrhea and, most significantly, infertility, which constitutes a serious consequence. To establish a definite diagnosis, surgical visualization is required [ 61 ]. According to our research, only a handful of population-based studies have been carried out to investigate the possible association between BPA exposure and the occurrence of endometriosis in humans ( Table 4 ). All seven studies assessed urine specimens and some considered creatinine adjustment [ 17 , 20 , 34 , 42 , 43 ]. Interestingly, the results of these studies were not in agreement with each other. In 2013, the ENDO study [ 17 ] aimed to examine the association of urine BPA with endometriosis by establishing two cohort groups, an operative and a population cohort. The latter group was screened through standardized pelvic magnetic-resonance imaging (MRI) for the assessment of the disease and no evident association with BPA exposure was found. As far as the operative group is concerned, again, no statistically significant correlation was found between elevated BPA levels and the diagnosis of endometriosis. Similarly, in 2019, Moreira Fernandez et al. found no association between endometriosis and urine BPA concentrations. In this case-control study, the participants were Brazilian women aged 18–45 and the diagnosis of the disease was confirmed or excluded by laparoscopy with a visual inspection of the pelvis and biopsy of suspected lesions [ 34 ]. In 2014, Upson et al. [ 20 ] collected data from the Women’s Risk of Endometriosis (WREN) study and did not observe a statistically significant correlation between total urinary BPA concentrations and endometriosis overall, after adjusting for possible confounders. Hence, the report that higher BPA levels may increase the risk of non-ovarian pelvic endometriosis is intriguing ( p > 0.005). By contrast, both Simonelli et al., in 2016 [ 26 ], and Rashidi et al., in 2017 [ 28 ], reported a significant correlation between endometriosis and BPA exposure. Simonelli et al. conducted a prospective case-control study that included 144 women from Southern Italy and, meanwhile, assessed the possible occupational and environmental exposure, concluding with the finding of statistically significantly higher urinary BPA levels in the patient group than in the control group and highlighting the need for further investigation regarding occupational exposure and certain lifestyle factors [ 26 ]. Rashidi et al. studied the cases of 100 women from Iran, taking into consideration possible confounding factors and indicated a positive association between urinary BPA concentrations and the presence of ovarian endometriomas [ 28 ]. The main objective of Peinado et al. (2020) [ 43 ] was to evaluate the concentrations of BPA and its analogues (BPS and BPF) regarding the levels of thiobarbituric-acid-reactive substances (TBARS) and the risk of endometriosis in women of reproductive age. This case-control study reports a possible relationship between inadvertent exposure to bisphenols and the risk of endometriosis and suggests a potential role of oxidative stress in the endocrine-disruptive effects of BPA in these women. Wen et al. (2020) [ 42 ] studied two hundred twenty (220) women investigating a possible association between urinary BPA concentrations and matrix metalloproteinase (MMP2, MMP9) expressions and the risk of different endometrioma (EM) subtypes. It is noteworthy that matrix-metalloproteinase activity is thought to be essential in the early phases of endometriosis development. Although this study reported no association between creatinine-adjusted urinary BPA concentrations and EMs overall, a statistically significantly positive correlation emerged when evaluating urinary BPA concentrations apropos of peritoneal EMs. This finding is partly consistent with the results of the study by Upson et al. [ 20 ]. In addition, a positive association was found between urinary BPA levels and serum MMP2 and MMP9 levels.

Recent studies have shown that EDCs, and particularly BPA, interfere with the female genital tract and may be associated with infertility, as well as infertility-related diseases, namely PCOS and endometriosis. Numerous studies suggest that, as an endocrine disruptor, BPA binds with Era, ERβ and transmembrane ERs, resulting in the induction of alternative estrogen signaling and the distortion of hormonal balance. Through binding, BPA either mimics (agonistic effect) or blocks (by inhibiting the aromatase activity) natural human estrogens, consequently disturbing the development, regulation and endocrine control of the female genital tract. The two-way estrogenic action of BPA could explain the diversity of our results, according to which one study found a positive correlation of BPA with E2 [ 24 ], while others reported an inverse correlation of BPA with E2 levels [ 38 , 46 , 49 , 51 ]. Nonetheless, most of the studies revealed no statistically significant correlation [ 23 , 35 , 41 , 47 ]. In addition, BPA is known to have adverse effects on the process of oocyte maturation and meiotic-cell-division machinery. Thus, BPA can impair oocyte survival, inhibit follicular growth and diminish ovarian reserves [ 19 , 41 ]. To confirm these actions, the epidemiological studies reported in this review examined the association of BPA with well-known ovarian-reserve markers, namely AFC and AMH. Overall, the studies reported an inverse correlation between ovarian predictors and BPA levels. On the other hand, the data reporting an association of day-3 FSH and BPA levels remain controversial. Furthermore, the estrogenic action of BPA could affect implantation and fertilization rates, which are highly modulated by estradiol and progesterone. Diminished oocyte maturity, along with possible chromosomal abnormalities, could also explain the impairment with regards to pregnancy rates. Indeed, various studies presented in the current review correlated high BPA levels with different IVF outcome measures, such as oocyte quality, embryo quality, fertilization rates, implantation rates and clinical pregnancy rates. Different endpoints were examined by each study, which makes definite conclusions difficult. Overall, the studies indicate that high BPA levels could affect IVF success in various stages, in either oocyte maturation or fertilization and implantation rates. Clinical pregnancy rates are also reported to be highly affected. It is worth mentioning that, recently, several studies have highlighted the protective role of soy-based foods against the negative effect of BPA on IVF outcomes. Similar to BPA, soy-food components are characterized by estrogenic activity and, therefore, have the ability to interfere with BPA-induced effects on DNA methylation [ 62 , 63 ]. Furthermore, several studies, mainly cross-sectional and case-cohorts, revealed higher BPA levels in women with fertility impairment compared to control groups, which suggests an association between high BPA levels and infertility. However, these studies, as well as epidemiological studies in general, inevitably hamper the interpretation of causality. Interestingly, Milczarek-Banach et al. conducted the only study in which the effect of different bisphenol analogues on thyroid function was examined. The researchers reported that urine bisphenol-C (BPC) is negatively associated with thyroid volume [ 40 ]. Thyroid-hormone levels and TSH are known to affect IVF outcomes [ 64 ] and research concerning BPA levels and thyroid-function association is scarce. Hence, more studies relevant to this topic are required. Growing evidence suggests that BPA exposure may be involved in the occurrence of PCOS. Indeed, several mechanisms explain how BPA can contribute to the pathogenesis of PCOS. Firstly, BPA can directly increase the synthesis of ovarian androgen levels in theca cells by increasing the levels of certain steroidogenic enzymes, such as P450c17, P450scc and StAR [ 65 ]. Secondly, BPA can also interact with granulosa cells by augmenting FSH-stimulated progesterone synthesis [ 66 ]. At the same time, BPA also has the capacity to displace sex hormones from sex-hormone-binding globulin (SHBG), which could also contribute to higher free-androgen levels [ 67 ]. Furthermore, BPA has an effect on obesity and metabolism by inhibiting the release of adiponectin, a protein that acts against the development of metabolic syndrome [ 68 ]. Furthermore, it has been suggested that PCOS is a pro-inflammatory state; inflammation is thought to play a vital role in the pathogenesis of PCOS [ 67 ]. Finally, BPA can directly interfere with ß-cells by increasing insulin production. The consequent hyperinsulinemia increases insulin resistance in peripheral tissues, which also contributes to the disarrayed metabolic profile of PCOS [ 69 ]. Most of the studies analyzed in our review reported a statistically significant association between PCOS and high concentrations of BPA in various human fluids (serum and urine specimens) due to increasing androgen levels and serum TT. Nonetheless, the retrospective case-control and cross-sectional designs of the existing human studies, which determine prevalence and do not unravel causal relationships, need to be addressed. It remains unclear whether the observed association indicates that BPA contributes to the development or presentation of the disease or whether the endocrine profile of PCOS alters the storage and clearance of this metabolite, leading to increased concentrations in different human fluids. Additionally, a strong correlation between elevated BPA exposure and hyperandrogenism in the setting of polycystic ovary syndrome was described by various authors [ 16 , 22 , 31 ], although it needs to be acknowledged that elevated androgen levels down-regulate the activity of UDP-glucuronosyltransferase, inducing a decrease in BPA clearance and an increase in its urine and blood concentration [ 70 ]. Certainly, accumulating evidence over the last decade strongly suggests a link between EDC exposure and the subsequent development of endometriosis. Notwithstanding the lack of knowledge of the mechanisms associated with the institution of the disease, it is well documented that ectopic-lesion growth is an estrogen-dependent process [ 71 ] commonly characterized by progesterone resistance and inflammatory disorder [ 72 ]. The epidemiological data on the effect of BPA exposure on the establishment of the disease are limited and controversial, with an increased endometriosis risk reported by some authors but no association by others. It is paramount that we develop a better understanding of the possible contribution of BPA exposure on the incidence and pathophysiology of endometriosis. Undoubtedly, it should be pointed out that there is no biomarker for endometriosis, which constitutes a barrier for research at the population level. Furthermore, the diagnostic method poses a certain challenge (surgical visualization with/without histologic confirmation vs. self-reported disease) that could possibly affect the validity of this disease in these studies. Altogether, our inconsistent findings suggest that further observational studies are required to elucidate the role of BPA in the pathogenesis and manifestation of endometriosis. There are possibly numerous factors contributing to the divergent results of our study. Firstly, previous researchers have used a variety of specimens (urine, blood, follicular fluid) for exposure assessment. Most studies indicate that urine-BPA measurement may be more efficient in determining exposure to this compound, because it probably reflects more long-term exposure in comparison to blood or serum measurements [ 35 , 52 ]. It is well known that in humans, after ingestion, BPA is rapidly metabolized and almost completely excreted in urine as the glucuronide conjugate because the free form of BPA is insoluble in water [ 73 ]. Moreover, blood measurement may pose a risk of contamination during sample collection [ 29 ]. Secondly, most of the studies were designed with a single-spot urine measurement of BPA. However, BPA is a non-persistent EDC with a urinary elimination half-time of less than 6 h [ 21 ]. Therefore, to avoid the misclassification of BPA exposure due to its quick metabolism, future studies are encouraged to measure 24-hour urine BPA. Furthermore, although some studies measured urine creatinine to evaluate the daily exposure for BPA, most studies did not. As highlighted by Wen et al.’s study in 2020, before creatinine adjustment, the absolute values of BPA at different time points varied significantly. However, after creatinine adjustment, urinary BPA levels at different time points showed high consistency, suggesting that the creatine-adjusted urine measurement of BPA may be more reliable [ 42 ]. Another issue that raises concerns is the fact that in all the studies, BPA was measured after the onset of the disease and not before. Thus, exposure to this metabolite was not disclosed at the time of the genesis of the disease. Lastly, although most of the studies adjusted in their statistical analysis for known confounders, such as BMI and age, most of them did not take into consideration simultaneous co-exposition to many other EDCs, which may also contribute to infertility impairment. The findings by Arya et al. are crucial and indicative; BPA was found to not be correlated to fecundity when studied individually, although the simultaneous study of three EDC (e.g., BPA, BP-3 and TCS) confusing factors found a statistically significant relationship [ 37 ].

In this appraisal of the recent literature, evidence indicates that BPA might play a vital role in the pathogenesis of female infertility. Our review indicated that BPA is negatively correlated with certain IVF parameters and endpoints, as well as PCOS. Regarding the association of BPA with endometriosis, recent data failed to reach definite conclusions. Although there is a variety of experimental studies in the literature concerning BPA and infertility, human studies are still limited. More insight would be gained by a consistent human-fluid analysis of BPA, such as urine vs. serum and, possibly, the use of biobanks to assess long-term consequences. Despite the lack of sufficient data to reach a consensus with regards to the possible role of BPA in the onset of certain gynecological manifestations, precautionary actions against excess exposure to this metabolite are strongly encouraged.