Biomonitoring of bisphenols A, F, S and parabens in urine of breastfeeding mothers: Exposure and risk assessment
Graphical abstract
Introduction
Bisphenols and parabens are man-made chemicals used in various consumer products. Bisphenol A (BPA) is used in the manufacture of polycarbonate plastic and epoxy resins and is found in different products like cans (food and drink), dental sealants, thermal receipts, food packaging, and personal care products (PCPs). Due to its toxicity, BPA has been banned in the manufacture of infant feeding bottles in Europe since 2011. Consequently, bisphenol analogues like bisphenol S (BPS) and bisphenol F (BPF) are used as a substitution for BPA in some consumer products (Chen et al., 2016). Parabens (alkyl esters of p-hydroxybenzoic acid) are widely used as antimicrobial preservatives, especially in cosmetics, pharmaceutical products, and in food and beverages. Methylparaben (MP), ethylparaben (EP), propylparaben (PP) and butylparaben (BP) are the most commonly used parabens. The widespread use of parabens as preservatives arises from their low toxicity, broad inertness, worldwide regulatory acceptance, and low cost (Jardim et al., 2015). However, some authors have stressed the reproductive toxicity of these substances (Garcia et al., 2017; Schreiber et al., 2019). Diet is considered an important source of bisphenols. Certain food groups such as canned food, fish, meat, and poultry have been associated with bisphenol levels (Sanchis et al., 2017). Exposure to parabens may occur through ingestion, inhalation and dermal absorption (Darbre and Harvey, 2008).
After oral ingestion, BPA suffers a metabolic process and is excreted mainly as BPA-glucuronide in urine with a half-life of less than 6 h. The metabolism of bisphenol analogues (BPS and BPF) and excretion in urine is less known, but it seems to be similar to BPA (Rochester and Bolden, 2015). Parabens may conjugate to β-D-glucuronide and sulphate, which reduces their bioactivity and facilitates urinary excretion. Generally, parabens are rapidly absorbed, metabolized, and excreted in urine from the body. Following excretion, the parent compounds can be measured in urine and have been shown to be valid biomarkers of exposure (Guo et al., 2017). Sakhi et al. (2018) confirmed that parabens have a short elimination half-life in humans, normally between 1 and 7 h. Although these substances, both bisphenols and parabens, are non-persistent chemicals and have short elimination half-lives in humans, their widespread use and potential endocrine-disrupting properties have made them chemicals of concern (Sakhi et al., 2018).
European plastic material regulation has established the migration limit of 0.05 mg of BPA per kg of food (EU, 2011), has banned the use of BPA in baby bottles, and has prohibited the migration of BPA from varnishes or coatings applied to materials in contact with food for infants and children 0–3 years of age (EU, 2018). Taking into account the “general toxicity” of bisphenols, only a temporary tolerable daily intake (t-TDI) of 4 μg kg bw−1day−1 has been established for oral exposure to BPA (EFSA, 2015). In the case of parabens, the EU allows and regulates the use of parabens in cosmetic products, food, and skincare pharmaceutical products. In addition, EFSA has established an acceptable daily intake (ADI) of 0–10 mg kg bw−1day−1 for the sum of methyl and ethyl acid para-hydroxybenzoic esters based on studies which showed non-observed-adverse-effects-levels (NOAELs) for both parabens. To date, no ADI for PP, BP, BPF, and BPS has been established (EFSA, 2004).
Apart from BPA, BPF and BPS have already been included as prioritised substances to be determined in human biomonitoring (HBM) studies (HBM4EU, 2017). Several biomonitoring studies have been implemented in order to determine urinary levels of BPF and BPS (Liao et al., 2012; Yang et al., 2014; Zhou et al., 2014). Although some HBM studies for bisphenols and parabens in urine have been performed in female populations (Arbuckle et al., 2014; Buckley et al., 2016; Callan et al., 2013; Heffernan et al., 2016; Jiménez-Díaz et al., 2016; Pollack et al., 2016; Sakhi et al., 2018), only one has studied breastfeeding women (Hines et al., 2015). Lee et al. (2017) have studied the distribution of bisphenols in biological samples such as urine and human milk from pregnant women before delivery, at delivery, and 1 month after delivery. Levels of BPA in urine were 2.23 ng mL−1 and 0.51 ng mL−1 in human milk. Several studies have described levels of bisphenols (geometric mean of total BPA: 0.29 ngmL−1) and parabens (mean MP: 2.18 ngmL−1) in human milk (Dualde et al., 2019; Schlumpf et al., 2010). In previous studies, our research group determined the levels of bisphenols and parabens in human milk, and the exposure and the risk to breastfed infants was assessed (Dualde et al., 2019, 2020).
The ratios between milk and urine levels for parabens and bisphenols have been previously studied (Hines et al., 2015; Fisher et al., 2017).
Several biomonitoring studies use biomonitoring equivalents (BE) or HBMI and HBMII values as biological reference values in urine (Apel et al., 2017; Aylward and Hays, 2011). Except for BPA, there are no BE or HBM values described for the compounds studied in our work. Katsikantami et al. (2019) suggested using the estimated daily intake (EDI) based on the internal concentration of compounds in order to estimate the risk. Once an EDI was estimated for mothers, risk assessment was performed calculating the hazard quotient (HQ) which is the ratio between the EDI and the ADI of the substance (Katsikantami et al., 2019; Yusà et al., 2018).
The aim of the present study was: i) to determine the levels of three bisphenols (BPA, BPS, and BPF) and four parabens (MP, EP, PP and BP) in the urine of breastfeeding mothers living in Valencia, Spain participating in the BETTERMILK project; ii) to study the factors influencing the bisphenol and paraben levels; and iii) to estimate the exposure and the risk assessment to bisphenols and parabens for mothers.
Section snippets
Study design and sample collection
A total of 180 breastfeeding women between 20 and 45 years of age were recruited from June to November 2015 at the University and Polytechnic La Fe Hospital (Valencia, Spain) as a part of the BETTERMILK project. Details of the study design were described previously (Yusà et al., 2017). 103 of the 180 lactating women provided urine samples, which were investigated. Table 1 describes the characteristics of the study population.
Urine samples were collected between 2 and 8 weeks after birth. The
Paraben and bisphenol urine levels
A total of 180 lactating mothers were selected to participate in the study. Urine specimens were obtained from 103 mothers. The participants completed a questionnaire with detailed physical and sociodemographic characteristics, and lifestyle and food consumption habits. These variables are shown in Table 1. Table SD-I describes food consumption by groups taking into account self-administered diet questionnaires. The frequency of use of cosmetic products in breastfeeding mothers is shown in
Discussion
Paraben and bisphenol concentrations in urine for different populations around the world are presented in Table 5. Higher BPA geometric mean concentrations have been described in American women (1.7 and 1.25 ng mL−1) (Pollack et al., 2016; Buckley et al., 2016), and in Australian pregnant women (1.6 and 5 ng mL−1) (Callan et al., 2013; Heffernan et al., 2016) than in the women in our study (0.9 ngmL−1). To our knowledge, regarding the exposure to bisphenols in breastfeeding women, the study by
Conclusions
Three bisphenols (BPA, BPF, and BPS) and four parabens (MP, EP, PP, and BP) were found in urine from Spanish breastfeeding mothers. BPA was the most frequently detected bisphenol, with concentrations ranging from values < LOQ to 40 μg/g creatinine. Low frequencies of detection were observed for BPF, BPS, and BP. MP and EP were the most frequently detected parabens in urinary samples, with concentrations in the 95th percentile of 617 μg/g creatinine (MP) and 35.2 μg/g creatinine (EP). PP was
CRediT authorship contribution statement
Yovana Sanchis: Conceptualization, Methodology, Writing - original draft. Clara Coscollà: Conceptualization, Methodology, Writing - review & editing. Francisca Corpas-Burgos: Formal analysis, Data curation. Máximo Vento: Resources. María Gormaz: Resources. Vicent Yusà: Conceptualization, Methodology, Investigation, Supervision.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The authors would like to thank the work of Eva Villoldo, responsible for the collection of samples, who performed her work with great efficiency. The study would not have been possible without the participating mothers and the effort and enthusiasm of the Division of Neonatology of the Pediatric Department at the University and Polytechnic La Fe Hospital. We want to particularly acknowledge the donors and the IBSPCV BioBank (PT13/0010/0064), integrated in the Spanish National Biobank Network,
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2022, Environmental PollutionCitation Excerpt :Consequently, levels reported in our study might not be completely representative of current urine phenol levels in Spanish pregnant women. In fact, the scarce literature available in Spain (n = 2 studies in either pregnant or breastfeeding women, recruitment period: 2015–2016) seems to point to a decrease in the levels of these pollutants compared to our levels (e.g. median of BPA in urine: 2.33 and 1.4 ng/mL in these two studies versus 2.73 ng/mL in the present study; median range of parabens in urine: 0.02–25.6 ng/mL in one of these studies versus 0.69–64.4 ng/mL in our study) (Martínez et al., 2021; Sanchis et al., 2020). Besides, in spite of our best efforts to avoid residual confounding, some associations may be attributable to it and some statistically significant associations could have resulted from chance, since multiple estimates were derived.
European interlaboratory comparison investigations (ICI) and external quality assurance schemes (EQUAS) for the analysis of bisphenol A, S and F in human urine: Results from the HBM4EU project
2022, Environmental ResearchCitation Excerpt :Mean LOQ values for external expert laboratories were systematically lower than those reported by participants. Table A6 (SM) presents the LOQ values obtained by all participants according to the instrumental method (LC versus GC) and compares these values with previous biomonitoring studies on bisphenols (Gys et al., 2020; Karrer et al., 2020; Sanchis et al., 2020). For BPA, and more significantly for BPS, LOQ values associated with the LC methods were systematically lower than those obtained by the GC method.
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Bettermilk project: E. Torres, M. Cernada, P. Correcher, A. Nuñez, A. Parra and A. Ramón.