Review articleBiomonitoring of human exposures to chlorinated derivatives and structural analogs of bisphenol A
Introduction
Bisphenol A (BPA), 2,2-bis(4-hydroxyphenyl)propane, is a synthetic compound that is widely used as a monomer in polycarbonate plastics and epoxy resins, being one of the world's highest production volume chemicals. Scientific reports linked BPA exposures to the development of obesity and type II diabetes mellitus (T2DM) in humans (Bodin et al., 2015, Chevalier and Fénichel, 2015, Lakind et al., 2014, Riu et al., 2011a, Rochester and Bolden, 2015). Numerous studies reported the association between urine BPA levels and long-term metabolic disorders such as diabetes/impairment of glucose metabolism (Hong et al., 2009, Kim and Park, 2013, LaKind et al., 2012, Lang et al., 2008, Liao et al., 2012a, Mutou et al., 2008, Oppeneer and Robien, 2015, Rezaee et al., 2006, Song et al., 2014b, Staples et al., 1998, Vandenberg et al., 2014, Vela-Soria et al., 2013, Yang et al., 2009, Yang et al., 2014a) and obesity (Bloom et al., 2011, Carwile and Michels, 2011, Galloway et al., 2010, Kim et al., 2012, Ko et al., 2014, Lee et al., 2014, Molina-Molina et al., 2013, Nakao et al., 2015, Rezaee et al., 2006, Stachel et al., 2003, Takeuchi et al., 2004, Vandenberg et al., 2010, Vandenberg et al., 2014, Vandenberg et al., 2007, Wang et al., 2012b, Zhai and Zhang, 2011, Zhao et al., 2012). The frequency of new incidences of the aforementioned metabolic diseases is expected to continue growing in the next couple of decades (Yach et al., 2006, Swinburn et al., 2011), suggesting the environment and lifestyle/behavior as major risk factors for metabolic diseases (Diamanti-Kandarakis et al., 2009, Jeon et al., 2015).
The BPA occurrence in the environment and consumer products is ubiquitous (Kang et al., 2006, Teppala et al., 2012, Von Gunten, 2003, Viñas et al., 2010). Concerns over the aforementioned health outcomes associated with BPA exposures in human studies have resulted for the gradual market entry of BPA structural analogs in consumer products that are speculatively considered safer (BPA-free) than BPA, such as bisphenol S (BPS), bisphenol F (BPF), bisphenol B (BPB), bisphenol AF (BPAF), and observed entering environment and human systems (Liao et al., 2012a, Liao et al., 2012b, Liao et al., 2012c, Liao et al., 2012d). The high reactivity of BPA with disinfectant chlorine (in the forms of either hypochlorite or free chlorine radicals) is evident in the instantaneous formation of chlorinated BPA derivatives (ClxBPA) (Gallard et al., 2004, Melzer et al., 2010, Yuan et al., 2011). Similar reactivity to disinfectant chlorine is anticipated for structural BPA analogs but this remains to be experimentally documented. The formation kinetics and reactions of ClxBPA derivatives has been documented in laboratory experiments using chlorinated tap water and BPA (Gallard et al., 2004). Hypochlorite ions are often added to finished tap water as disinfectant and they are held responsible for the electrophilic attack of phenolic groups in BPA, acting as a precursor of ClxBPA formation (Gallard et al., 2004, Migeot et al., 2013, Yuan et al., 2011). The main ClxBPA derivatives reported so far in the literature are: mono-(ClBPA), di-(Cl2BPA), tri-(Cl3BPA) and tetra-chlorobisphenol (Cl4BPA) (Lee et al., 2004, Riu et al., 2014). Available carbon atom positions for chlorination on the BPA molecule and resulting in the formation of respective ClxBPA, and the structural analogs of BPA are presented in Table 1.
Occurrence of ClxBPA derivatives has been widely reported in a suite of water bodies bodies (Ballesteros et al., 2006, Bastos et al., 2008; Bourgin et al., 2013a, Bourgin et al., 2013b, Bulloch et al., 2015, Casatta et al., 2015, Chang et al., 2014, Chang et al., 2012, Dorival-Garcia et al., 2012a, Dorival-Garcia et al., 2012b, Dupuis et al., 2012, Fan et al., 2013, Fukazawa et al., 2001, Fukazawa et al., 2002, Gallard et al., 2004, Gallart-Ayala et al., 2007, Gallart-Ayala et al., 2010, Kosaka et al., 2012, Lane et al., 2015, Li et al., 2015, Ruan et al., 2015, Takemura et al., 2005, Voordeckers et al., 2002, Yuan et al., 2011, Zafra-Gómez et al., 2008, Zhao et al., 2012, Yuan et al., 2011, Yuan et al., 2010, Zafra-Gómez et al., 2008, Zafra et al., 2003). In addition, BPA is frequently detected in thermal receipts (Fan et al., 2015, Hormann et al., 2014) and certain personal care- and household-cleaning products, such as, bar soaps, facial/body lotions, shampoo, dishwashing and laundry detergent, and toilet bowl cleaner (Dodson et al., 2012). Reported BPA levels in these consumer products ranged between < 10 μg g− 1 and up to ~ 100 μg g− 1 (Dodson et al., 2012), while it was as high as 20 mg g− 1 on thermal receipt paper (Hormann et al., 2014). Residual BPA in these products when come in contact with chlorine-containing water or household cleaning products may react to yield ClxBPA (unpublished experimental observations in our laboratory). Recycled plastic and paper raw materials often contain residual BPA that can react yield ClxBPA in a suite of personal care, and household cleaning products and food contact papers (Zhou et al., 2015). A suite of exposure sources to ClxBPA in the domestic environment is anticipated to drive the nature and range of halogenated derivatives that can form when residual BPA comes in contact with chlorine and other chemical constituents in household tap water and consumer products. This may lead to subsequent exposure to humans with unknown intensities, duration of exposures and possible health effects.
During the past decade, structural BPA analogs have been replacing BPA in numerous industrial, commercial and consumer products, such as, container linings (Oldring et al., 2006), infant food formulae (Cunha et al., 2011), polycarbonate food container linings (Fromme et al., 2002), thermal receipts (Becerra and Odermatt, 2012, Liu et al., 2005), and canned and packaged food and beverages (Cacho et al., 2012, Grumetto et al., 2008, Liao and Kannan, 2013, Viñas et al., 2010). As a result, BPA structural analogs have been also detected in various environmental media, such as, indoor dust (Liao et al., 2012b, Wang et al., 2012c), food (Petersen et al., 2003), food contact recycled paper items (Perez-Palacios et al., 2012), water and sediment (Liao et al., 2012d), etc.
An increasing frequency of scientific reports are found in the literature dealing with the sources and routes of human exposure, biomonitoring, metabolism, and toxicity of ClxBPA and BPA structural analogs in ecotoxicological and animal studies, albeit less in humans. The occurrence of BPA structural analogs in human matrices has been recently reported (Vela-Soria et al., 2014a, Yoshihara et al., 2004, Zafra-Gómez et al., 2008, Zhou et al., 2014). Hence, it is a timely topic to summarize the current research status and discuss future opportunities in this review. The primary objective of this review was to survey all available studies reporting biomonitoring of ClxBPA and BPA structural analogs in human matrices. Focus was paid on describing the analytical methodologies practiced for the analysis of ClxBPA and BPA structural analogs using hyphenated chromatography and mass spectrometry techniques, because current methodologies for extraction and analysis in human matrices are often complex and time-consuming. A brief discussion was also provided on the human exposure sources and routes to ClxBPA, their metabolism and toxicity observed from in vitro and in vivo studies and human health effects, including current limitations and future research needs. In the following sub-sections, we review each one of these topics by gathering relevant reported studies in the literature.
Section snippets
Literature search
A comprehensive literature search in Scopus (1960 onwards) was performed in order to identify studies reporting biomonitoring of ClxBPA and BPA structural analogs in human matrices. Using multiple combinations of keywords (bisphenol* AND (chlorin* OR chlorinated OR chloro*) AND (derivative* OR analog* OR substitute*)) we performed the search on 25–26 May 2015 that resulted in 442 articles. PubMed and Web of Science search using the same keywords resulted in 58 and 272 articles, respectively;
Methodological advances in biomonitoring protocols
Biomonitoring-based protocols to assess internal exposures to ClxBPA and structural BPA analogs relied upon GC–MS/MS and LC–MS/MS techniques both satisfactorily performing in regards to analytical method accuracy and sensitivity for ClxBPA quantitation (as in the example of breast milk, Rodriguez-Gomez et al., 2014b). However, LC–MS technology is most commonly used in human biomonitoring protocols of ClxBPA derivatives (10 out of 14 studies, Table 4). A single methodology for ClxBPA extraction
Conclusion
Collective evidence reviewed in this report suggested a widespread occurrence of ClxBPA and structural analogs of BPA in human biospecimen matrices and various environmental media as fueled by recent years' growing scientific interest. Exposure sources and pathways of ClxBPA and structural BPA analogs in a suite of environmental media and consumer products were evident, yet to be fully elucidated. It was suggested that the increased halogen content of ClxBPA could modify the physicochemical
Competing financial interests
The authors declare no competing financial interests.
Acknowledgments
KCM would like to thank the European Structural Funds and the Cyprus Research Promotion Foundation project #0713/18 for partially funding this study. J. V. van Vliet-Ostaptchouk is supported by a Diabetes Funds Junior Fellowship from the Dutch Diabetes Research Foundation (project no. 2013.81.1673).
References (177)
A multi-class bioanalytical methodology for the determination of bisphenol A diglycidyl ethers, p-hydroxybenzoic acid esters, benzophenone-type ultraviolet filters, triclosan, and triclocarban in human urine by liquid chromatography-tandem mass spectrometry
J. Chromatogr. A
(2014)Molecular docking of bisphenol A and its nitrated and chlorinated metabolites onto human estrogen-related receptor-gamma
Biochem. Biophys. Res. Commun.
(2012)Sensitive gas chromatographic-mass spectrometric method for the determination of phthalate esters, alkylphenols, bisphenol A and their chlorinated derivatives in wastewater samples
J. Chromatogr. A
(2006)A standardized method for assessment of oxidative transformations of brominated phenols in water
Chemosphere
(2008)Bisphenol A induces reactive oxygen species generation in the liver of male rats
Toxicology
(2003)Chlorination of bisphenol A: non-targeted screening for the identification of transformation products and assessment of estrogenicity in generated water
Chemosphere
(2013)Differential chemical profiling to identify ozonationby-products of estrone-sulfate and firstcharacterizationofestrogenicity in generateddrinkingwater
Water Res.
(2013)System suitability in bioanalytical LC/MS/MS
J. Pharm. Biomed. Anal.
(2007)Stir bar sorptive extraction coupled to gas chromatography–mass spectrometry for the determination of bisphenols in canned beverages and filling liquids of canned vegetables
J. Chromatogr. A
(2012)Reliable quantification of bisphenol A and its chlorinated derivatives in human breast milk using UPLC–MS/MS method
Talanta
(2012)
Urinary bisphenol A and obesity: NHANES 2003–2006
Environ. Res.
Tracing endocrine disrupting chemicals in a coastal lagoon (Sacca di Goro, Italy): sediment contamination and bioaccumulation in Manila clams
Sci. Total Environ.
Aerobic degradation of tetrabromobisphenol-A by microbes in river sediment
Chemosphere
Simultaneous quantification of multiple classes of phenolic compounds in blood plasma by liquid chromatography-electrospray tandem mass spectrometry
J. Chromatogr. A
Endocrine disruptors: New players in the pathophysiology of type 2 diabetes?
Diabete Metab.
Quantification of free and total bisphenol A and bisphenol B in human urine by dispersive liquid-liquid microextraction (DLLME) and heart-cutting multidimensional gas chromatography–mass spectrometry (MD-GC/MS)
Talanta
Stir bar sorptive extraction for trace analysis
J. Chromatogr. A
Use of solid-phase microextraction followed by on-column silylation for determining chlorinated bisphenol A in human plasma by gas chromatography–mass spectrometry
J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.
Analysis of bisphenol A and its chlorinated derivatives in sewage sludge samples Comparison of the efficiency of three extraction techniques
J. Chromatogr. A
Improved sample treatment for the determination of bisphenol A and its chlorinated derivatives in sewage sludge samples by pressurized liquid extraction and liquid chromatography-tandem mass spectrometry
Talanta
A new chapter in the bisphenol A story: bisphenol S and bisphenol F are not safe alternatives to this compound
Fertil. Steril.
Bisphenol-A and chlorinated derivatives in adipose tissue of women
Reprod. Toxicol.
Occurrence of phthalates and bisphenol A and F in the environment
Water Res.
Identification and quantification of chlorinated bisphenol A in wastewater from wastepaper recycling plants
Chemosphere
Chlorination of bisphenol A: kinetics and by-products formation
Chemosphere
On-line solid phase extraction fast liquid chromatography-tandem mass spectrometry for the analysis of bisphenol A and its chlorinated derivatives in water samples
J. Chromatogr. A
Are potential sources for human exposure to bisphenol-A overlooked?
Int. J. Hyg. Environ. Health
Community level exposure to chemicals and oxidative stress in adult population
Toxicol. Lett.
Minireview: PPARγ as the target of obesogens
J. Steroid Biochem. Mol. Biol.
Determination of Bisphenol A and its chlorinated derivatives in placental tissue samples by liquid chromatography-tandem mass spectrometry
J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.
Influence of household cleaning practices on the magnitude and variability of urinary monochlorinated bisphenol A
Sci. Total Environ.
Human exposure to bisphenol A
Toxicology
Novel stir bar sorptive extraction methods for environmental and biomedical analysis
J. Pharm. Biomed. Anal.
Association between urinary concentrations of bisphenol A and type 2 diabetes in Korean adults: a population-based cross-sectional study
Int. J. Hyg. Environ. Health
Estrogenic activity of alkylphenols, bisphenol S, and their chlorinated derivatives using a GFP expression system
Environ. Toxicol. Pharmacol.
Identification of estrogenic activity of chlorinated bisphenol A using a GFP expression system
Environ. Toxicol. Pharmacol.
Chlorination and chloramination of bisphenol A, bisphenol F, and bisphenol A diglycidyl ether in drinking water
Water Res.
Effects of chlorine on the decrease of estrogenic chemicals
Water Res.
Formation of organochlorine by-products in bleached laundry
Chemosphere
Transformation of bisphenol A in water distribution systems: a pilot-scale study
Chemosphere
Exposure to bisphenol A is associated with low-grade albuminuria in Chinese adults
Kidney Int.
Screening estrogenic oxidized by-products by combining ER binding and ultrafiltration
Environ. Toxicol. Pharmacol.
In vitro study on the agonistic and antagonistic activities of bisphenol-S and other bisphenol-A congeners and derivatives via nuclear receptors
Toxicol. Appl. Pharmacol.
Induction of apoptosis by UV-irradiated chlorinated bisphenol A in Jurkat cells
Toxicol. in Vitro
Determination of the xenoestrogens 4-nonylphenol and bisphenol A by high-performance liquid chromatography and fluorescence detection after derivatisation with dansyl chloride
J. Chromatogr. A
Ipso substitution of bisphenol A catalyzed by microsomal cytochrome P450 and enhancement of estrogenic activity
Toxicol. Lett.
Cleaning products and air fresheners: Exposure to primary and secondary air pollutants
Atmos. Environ.
Preliminary evidence of the association between monochlorinated bisphenol A exposure and type II diabetes mellitus: A pilot study
J. Environ. Sci. Health A Tox. Hazard. Subst. Environ. Eng.
Association between urinary levels of bisphenol A and its monochlorinated derivative and obesity
J. Environ. Sci. Health A Tox. Hazard. Subst. Environ. Eng.
Stir bar sorptive extraction (SBSE), a novel extraction technique for aqueous samples: Theory and principles
J. Microcolumn Sep.
Cited by (61)
Recent advances of mass spectrometry-based analytical methods for endocrine disrupting chemicals in human matrices
2024, TrAC - Trends in Analytical ChemistryConstruction of copper-manganese based aminoclays with significant laccase-like activity and its prominent degradation performance towards bisphenol A
2024, Journal of Environmental Chemical EngineeringIdentification of Aloe-derived natural products as prospective lead scaffolds for SARS-CoV-2 main protease (M<sup>pro</sup>) inhibitors
2022, Bioorganic and Medicinal Chemistry LettersTetrachlorobisphenol A induced immunosuppression and uterine injury in mice
2021, Ecotoxicology and Environmental Safety