Bisphenols: More unnecessary surprises

ABSTRACT

A recent biomonitoring study “Bisphenol A, Bisphenol S, and 4-Hydroxyphenyl 4-Isoprooxyphenylsulfone (BPSIP) in Urine and Blood of Cashiers” reported on levels of BPA, BPS, and a novel BPS-derivative (BPSIP) in cashiers compared to non-cashiers. Our study was the first to detect BPSIP in humans. In this commentary we discuss our findings in the context of considering bisphenols as a class in health assessments and how technological advances in exposure assessment could be utilized to more efficiently identify emerging chemicals of interest.

KEYWORDS:

• bisphenol A
• bisphenol AP
• bisphenol AF
• bisphenol B
• bisphenol C
• bisphenol E
• bisphenol F
• bisphenol P
• bisphenol S
• bisphenol Z
• endocrine disruption
• mixtures

Introduction

Human exposure to bisphenol A (BPA) is widespread¹² and BPA is associated with a wide range of health outcomes in animal and human studies.³² Based on its use in the manufacture of polycarbonate plastic and epoxy resins in food packaging containers and can linings, the primary route of exposure to BPA in the population is thought to be oral; however, other sources of exposure have also been identified. For example, dermal exposure may also be a significant route as BPA and BPA analogs such as bisphenol S (BPS) are used as a dye developer in thermal paper products, including cash register receipt paper.^12,20,30

In June 2015 we published a biomonitoring study "Bisphenol A, Bisphenol S, and 4-Hydroxyphenyl 4-Isoprooxyphenylsulfone (BPSIP) in Urine and Blood of Cashiers" ²⁸ in which we reported on levels of BPA, BPS, and a novel BPS-derivative (BPSIP) in cashiers compared to non-cashiers. In brief, BPS concentration in urine was significantly higher in post- than pre-shift in 33 cashiers who handled receipts containing BPS. BPA concentrations in urine from 31 cashiers who handled BPA receipts were as likely to be lower as higher in samples collected after a shift, but on average were significantly higher than in non-cashiers controls. BPSIP was detected more frequently in urine of cashiers handling BPSIP receipts compared to non-cashiers, and interestingly, while only a few cashiers had detectable levels of total BPA or BPS in serum, BPSIP tended to be detected more frequently. Our study was the first to detect BPSIP in humans.

In this commentary we discuss our findings in the context of considering bisphenols as a class of chemicals in health assessments and how technological advances in exposure assessment could be utilized to more efficiently identify emerging chemicals of interest.

It's time to consider bisphenols as a class in health assessments

In our study in cashiers we identified occupational exposure to BPA, BPS, and BPSIP. Most participants had detectable levels of at least 2 of these chemicals in their urine. We did not attempt to measure other BPA analogs in our study, but bisphenol B and 4,4-bisphenol F have been detected in urine or blood in other studies in non-occupational settings^6,7,11,33,34 (Table 1). These and other bisphenols (bisphenol AP, bisphenol AF, bisphenol P, bisphenol Z) can be found in food and beverage containers.^{1,4,8,9,10,13,14,17} Still other bisphenols have also been identified as theoretical alternatives to BPA in thermal paper (2,4-bisphenol S, BPS-MAE, TGSA, BPS-MPE, bisphenol C, bisphenol PH), although the extent to which they are actually being used is not known²⁹ nor is there any legal requirement for chemical manufactures to release this information.

Table 1. Bisphenol A analogs (NTP 2013; NTP,2014). Italics indicate that this chemical has been suggested for use as described, but its use or detection has not been confirmed.

Structure	Chemical (CASRN)	Detection	Structure	Chemical (CASRN)	Detection
	Bisphenol S(80-09-1)	blood^1, food^2, dust^3, sediment^4, receipts^5^,^6^,^7^,^8, urine^9^,^10		4,4-Bisphenol F(620-92-8)	food^2^,^11^,^12, dust^3, sediment^4, receipts^8, urine^9^,^10, PCP^13, municipal sewage sludge^22
	Bisphenol AP(1571-75-1)	food^2, dust^3, sediment^4, receipts^8		Bisphenol AF(1478-61-1)	food^2, dust^3, sediment^4, municipal sewage sludge^22
	Bisphenol B(77-40-7)	food^2, 14,-18, dust^3, sediment^4, blood^19, urine^20		Bisphenol Z(843-55-0)	food^2^,^11 sediment^4, PCP^13
	BPSIP(95235-30-6)	urine^21, receipts^21		2,2-Bisphenol F(2467-02-9)	resins^24
	Bisphenol E(2081-08-5)	municipal sewage sludge^22		TMBPA(5613-46-7)	polycarbonate resin^r23
	Bisphenol C(79-97-0)	receipts^8		Bisphenol PH(24038-68-4)	receipts^8
	2,4-BPS(5397-34-2)	receipts^8		TGSA(41481-66-7)	receipts^8
	BPS-MAE(97042-18-7)	receipts^8		BPS-MPE(63134-33-8)	receipts^8
	MBHA(5129-00-0)	receipts^8

Italics indicate that this chemical has been suggested for use as described, but its use or detection has not been confirmed.

Abbreviations: 2,4-BPS (2,4'-Bis(hydroxyphenyl)sulfone); Bisphenol PH (4,4'-Isopropyllidenebis(2-phenylphenol)); BPS-MAE (Phenol,4-[[4-(2-propen-1-yloxy)phenyl]sulfonyl]-); BPS-MPE (4-Hydroxy-4'-benzyloxydiphenylsulfone); D-8 (4-Hydroxyphenyl 4isoprooxyphenylsulfone); MBHA (Methyl bis(4-hydroxyphenyl)acetate); PCP (personal care products); PHBB (Benzyl 4-hydroxybenzoate); TGSA (Bis-(3-allyl-4-hydroxyphenyl) sulfone); TMBPA (Tetramethyl bisphenol A)

References

^{1 (18)},

^{2 (17)},

^{3 (19)},

^{4 (21)},

^{5 (20)},

^{6 (1)},

^{7 (2)},

^{8 (30)},

^{9 (33)},

^{10 (34)},

^{11 (4)},

^{12 (13)},

^{13 (5)},

^{14 (8)},

^{15 (9)},

^{16 (10)},

^{17 (14)},

^{18 (13)},

^{19 (6)},

^{20 (7)},

^{21 (28)},

^{22 (27)},

^{23 (16)}, ²⁴⁽³⁾.

Notes: BPZ assessed in dust but not detected,¹⁹ BPP assessed in sediment but not detected.²¹

In addition to likely having similar sources of exposure, these chemicals may also have similar biological activity. A network analysis in which the biological activity across the Tox21 high-throughput screening platform (https://ncats.nih.gov/sites/default/files/factsheet-tox21.pdf) shows a clustering of analogs near BPA. These chemicals also cluster near reference estradiol derivatives, which suggests that BPA analogs have at least some overlap in their biological activities with estradiol in the Tox21 assays (Fig. 1).

Figure 1. Similarity of BPA analogs across Tox21 high throughput screening network. A correlation network was drawn using Cytoscape software (version 3.1.1)²⁶ to describe the similarity of BPA analogs with respect to BPA (yellow) and several estradiol derivatives (red). The correlation network was derived from the direction adjusted, weighted area under the curve (wAUC) values from dose-response measurements from 39 biological assays for 11,153 chemicals in the Tox21HTS platform.¹⁵ A correlation threshold of 0.75 was set for inclusion in the network. Compounds included in the Tox21 network analysis include: BPA (bisphenol A), BPAF (bisphenol AF), BPE (bisphenol E), 2,2-BPF (2,2-bisphenol F), 4,4-BPF, BPB (bisphenol B), BPC (bisphenol C), BPS (bisphenol S), BPZ (bisphenol Z). TMBPA (tetramethyl bisphenol A )and TGSA (bis-(3-allyl-4-hydroxyphenyl) sulfone ) did not reach the threshold correlation and are not included in the network. Some compounds are represented multiple times because they occurred more than once in the Tox21 library. Chemicals clustering with only one or a few near neighbors are arrayed in the rows at the bottom of the larger network.

Given that a number of these chemicals may have similar sources of exposure (food packaging, thermal paper), it may be possible that BPA urine levels in epidemiology studies serve as a surrogate indicator of exposure to the broader class of BPA-related chemicals. If true, this may help explain findings from some epidemiological studies reporting adverse health effects associated with "low" human urine levels of BPA.^24,25,31,32 Of course, consideration of exposure to a class of chemicals is not a new concept in toxicology or epidemiology (e.g., dioxins, organophosphate pesticides) but has yet to be extended to bisphenols. Future research should better characterize patterns of co-exposure and take into account similar biological properties and exposures to BPA analogs.

Taking better advantage of technological advances in exposure science and high throughput screening

The somewhat unanticipated discovery of BPSIP in the blood and urine of cashiers, and the completely unanticipated discovery of this chemical in samples from non-cashiers raises several important public health issues. Clearly there is very little known about the health effects of exposures to BPSIP, and the reason that this chemical was of possible interest to us was simply because of its appearance on a list of potential BPA replacement chemicals in thermal paper.²⁹ BPA has a myriad of known uses, although recognition of the very high concentrations in thermal receipt paper was only relatively recently brought to the attention of the public.^2,20 As we were in the process of recruiting volunteers to participate in our cashier study, use of BPA in thermal paper was becoming known, and stores began switching to "non-BPA" receipt paper containing BPS. In response, research into the possible health effects of BPS was initiated, which must now expand to include consideration of BPSIP.

Clearly environmental health research cannot keep ahead, or even keep up with the rate and number of new materials that modern industry is introducing into commerce. Absent an industry obligation to disclose ingredients, we first must detect and identify novel substances before we can decide what to further evaluate for potential adverse health effects. Fortunately, new research programs targeting the "exposome" are taking a holistic analytical approach toward the "untargeted" measurement of thousands of exogenous and endogenous compounds in human biospecimens. Although it is not currently possible to identify more than a small fraction of the tens of thousands of substances that comprise the exposome, projects such as HELIX (http://www.projecthelix.eu/), EXPOsOMICS (http://www.exposomicsproject.eu/), HEALS (http://www.heals-eu.eu/), and HERCULES (http://emoryhercules.com/) are making inroads in this area. Also, new analytical chemistry biospecimen analysis programs focusing on children and supported by the National Institute of Environmental Health Sciences will start coming on line next year (http://www.niehs.nih.gov/research/supported/dert/programs/chear/). Our interest in BPA and our large institutional investment in BPA-related research (https://www.niehs.nih.gov/health/topics/agents/sya-bpa/)²⁵ is not simply aimed at this single substance, but rather is intended to explore the range of health implications that may be expected from exposures to environmental levels of endocrine disrupting substances. At this point we do not know enough to predict whether BPSIP represents a risk to the developing human, but the class studies mentioned earlier should provide clues. What is perhaps more unsettling is the fact that when questioned as to where the BPSIP found in non-cashiers was coming from, our industry colleagues could not provide an answer. So, the challenge for environmental health researchers is even more daunting. First we must find out what we are being exposed to; second whether the exposures have any potential health effects; but ultimately, we are still left with the task of figuring out how people are being exposed. Industry needs to accept its public health obligations to identify and evaluate the safety of substances it introduces into our daily lives. At the same time, federal high throughput screening programs should develop mechanisms to assist industry to enable rapid, valid screening for potential alternatives. This would provide no guarantee that new alternatives would in fact be safer, but would at least provide some data on which to make responsible replacement decisions.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

We gratefully acknowledge the contributions of Drs. Thaddeus Schug and Nigel Walker for reviewing a draft version of the commentary.

Funding

Funding for the preparation of this commentary was supported by the National Institute of Environmental Health Sciences (NIEHS).