Prenatal exposure to bisphenols and cognitive function in children at 7 years of age in the Swedish SELMA study

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Environment International 150 (2021) 106433

Available online 23 February 2021

Prenatal exposure to bisphenols and cognitive function in children at 7 years of age in the Swedish SELMA study

Carl-Gustaf Bornehag

^a^,^b^,^*

, Elin Engdahl

^c

, Maria Unenge Hallerb¨ack

^a

, Sverre Wikstr¨om

^d

, Christian Lindh

^e

, Jo¨elle Rüegg

^c^,^a

, Eva Tanner

^b

, Chris Gennings

^b

aKarlstad University, Karlstad, Sweden

bIcahn School of Medicine at Mount Sinai, New York City, USA

cUppsala University, Uppsala, Sweden

dOrebro University, ¨Orebro, Sweden ¨

eLund University, Lund, Sweden

A R T I C L E I N F O Handling editor: Martí Nadal Keywords:

Bisphenols BPA BPS

BPF Cognitive function Prenatal exposure

A B S T R A C T

Background: Experimental evidence demonstrates that exposure to bisphenol A (BPA), and the recently intro- duced alternatives bisphenol S (BPS) and bisphenol F (BPF) alter normal neurodevelopment. More research is needed to evaluate the associations between exposure to individual BPA alternatives and neurodevelopmental outcomes in humans.

Objective: The present study aimed at examining the individual associations between prenatal BPA, BPS and BPF exposure and cognitive outcomes in children at age 7 years.

Method: Women were enrolled in the Swedish Environmental Longitudinal Mother and Child, Asthma and Al- lergy (SELMA) study, at gestational median week 10.0, and their children were examined for cognitive function at 7 years of age (N = 803). Maternal urinary BPA, BPS, and BPF concentrations were measured at enrollment and childreńs cognitive function at the age of 7 years was measured using the Wechsler Intelligence Scale for Children IV (WISC-IV).

Results: All three bisphenols were detected in over 90% of the women, where BPA had the highest geometric mean concentrations (1.55 ng/mL), followed by BPF (0.16 ng/mL) and BPS (0.07 ng/mL). Prenatal BPF exposure was associated with decreased full scale IQ (β = − 1.96, 95%CI; − 3.12; − 0.80), as well as with a decrease in all four sub scales covering verbal comprehension, perceptual reasoning, working memory and processing speed.

This association corresponded to a 1.6-point lower IQ score for an inter-quartile-range (IQR) change in prenatal BPF exposure (IQR = 0.054–0.350 ng/mL). In sex-stratified analyses, significant associations with full scale IQ were found for boys (β = − 2.86, 95%CI; − 4.54; − 1.18), while the associations for girls did not reach significance (β = − 1.38, 95%CI; − 2.97; 0.22). No significant associations between BPA nor BPS and cognition were found.

Discussion: Prenatal exposure to BPF was significantly associated with childreńs cognitive function at 7 years.

Since BPF is replacing BPA in numerous consumer products globally, this finding urgently call for further studies.

1. Introduction

Bisphenol A (BPA) was first synthesized in 1891 and its estrogenic properties discovered by Edward Charles Dodds in the 1930s while developing estrogenic pharmaceuticals. However, BPA was never commercialized for its estrogenic properties but instead for the usage in epoxy resins and polycarbonate plastics where it has been extensively used during the past 60 years (Vogel, 2009). The ubiquitous use of this chemical is reflected in its presence in urine samples of >95% of

pregnant women globally (Woodruff et al., 2011; Braun et al., 2011).

BPA is a recognized endocrine disrupting chemical (EDC), since it can interfere with hormonal signaling (WHO/UNEP, 2013). As hormones are important for brain development, it may not be surprising that prenatal exposure to BPA has been associated with impaired neurodevelopment in children, primarily with behavioural changes like anxiety, depression, aggression and hyperactivity (Ejaredar et al., 2017;

Mustieles et al., 2015; Rochester et al., 2018). The associations observed between BPA exposure and neurodevelopmental outcomes show clear

* Corresponding author at: Public Health Sciences, Karlstad University, 651 88, Karlstad, Sweden.

E-mail address: carl-gustaf.bornehag@kau.se (C.-G. Bornehag).

Contents lists available at ScienceDirect

Environment International

journal homepage: www.elsevier.com/locate/envint

https://doi.org/10.1016/j.envint.2021.106433

Received 9 October 2020; Received in revised form 29 January 2021; Accepted 29 January 2021

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differences depending on sex of the exposed foetus (Braun et al., 2011;

Harley et al., 2013; Evans et al., 2014; Perera et al., 2016; Braun et al., 2017b; Stacy et al., 2017; Jensen et al., 2019; Freire et al., 2020).

Due to its health risks in sensitive populations, the European Union and Canada now prohibit BPA in consumer products designed for children, such as baby bottles, food contact materials for baby food and toys (European Commission., 2011, Canada, 2010). However, as the use of BPA is decreasing, usage of BPA analogues is on the rise. Two common BPA analogues are Bisphenol S (BPS) and Bisphenol F (BPF). As with BPA, these analogues are present in canned food, thermal receipt papers, personal care products, and water pipes (Chen et al., 2016). The shift from BPA to BPF and BPS containing products is also observed in human exposure studies. For example, while BPA concentrations in urine decreased between 2011 and 2016 among pregnant women in Puerto Rico, as well as between 2000 and 2014 in US adults, BPS concentrations increased (Ashrap et al., 2018; Ye et al., 2015). Similarly, while BPA concentration in Swedish mothers slightly declined between 2009 and 2014, there was a clear increase in urinary BPF levels (Gyllenhammar et al., 2017). The presence of BPA in women of reproductive age is of interest since this chemical can cross the placenta and reach the foetus (Liu et al., 2017). Furthermore, bisphenols likely reach the fetal brain since they have been detected in human adult brain, and thus are able to cross the blood–brain barrier. For example, one study detected BPA and BPF in postmortem brain tissues in 23 out of 24 Dutch adults (Char- isiadis et al., 2018).

BPA, BPS, and BPF are structurally similar, and show similar endocrine disrupting properties (Rochester and Bolden, 2015; Rosenfeld, 2017). The estrogenic responses of all three bisphenols are well established (Molina-Molina et al., 2013; Rosenmai et al., 2014; Kitamura et al., 2005; Cano-Nicolau et al., 2016; Pelch et al., 2019) but these compounds can, to varying extent, also bind to other hormonal receptors as well as interfere with steroid hormone synthesis (Rosenmai et al., 2014). For example, BPA and BPF (but not BPS) have been shown to bind the thyroid hormone transport protein transthyretin (Sauer et al., ˇ 2021), and all three bisphenols (although BPS to a lesser extent) display clear anti-androgenic activity (Rosenmai et al., 2014; ˇSauer et al., 2021).

There is experimental evidence that BPA, BPS and BPF affect neurodevelopmental processes and behaviour (Yin et al., 2019; Gu et al., 2019; Catanese and Vandenberg, 2016; Kinch et al., 2015; Rosenfeld, 2017). Furthermore, there is increasing consistent epidemiological evidence that prenatal exposure to BPA affects child neurobehavior (Mus- tieles et al., 2015). However, human studies specific to neurodevelopmental outcomes and exposure to the BPA alternatives are scarce. One study has reported that higher concentrations of BPS during pregnancy is associated with lower psychomotor development in the children at two years of age (Jiang et al., 2020). We previously showed that prenatal exposure to a mixture of 26 potential endocrine disrupting chemicals was associated with lower IQ among 7-year old children in the Swedish Environmental Longitudinal Mother and Child, Asthma and Allergy (SELMA) study (Tanner et al., 2020). The whole mixture effect was largely weighted by bisphenol compounds, warranting further investigation. Therefore, to inform the single chemical risk assessment paradigm, the present study aimed at examine the individual associations between prenatal BPA, BPS and BPF exposure and cognitive outcomes in children at the age of 7 years.

2. Methods 2.1. Study population

The SELMA study is a population-based pregnancy cohort that recruited more than 2,300 women in the first trimester from prenatal clinics in V¨armland county, Sweden, from November 2007 to March 2010. Detailed recruitment and sample collection procedures have been described previously (Bornehag et al., 2015, Bornehag et al., 2012).

Participants provided written consent and the study was approved by

the Regional Ethical Review Board (Uppsala, Sweden).

We aimed at assessing cognitive function in 1,000 children at 7 years of age. Families were invited consecutively based on the child’s age and 924 were ultimately assessed. The current analysis includes 803 children with complete data on exposure, outcome, and potential confounding variables (Table 1).

2.2. Prenatal bisphenol exposure

First-morning void urine samples were collected from mothers during their first prenatal visit (median 10 weeks of pregnancy). Samples were stored at –20 ^◦C and analysed at the Laboratory of Occupational and Environmental Medicine at Lund University, Lund, Sweden.

The urine samples were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) described by Gyllenhammar et al (Gyllenhammar et al., 2017) to quantify BPS, BPF and BPA. Briefly, samples were deconjugated using β-glucoronidase, and incubated for 30 min. Labeled internal standards for each compound were used. The samples were analyzed in a randomized order and in duplicate.

The limits of detection (LOD) were 0.03, 0.03, 0.2 ng/mL for BPS, BPF and BPA respectively. For concentrations below the LOD, reported (measured) concentrations were used in the statistical calculations (Perkins and Schisterman, 2006). The laboratory is a reference laboratory for analyses of urinary BPA in the Erlangen inter-comparison program (Professor Dr. med. Hans Drexler, Institute and Out-Patient Clinic for Occupational, Social and Environmental Medicine, University of Erlangen-Nuremberg, Germany) with results within the tolerance limits.

To adjust the bisphenol levels for urinary dilution, creatinine was analyzed at the Department of Clinical Chemistry, Lund University Hospital. The laboratory is accredited for creatinine analysis and is using an enzymatic colorimetric method (Mazzachi et al., 2000). The unit for adjusted bisphenol levels is nmol/mmol.

2.3. Cognitive function in children at age 7 years

Nine trained psychologists evaluated cognitive functioning using the Table 1

Description of the study participants.

Characteristics All

children Boys Girls p-value

* N = 803 N = 400 N = 403 N (%)

Mothers education (university

level or higher) 543

(67.6) 272

(68.0) 271

(67.2) 0.819 Mothers smoking during

pregnancy 27 (3.4) 15 (3.8) 12 (3.0) 0.544

Mean (SD) Mothers age (year) 31.4 (4.7) 31.4

(4.6) 31.5

(4.8) 0.916 Mothers weight (kg) 69.4 (14) 69.0

(13) 69.9

(14) 0.350

Mothers IQ score^** 114.4

(16) 114.6

(16) 114.2

(15) 0.714 Child́s cognition scores^***

Full Scale IQ 99.9 (13) 97.9

(13) 101.9 (12)

<0.001 Verbal Comprehension 100.8

(11) 99.6

(12) 102.0

(11) 0.003 Perceptual Reasoning 106.2

(12) 105.8

(13) 106.8

(12) 0.218

Working Memory 89.8 (13) 88.3

(13) 91.3

(14) 0.002

Processing Speed 98.9 (15) 95.6

(15) 102.2 (15)

<0.001

* Differences between boys and girls were analyzed with χ²test for categorical variables and with t-test for continuous variables.

** Shortened Ravens Standard Progressive Matrices.

*** WISC-IV.

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Wechsler Intelligence Scale for Children (WISC-IV), 4th edition (Wechsler, 2003). Four sub scales were used including the Verbal Comprehension Index measuring verbal reasoning and comprehension, the Perceptual Reasoning Index measuring problem solving and visual processing, the Working Memory Index measuring mental control, and the Processing Speed Index measuring the speed and accuracy of visual information processing (Prifitera et al., 2005). A full-scale IQ was used, reflecting overall cognitive abilities based on the sub-scales, which is indexed to have a mean and standard deviation of 100, and 15, respectively.

2.4. Co-factors

At enrollment, data on mothers’ education level (university or higher) and smoking (any smoking during pregnancy reported at recruitment) were collected by questionnaires and data on the mothers’

pre-pregnancy weight was collected from the National birth register.

Maternal IQ was assessed using the shortened Ravens Standard Pro- gressive Matrices (Van der Elst et al., 2013; Raven et al., 1998). These factors together with sex of the child and the mothers age were used for basic adjustments (Model 1) including 803 children. Missing values for the variables in Model 1 is described in Supplemental Table 1.

In a sensitivity analysis, we assessed additional covariates (Model 2), based on prior literature, including birthweight, prematurity (<37 week of pregnancy) and parity from the National birth register and breast feeding from questionnaires when the child was 6 months. When adding these additional co-factors to the statistical model the sample size became smaller (N = 712).

2.5. Statistics

For univariate analyses, we log10-transformed the creatinine- adjusted bisphenols to approximate a normal distribution and calcu- lated geometric means (GM) and 95% confidence intervals (95% CI). In the descriptive statistics presented, the χ²test and t-tests were used to assess potential differences between boys and girls. We also evaluated Pearson correlations between creatinine-adjusted BPA, BPS, and BPF, and tested for trends in exposure levels across the sampling period.

Associations between log-transformed prenatal bisphenol exposure (ng/mL) and cognitive function at 7 years of age was estimated with crude and adjusted linear regression. For the adjusted models we chose covariates based on prior literature and our own data, (see directed acyclic graph (DAG) in Supplemental Fig. 1) (Eriksen et al., 2013; Bor- nehag et al., 2018); the final linear model was adjusted for sex of the child, and maternal age, education, IQ, weight and smoking (Model 1).

Since prior literature suggests boys and girls to have different neurodevelopmental responses to BPA exposure (Mustieles and Fernandez, 2020), we examined the interaction effect of sex and exposure and conducted sex-stratified analyses. In a sensitivity analysis, we assessed additional covariates based on prior literature, including birth weight, prematurity, parity, and breast feeding at six months of age (Model 2) (Eriksen et al., 2013; Oken et al., 2008). We also assessed potential nonmonotonicity using bisphenol tertiles as the exposure variable adjusting for Model 1 co-variates.

Analyses were conducted in SPSS, version 25.

3. Results

The study participants consisted of 803 mother–child pairs (400 boys and 403 girls) for which we had information on all variables described in Table 1. Sixty eight percent of the mothers achieved a college education or higher and 3.5% were active smokers during pregnancy. The mean IQ of the mothers was 114. Among the children, 4.4% were born before gestational week 37. The mean full scale IQ score was 100 with signif- icant higher mean score in girls compared to boys (102 vs. 98, p <

0.001). Compared to boys, girls had also significantly higher scores for

verbal comprehension (102 vs. 100, p = 0.003), working memory (91 vs.

88, p = 0.002), and processing speed (102 vs. 96, p < 0.001). There was no difference in perceptual reasoning scores by sex.

Descriptive statistics for the three bisphenols are reported in Table 2 and in Supplemental Table 2. BPA was found above the level of detection (LOD) in all samples, while 97.4% and 91.4% of the samples contained BPS and BPF above the LOD, respectively. BPA had the highest GM concentrations (1.55 ng/mL), followed by BPF (0.16 ng/mL) and BPS (0.07 ng/mL). There were no significant differences in urine concentrations by sex of the foetus. Urinary levels of the bisphenols were weakly correlated (BPA vs. BPS, r = 0.18, p < 0.01; BPA vs. BPF, r = 0.14, p < 0.01; BPS vs. BPF r = 0.10, p < 0.01).

3.1. Association between prenatal bisphenol exposure and cognitive function in children

Prenatal BPF exposure was significantly associated with lower cognitive function in both crude and adjusted analyses (Fig. 1). The largest magnitude was observed for full scale IQ (β = − 1.96, 95%CI;

− 3.12; − 0.80), p = 0.001), when adjusting for sex of the child, and maternal age, education, IQ, weight and smoking (Model 1), that is a 1.96 point decrease in IQ score per each log-unit increase in BPF concentrations, or a 1.6-point lower IQ score for an inter-quartile-range (IQR) change in prenatal BPF exposure (IQR = 0.05 – 0.35 ng/mL, Table 2). Significant adjusted associations were also observed between BPF and all four sub-scales, with the largest association observed for processing speed: verbal comprehension (β = − 1.10 (95%CI − 2.16;

− 0.03), p = 0.044), perceptual reasoning (β = − 1.51 (95%CI − 2.67;

− 0.35), p = 0.011), working memory (β = − 1.74 (-3.00; − 0.47), p = 0.007), and processing speed (β = − 1.83 (95%CI − 3.28; − 0.38), p = 0.014).

In a sensitivity analysis, we assessed additional covariates including birth weight, prematurity, parity, and breast feeding at six months of age in the statistical model (Eriksen et al., 2013; Oken et al., 2008). How- ever, no major changes in associations between prenatal BPF exposure and cognitive function were observed (Fig. 1, Model 2). In analyses of bisphenol tertiles, the highest BPA and BPS were not associated with WISC-IV scores. Compared to the lowest tertile of BPF, the highest tertile was associated with lower IQ, working memory and processing speed (Supplemental Table 2) indicating dose response associations.

We observed no statistical interaction between child sex and bisphenol exposure on cognitive outcomes (Fig. 2). However, sex- stratified analyses adjusted for Model 1 covariates revealed that associations between BPF and cognitive functioning reached significance in boys but not in girls, although the direction of the beta coefficients were in the same directions in both sexes. The association for IQ corresponded to a 2.3-point decline in IQ score for an IQR change in prenatal BPF exposure among boys. We found no evidence for an association between prenatal exposure for BPA or BPS and cognitive function in total nor sex- stratified analyses.

4. Discussion

This study is the first to show that prenatal BPF exposure is associated with impaired cognitive development in children. Our finding imply that boys may be more susceptible to BPF exposure in utero with regards to cognitive development. This is in line with reports showing an overall higher risk of neurodevelopmental problems, specifically cognitive deficits, in boys compared to girls prenatally exposed to different drugs (Traccis et al., 2020). The notion that boys would be more susceptible to prenatal chemical exposure is also reflected in an overall higher risk of neurodevelopmental disorders in males, compared to females, which may be due to differences in biological mechanisms, for example hormone signaling, between sexes (May et al., 2019). The difference in association strength observed between BPF and cognition in the sexes is in line with previous findings where BPA has been shown

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Table 2

Distribution of urinary levels of three bisphenols in 803 pregnant women and comparisons between mothers with boys and girls foetus. A further description including percentiles is available in Supplemental Table 2.

Phenols Urinary levels (ng/mL) p-value*

All women

(N = 803) Boys

(N = 400) Girls

(N = 403)

25% Median 75% GM

(95% CI) GM

(95% CI)

BPA 0.84 1.44 2.66 1.55

(1.46–1.64) 1.54

(1.41–1.68) 1.53

(1.41–1.66) 0.901

BPS 0.04 0.07 0.12 0.07

(0.06–0.07) 0.07

(0.06–0.08) 0.07

(0.06–0.08) 0.584

BPF 0.05 0.13 0.35 0.16

(0.14–0.18) 0.16

(0.14–0.19) 0.15

(0.13–0.18) 0.632

*Differences between boys and girls analyzed with t-test.

Fig. 1. Association between prenatal bisphenol exposure and cognitive function in children at 7 years of age. * Linear regression model 1: Adjusted for sex of the child, and maternal age, education, IQ, weight and smoking. ** Linear regression model 2: Adjusted for sex of the child, and maternal age, education, IQ, weight and smoking, plus birth weight, prematurity, parity, and breast feeding at six months of age.

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to affect the fetus differently depending on its sex (Braun et al., 2011;

Harley et al., 2013; Evans et al., 2014; Perera et al., 2016; Braun et al., 2017b; Jensen et al., 2019; Braun et al., 2017a). Furthermore, a recent study investigating associations between urinary BPF levels and meta- bolic outcomes also found stronger associations in boys than in girls (Liu et al., 2019). Since we could not find any association with BPA or BPS in neither boys nor girls, the results may indicate a functional difference between these three bisphenols.

Our lack of/null associations regarding BPA and cognitive development, in one way contradict some studies where prenatal or cord-blood BPA has been associated with lower full scale IQ at 7 years of age (Lin et al., 2017), lower verbal scores in boys at 21 months of age, (Jensen et al., 2019), and poorer working memory in 3 year old boys (Braun

et al., 2017a) and 9–11 year old boys (Rodriguez-Carrillo et al., 2019) and placenta BPA have been associated to lower verbal scores in 4–5 year old boys (Freire et al., 2020). However, our data are in line with most other studies where BPA has not been associated with cognitive development (Casas et al., 2015; Nakiwala et al., 2018; Rodriguez- Carrillo et al., 2019; Minatoya et al., 2017). One reason for lack of/

null association with BPA findings may be that BPA has more impact on neurodevelopment in the behavioral domain, which has been shown and discussed earlier (Mustieles and Fernandez, 2020; Rodriguez-Carrillo et al., 2019). In the current study, behavioral outcomes were not evaluated.

When comparing our BPA, BPF and BPS detection frequencies and levels (Table 2) to other studies analyzing these three chemicals, all Fig. 2. Sex-stratified association between prenatal bisphenol exposure and cognitive function at 7 years of age. Results from linear regression model 1 (adjusted for sex of the child, and maternal age, education, IQ, weight and smoking) on cognitive test scores at age 7 years, stratified by sex (N = 400 boys and 403 girls). p-values obtained for the association between bisphenol exposure and cognitive test scores, in sex-stratified analyses, and for the interaction effect of sex and exposure (Sex^xBP) on cognitive test scores.

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studies found BPA to have the highest median concentration, varying between 0.7 and 2.0 µg/L (In our study: 100% detection, GM 1.55 µg/L).

However, BPF was more abundant than BPS in studies from Sweden and China (Gyllenhammar et al., 2017; Jiang et al., 2020), while BPS was more abundant in the United States and Puerto Rico (Ashrap et al., 2018;

Lehmler et al., 2018). We detected BPF and BPS in 91% and 97% of the women (GM 0.16 µg/L and GM 0.07 µg/L respectively), compared to BPF detections between 41 and 98% (0.3–0.6 µg/L) and BPS detections between 68 and 90% (0.04 – 0.5 µg/L) observed by others (Ashrap et al., 2018; Gyllenhammar et al., 2017; Jiang et al., 2020; Lehmler et al., 2018). We can only speculate on the reasons for these differences in measured values. They could be due to methodological differences between analytical laboratories or actual exposure differences between populations due to different exposure sources or different collection times.

We found median BPF levels in the SELMA mothers to be about 10 times lower than the BPA levels (Table 2), potentially adding an additional dimension to the question why the associations observed with BPF are much stronger than with BPA. However, EDCs are known to evoke non-monotonic dose responses and thus to have different effects depending on concentration (Vandenberg et al., 2012), which may partly explain that BPF shows the strongest associations despite being present in lower levels than BPA. However, we did not find evidence for a non-monotonic dose response relationship in the current data. Alter- natively, these compounds might have different toxicokinetic properties, and thus the actual foetal exposure might not correlate linearly to the levels in mother’s urine. Notably, in sheep, BPF has a longer half-life in maternal circulation, but a faster clearance from foetal circulation, compared to BPA and BPS (Gingrich et al., 2019).

It is intriguing, yet mechanistically difficult to explain, that only an association between BPF and cognition was observed. All three bisphenols assessed in this study have the potential to interfere with the endocrine systems that are important for neurodevelopment and could potentially be involved in effects on cognition. Yet, experimental studies have shown that BPA, BPS and BPF vary in their specific effects and potencies on different hormonal systems (Rochester and Bolden, 2015), which might underlie the observed differences.

Although several hormones are important for cognitive development, the most well established are thyroid hormones (THs). Distur- bances in TH levels during early foetal development are known to impair cognitive function (Haddow et al., 1999; Korevaar et al., 2016; Pop et al., 1999; Willoughby et al., 2014) and cause IQ loss in the child (Haddow et al., 1999; Korevaar et al., 2016). In the SELMA mothers, we have observed a positive association between BPF levels and free triio- dothyronine (FT3), which was not observed for BPA or BPS (Derakhshan et al., 2020), indicating a difference of these bisphenols in their effect on the thyroid system. Moreover, all three bisphenols in this study have been shown to interfere with TH signaling in different experimental systems (Zhu et al., 2018; Lee et al., 2019; Zhang et al., 2018; Huang et al., 2016; Lee et al., 2017). However, BPF may differ from BPA and BPS in some aspects of this thyroid disrupting effects (Lee et al., 2019;

Lee et al., 2017). Nevertheless, more experimental results are needed to decipher the role of BPF, and its possible differences compared to BPA and BPS, on TH signaling before concluding if BPF-mediated disturbance in TH signaling may be an underlying cause in the association with lower IQ observed in this study. Since relatively little is known about how BPF can affect neurodevelopment, it is likely that other mechanisms and pathways can contribute to the associations described here.

In this study population, we recently used a whole mixture approach to identify chemicals of concern in relation to lower IQ among 26 chemicals in prenatal urine and serum using weighted quantile sum (WQS) regression (Tanner et al., 2020). We found BPF to have the largest contribution (weight) to the mixture. We also found that BPA and BPS contributed to the mixture effect, particularly for boys and girls respectively, although at much lower weights compared to BPF. The analyses of the present study confirms the association between BPF and

cognition observed with the whole mixture approach, but does not find any evidence that BPA or BPS has the same effect. Since correlations between bisphenols were low, it is unlikely that these differing results regarding BPA and BPS were solely due to collinearity in the WQS mixture analysis or co-pollutant confounding in the single chemical analysis. Also, BPF and BPS are replacing BPA in consumer products, rather than co-occurring. Although we controlled for known confounders, residual confounding may explain these differences. Further research on bisphenol exposure sources and patterns may help identify additional unknown confounding variables. For comparison with our results and to obtain a better understanding of how bisphenols impact neurodevelopment, we recommend that future epidemiologic studies also measure BPA analogues and incorporate both mixture and single chemical statistical analyses.

We observed that one IQR increase in BPF exposure was associated with a 2-point drop in full scale IQ. When we collected the samples in 2007–2010 almost all individuals were found exposed to BPF, and since this exposure is likely to increase due to BPA substitutions, we find such magnitude worrying. A 2-point drop, on an individual level, may not be noticed by the affected individual but is worrying since a 2-point shift in IQ level of a population will lead to less individuals with very high IQ and increase the number of individuals with very low IQ (Bellinger, 2007). A shift in population IQ can lead to increased intellectual disability and productivity loss, which brings high costs for the society (Bellanger et al., 2015; Gaylord et al., 2020). Considering the fact that almost all (91%) of the SELMA mothers that were included in this study had BPF levels above the LOD, and that this exposure is likely to increase due to BPA substitution, we consider our findings as alarming from a public health perspective.

4.1. Strengths and limitations

The study had additional strengths and limitations. The study design, the sample size and control for potential confounders gave us good opportunities to find relevant associations. However, although we controlled for many relevant confounders, there may be residual confounding from variables we were unable to collect. Furthermore, urinary levels of bisphenols may fluctuate over time due to short half-lives and the number of products that act as sources. One single measurement may therefore be questioned as a representative measure for exposure. To resolve this problem, we used first morning void samples, which we regarded as the baseline level for that day.

5. Conclusion

This study shows for the first time that prenatal BPF exposure is associated with decreased cognitive function in children at 7 years, with significant associations in boys. These findings raise concerns since BPF is increasingly used to replace BPA, and thus exposure of humans and wildlife is rising globally. Since there are currently no regulatory guideline values for BPF, our results will inform future risk assessments.

Funding

This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme [project: EDC-MixRisk; grant number 634880], the Swedish research council for sustainable development (Formas) [grant number 2017-00513], and the Powering Research Through Innovative Methods for Mixtures in Epidemiology (PRIME) Program [grant number R01ES028811-01].

Declaration of Competing Interest None.

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Appendix A. Supplementary material

Supplementary data to this article can be found online at https://doi.

org/10.1016/j.envint.2021.106433.

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