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. 2024 Jan 23;198(2):185–190. doi: 10.1093/toxsci/kfad136

Evidence evaluated by European Food Safety Authority does not support lowering the temporary tolerable daily intake for bisphenol A

Robyn L Prueitt 1,✉, Julie E Goodman 2
PMCID: PMC10964741  PMID: 38265237

Abstract

The European Food Safety Authority (EFSA) recently derived a tolerable daily intake (TDI) for bisphenol A (BPA) of 0.2 ng/kg bw/day. There are several issues with EFSA’s hazard assessment review process, including that it was based on a limited subset of relevant studies. Multiple public commenters on EFSA’s draft evaluation of BPA, including several European regulatory agencies, noted these issues, yet they were not adequately addressed by EFSA in the final evaluation. The TDI for BPA was based on an intermediate immunotoxicity endpoint in mice that has not been observed in other species; there is no evidence that it is a precursor event to any downstream pathological outcome. The TDI is several orders of magnitude lower than estimates of safe doses of BPA established by agencies worldwide, including EFSA’s temporary TDI (t-TDI) for BPA established in 2015. Overall, the EFSA hazard assessment review process has led to a conclusion that there are low-dose effects of BPA based on very few, lower quality experimental animal studies. This conclusion is not supported by the totality of the available evidence, which includes multiple high-quality studies not considered by EFSA and indicates that the t-TDI established in 2015 is protective of human health.

Keywords: bisphenol A, European Food Safety Authority, hazard assessment, regulatory review, tolerable daily intake, weight of evidence

The European Food Safety Authority (EFSA) first established a tolerable daily intake (TDI) for bisphenol A (BPA) of 0.05 mg/kg bw/day in 2006 (EFSA, 2006). In 2015, the EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids reviewed the literature on the potential health effects of BPA exposure and established a slightly lower temporary TDI (t-TDI) of 4 μg/kg bw/day (EFSA CEF, 2015). This EFSA Panel compared the t-TDI with exposure estimates and concluded that there is no health concern for any age group from estimated levels of dietary exposure to BPA and that the health concern is low for estimated aggregated exposure to BPA from dietary and non-dietary sources (EFSA CEF, 2015).

On December 15, 2021, the EFSA Panel on Food Contact Materials, Enzymes, and Processing Aids (CEP) released a draft Opinion entitled “Re-evaluation of the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs” (referred to herein as the “draft Opinion”) (EFSA CEP, 2021). This evaluation focused only on studies published since 2013 for most endpoints and did not include a fully integrated interpretation of newer and older studies. The EFSA CEP Panel identified the immune system as the most sensitive target for BPA toxicity and proposed a TDI of 0.04 ng/kg bw/day, which is 100 000 times lower than the t-TDI established by EFSA in 2015 (EFSA CEF, 2015).

EFSA received 181 unique comments from the public consultation on the draft Opinion (EFSA CEP, 2023a). Several issues were brought up by multiple commenters, particularly with regard to the hazard assessment review process. The EFSA CEP Panel provided a response to all of these comments (EFSA CEP, 2023a), but in our opinion, it did not provide adequate scientific justification in its responses. Instead, in most cases, the EFSA CEP Panel simply repeated the same text for its decisions as in the draft Opinion. The EFSA CEP Panel ultimately increased the TDI in its final Opinion, but only 5-fold, to 0.2 ng/kg bw/day (EFSA CEP, 2023b). This TDI is based on the same immunotoxicity endpoint as the draft TDI, but differences in benchmark dose (BMD) modeling and uncertainty factors (UFs) resulted in a final TDI that is 20 000-fold lower than the t-TDI established in 2015 (rather than 100 000-fold lower). Below, we discuss the key issues with the draft Opinion, including some arguments brought up by commenters and in the published literature (eg, Zagorski and Kaminski, 2023), and how these issues remain in the final Opinion and bear on the derivation of the final TDI.

EFSA hazard review process

In 2016, EFSA was mandated by the European Commission “to take into consideration new data available from the results of the US NTP/FDA study due in 2017 as well as all other new available information not previously evaluated by EFSA” (EFSA CEP, 2023b). The EFSA CEP Panel interpreted this as a mandate to conduct the evaluation only based on new information not considered in the 2015 EFSA evaluation of BPA. This was primarily limited to studies published from January 1, 2013, until October 15, 2018, and included studies of several health outcome categories, including the immune, male reproductive, female reproductive, developmental, metabolic, and neurodevelopmental systems (EFSA CEP, 2023b).

However, the mandate only indicates that new information should be included, and not that it should be the only information evaluated. Such an interpretation goes against EFSA’s own guidance on using a weight-of-evidence approach, which states that all potentially relevant evidence should be considered, and limitations on time and resources may require a focus on the most relevant and/or reliable evidence, not on evidence from a limited time period (EFSA, 2017). EFSA did not impose such limits on the literature reviewed for its hazard evaluation and derivation of a t-TDI for BPA in 2015 (EFSA CEF, 2015). In the current review, limiting the time period resulted in the exclusion of multiple high-quality, robust studies conducted following stringent guidelines and that provide consistent, reproducible, and reliable results that greatly contribute to the weight of evidence. The EFSA CEP Panel did not adequately integrate any older studies with the newly reviewed studies to assess whether they support or contradict one another for a specific endpoint or health outcome category; thus, the BPA review does not constitute a true weight-of-evidence evaluation.

In addition, the EFSA CEP Panel ranked individual studies in quality tiers based on expert judgment regarding several aspects of study quality, but there was often no clear guidance provided on the basis of these judgments. For example, the experts were asked to judge experimental animal studies on whether outcome assessors were adequately blinded to the study group, or whether an appropriate number of animals was used in each study group, but there was no guidance on what “adequately” blinded means or on the “appropriate” number of animals to use. In several instances, this lack of guidance led to different ratings of the study quality aspects and to the ranking of the same study in different tiers when evaluated by different reviewers.

Furthermore, EFSA grouped endpoints into health outcome categories based on judgments of whether the endpoints are related, but there was no evaluation of how the endpoints should reflect an underlying mode of toxic action and no distinction of precursor, transitory, intermediate, or frank apical effects. Dose-response analysis was based largely on the ability to carry out BMD analyses on each dataset, and the endpoint with the lowest BMD lower confidence limit (BMDL) was selected. This resulted in very sensitive endpoints being chosen to characterize the toxicity potential of the health outcome category, even when these endpoints have unclear connections to apical toxicity.

TDI derivation

The EFSA CEP Panel concluded that the immune system was the most sensitive health outcome category based on the study by Luo et al. (2016). Luo et al. (2016) exposed pregnant ICR mouse dams to 10, 100 or 1000 nM BPA (equivalent to 0.475, 4.75, or 47.5 μg/kg bw/day) via drinking water from gestational day 0 to postnatal day 21. At postnatal days 21 and 42, offspring blood samples and spleens were collected. The authors reported that BPA caused a dose-dependent and sex-specific increase in the percentage of Th17 cells (a subpopulation of T helper lymphocytes) among all T helper lymphocytes in the spleen.

The Th17 cell endpoint is the basis of the proposed TDI and was selected solely for having the lowest BMDL. The EFSA CEP Panel did not fully consider the reliability of the underlying study, or whether this is an adverse effect and whether this observation is consistent and coherent with other studies in both animals and humans. The final Opinion noted that the assessments of immunotoxicity endpoints, including the Th17 cell endpoint, differed substantially among the experts on the EFSA CEP Panel, increasing the uncertainty in the use of this endpoint as a critical effect.

The EFSA CEP Panel noted that the percentage of Th17 cells is an intermediate endpoint (EFSA CEP, 2023b). Using such an endpoint for BMD analysis and derivation of a TDI goes against the stated general approach by the EFSA CEP Panel that for clusters of immune-related endpoints, only those directly linked to an apical endpoint should be used for BMD analysis rather than intermediate endpoints, and that an endpoint must have a clear causal relationship with an adverse outcome to be used in risk assessment (EFSA CEP, 2023b). In addition, the EFSA CEP Panel stated, “For Th17 cells, there is currently insufficient information available on the normal variability of this measure, either in the mouse strain used in the study, or other strain, or in humans” (EFSA CEP, 2023b), indicating that the EFSA CEP Panel questioned the adversity of the Th17 cell endpoint. Further, the EFSA CEP Panel indicated that the need for application of a UF for use of an intermediate endpoint as a reference point should be considered, but did not do so because of a lack of relevant quantitative data or specific risk assessment guidance for using intermediate endpoints in this manner.

Notably, the EFSA CEP Panel increased the benchmark response level for the increase in Th17 cell percentage from 20% in the draft Opinion to 40% in the final Opinion to account for variability of human lymphocyte populations. The EFSA CEP Panel stated that even though the normal variability of Th17 cell numbers is unclear, a 40% increase in this parameter in the general population may move individuals at the higher end of the range to outside the normal range, even if a 40% increase in an individual may not necessarily imply an adverse outcome for that individual (EFSA CEP, 2023b). This statement, as well as the fact that the EFSA CEP Panel determined that the 20% benchmark response used for the draft TDI was too stringent given the variability in Th17 cell number, provides further support that the much smaller increases in Th17 cell percentages in mouse spleen (generally increasing from a range of 1.2%–1.3% in untreated mice to 2%–3% in BPA-treated mice) used as the basis for the TDI do not constitute an adverse effect and should not be used as a reference point for deriving a TDI. In the final Opinion, the EFSA CEP Panel also applied a UF of 2 (in addition to the default UF of 25) to the reference point because an assessment by expert judgment, as part of the uncertainty analysis, determined there was a 57%–75% probability that the lowest estimated BMDL for other sensitive health endpoints for which BMDLs could not be calculated was below the reference point for the Th17 cell endpoint (EFSA CEP, 2023b).

Limitations of Th17 cell study

Many of the public comments, as well as published commentaries, on the draft Opinion have highlighted important shortcomings of the Luo et al. (2016) study and the issues with the EFSA CEP Panel’s interpretation of the study. Luo et al. (2016) analyzed 10-11 mice per sex in each dose group but did not calculate sample size with a power analysis. Low statistical power due to small sample size not only reduces the chance of detecting a true effect (if there is one) but can also reduce the likelihood that an observed, statistically significant effect is actually a true effect and can exaggerate the magnitude of any true effects that are detected (Button et al., 2013). Luo et al. (2016) also did not blind investigators to dose groups, used polycarbonate cages that could have contributed to additional exposures to BPA, and did not confirm BPA exposure with internal dosimetry. In addition, the authors postulated an increase in the percentage of Th17 cells in the spleen from evaluating the percentage of Interleukin-17 (IL-17+) cells among all CD4+ T cells, not from actual Th17 cell counts. As discussed by Zagorski and Kaminski (2023), IL-17 is produced by a variety of immune cells, not just Th17 cells, so the percentage of IL-17+ cells in the spleen may not represent the percentage of Th17 cells. Also, the BPA-induced increase in IL-17+ cell percentage was identified after ex vivo stimulation of isolated splenocytes with a nonspecific leukocyte activator, which is not a physiologically relevant process, and the resulting increase in IL-17+ cell percentage was weak and not much different than the background frequency (Zagorski and Kaminski, 2023). The increased percentage of Th17 cells was also likely transient, as it decreased between the 2 time periods of analysis of the mice (postnatal days 21 and 42) (Kimber et al., 2022; Zagorski and Kaminski, 2023). Despite these major limitations of the Luo et al. (2016) study, all of which were discussed by commenters on the draft Opinion, the EFSA CEP Panel maintained that the study falls into the highest quality tier in its final Opinion (EFSA CEP, 2023a).

Supporting evidence

The EFSA CEP Panel claimed that the TDI for BPA was not based on a single study, but on the weight of the evidence from the entire dataset evaluated, and pointed to studies by Bodin et al. (2014) and Malaisé et al. (2017, 2018) as supporting studies (EFSA CEP, 2023a). However, Kimber et al. (2022) and Zagorski and Kaminski (2023) noted that these “supporting” studies had similar shortcomings and evaluated much higher doses than those studied by Luo et al. (2016), and do not provide evidence to support an increased percentage of Th17 cells as an adverse, systemic, or consistent endpoint across studies, particularly at the very low doses used in the derivation of the TDI.

The results of the studies that reported effects on Th17 cells in mice are also not consistent with the results of well-conducted studies in rats that were part of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA) program (Camacho et al., 2019; Li et al., 2018a,b). These studies showed no consistent or dose-dependent effects on cellular immunity or other immunotoxicity endpoints in rats exposed to BPA at doses ranging from 0.0025 to 25 mg/kg bw/day during the developmental and adult exposure period, though Th17 cells were not specifically evaluated. This suggests that there may be species differences in the effects of BPA on immune function, including Th17 cells, such that mice are more sensitive than other species (Kimber et al., 2022). This is supported by an in vitro study showing that BPA increased IL-17 production from mouse T cells, but not human T cells (Malaisé et al., 2020), and another study describing differences between human and mouse Th17 cells (Tuomela et al., 2016).

Mode of action

In an attempt to associate the Th17 cell endpoint to an adverse outcome, the EFSA CEP Panel stated in its draft Opinion that Th17 cells play a role in the development of allergic lung inflammation, but when evaluating studies for the endpoint of allergic lung inflammation, it did not consider Th17 cell percentage increases as a key adverse event. Rather, the EFSA CEP Panel considered immunoglobulin E (IgE) production as the key adverse event, as IgE production is an important factor in inducing allergic reactions in the lung. The EFSA CEP Panel also stated that Th17 cells and their production of the cytokine IL-17 are important in the pathogenesis of allergic lung inflammation and asthma, but, conversely, also stated that changes in IL-17 levels can be “triggered by different stimuli including physiological stimuli and it is not considered very close to the apical endpoint of allergic lung inflammation” (EFSA CEP, 2023b). These notable contradictions indicate that the EFSA CEP Panel is unclear as to whether Th17 cell percentages play a role in allergic lung inflammation.

In its response to comments on the draft Opinion, the EFSA CEP Panel justified its use of Th17 cell percentage increases as the endpoint for the BPA TDI by proposing the involvement of Th17 cells in a hypothesized set of key events leading to a hypothesized adverse effect (allergic lung inflammation), despite the lack of any evidence to support this speculation. The EFSA CEP Panel stated that it amended the text of the final Opinion to provide clarification on the purported mechanistic link between Th17 cells and adverse immune conditions and that language suggesting a direct link between Th17 cells and IgE levels was removed (EFSA CEP, 2023a). However, the final Opinion still states that activation of Th17 cells and secretion of IL-17 may increase the immune response of Th2 cells, including IgE, and this can aggravate the severity of allergic asthma (EFSA CEP, 2023b).

The EFSA CEP Panel’s purported association between BPA-induced increases in the percentage of Th17 cells, their production of IL-17, and the development or exacerbation of allergic lung inflammation and asthma is not supported by human or experimental animal studies, and this was pointed out by commenters on the draft Opinion as well as in the published literature (Kimber et al., 2022; Zagorski and Kaminski, 2023). Epidemiology studies of BPA exposure and allergy or asthma are inconsistent and inconclusive (Kimber et al., 2022; Zagorski and Kaminski, 2023). While Th17 cells are involved in several autoimmune and respiratory disease processes, they have not been shown to be involved in IgE-mediated diseases, such as asthma (Cosmi et al., 2016; Gurczynski and Moore, 2018; Li et al., 2016; Simonian et al., 2009). Evidence suggests that IL-17 also does not play a critical role in asthma, as there was no correlation between Th17 cell or IL-17 levels in children with asthma (Moreno-Cordova et al., 2021), and clinical trials evaluating a monoclonal antibody against the IL-17 receptor had no effect on participants with severe asthma (Busse et al., 2013). Experimental animal studies are also inconsistent with respect to the effects of BPA on allergic lung inflammation. A study by O’Brien et al. (2014), which was considered a key study by the EFSA CEP Panel, reported increased IgE levels in the lungs of an allergic asthma mouse model after oral perinatal exposure to BPA doses of approximately 0.008, 8, and 8000 μg/kg bw/day, but also reported BPA-induced decreases in IL-17 levels in the lungs and a lack of airway inflammation. O’Brien et al. (2014) also did not observe an increase in neutrophils in the lungs, which is a hallmark of IL-17-mediated airway inflammation (Zagorski and Kaminski, 2023). O’Brien et al. (2014) did not evaluate whether the BPA-induced IgE increase resulted in adverse effects on lung function. In fact, none of the studies that evaluated Th17 cells in mice discussed above examined Th17 cell levels in the lungs or whether the observed changes in Th17 cell percentages were systemic and associated with lung inflammation, lung injury, or deficits in lung function.

Alternative basis for TDI

The EFSA CEP Panel responded to comments that the critical effect of increased Th17 cells was too sensitive and not supported as a reference point for a TDI by stating that the BMD analysis of some of the reproductive and metabolic endpoints that had also been considered as critical effects in the TDI derivation would have yielded TDI values only up to about 7-fold higher than the proposed TDI (EFSA CEP, 2023a). However, like the immunotoxicity endpoint of increased Th17 cells, the specific reproductive and metabolic endpoints selected for BMD analysis by the EFSA CEP Panel were also selected simply because they were the most sensitive reproductive or metabolic effects, even though they were not consistently shown across studies, were not clearly adverse or relevant to humans, or were not associated with any functional deficits in fertility or metabolism, indicating that their use as critical effects in the derivation of a TDI is also not supported.

European Regulatory Agency Opinions

Both the European Medicines Agency (EMA) and the German Federal Institute for Risk Assessment (BfR) provided public comments on the draft EFSA Opinion (EFSA CEP, 2023a), and also issued reports (jointly with EFSA) on the diverging views between these agencies and the EFSA final Opinion (BfR and EFSA, 2023; EFSA and EMA, 2023). EMA and BfR both stated that there is insufficient evidence to conclude that the intermediate endpoint of increased Th17 cell percentage leads to an adverse immune outcome, such as inflammation, in experimental animals or humans (BfR and EFSA, 2023; EFSA and EMA, 2023). EMA stated that it requires demonstrated evidence of causality within the design and scope of the studies reviewed rather than “the hypothesized cascade of steps in EFSA’s approach to conclude on a hypothesized adverse effect” (EFSA and EMA, 2023). BfR and EFSA (2023) stated that it would not consider the study by Luo et al. (2016) in the weight of the evidence because of its questionable BPA dosing based on likely background BPA contamination. BfR and EFSA (2023) also stated that limiting the identification of studies to the time period of 2013–2018 could have biased the evaluation by the time period in which the studies were conducted, and that the EFSA CEP Panel used conservative, worst-case assumptions throughout each step of its evaluation process, resulting in an overly conservative TDI. Neither EMA nor BfR support the EFSA CEP Panel’s final TDI of 0.2 ng/kg bw/day (BfR and EFSA, 2023; EFSA and EMA, 2023).

Because BfR did not agree with the final BPA TDI derived by the EFSA CEP Panel, BfR (2023) established its own TDI value. To do so, BfR (2023) only considered the same critical endpoints identified by EFSA (ie, the most sensitive immunotoxicity, reproductive, and metabolic endpoints) from studies published in the same limited time frame as in the EFSA evaluation (despite acknowledging how this could have biased the evaluation), and conducted its own evaluation of study quality and reliability. BfR (2023) did not identify any Tier 1 (ie, high quality) studies for the critical endpoints identified by EFSA, but based its TDI on reduced sperm count observed in 2 Tier 2 studies in rats exposed during adulthood. BfR (2023) stated that this was a conservative approach, given that the results were discrepant with studies using other exposure scenarios, and even the EFSA CEP Panel concluded that effects on sperm counts were not likely in any exposure scenario (EFSA CEP, 2023b). The resulting TDI of 0.2 μg/kg bw/day is 20-fold lower than the 2015 EFSA t-TDI of 4 μg/kg bw/day (EFSA CEF, 2015) and 1000-fold higher than the EFSA final TDI of 0.2 ng/kg bw/day (EFSA CEP, 2023b). Even though BfR (2023) did not consider the intermediate endpoint of increased Th17 cell percentage to be adverse or relevant to humans, the agency noted that its TDI of 0.2 μg/kg bw/day would be protective for a benchmark response of 100% (ie, a doubling of effect size) for this endpoint.

Conclusions

EFSA’s final TDI for BPA of 0.2 ng/kg bw/day is 20 000-fold lower than the t-TDI established by EFSA in 2015 (EFSA CEF, 2015). The low-dose effects chosen for BMD analyses are not supported as critical effects for derivation of a TDI because they are not consistently shown across studies, are of not clearly adverse or relevant to humans, and are not associated with downstream adverse effects. Multiple public commenters on the draft Opinion noted that there is no support for the critical effect of increased Th17 cells for use as a reference point for a TDI for BPA. While BPA has been shown to increase Th17 cell percentages in the mouse spleen under certain experimental conditions, this effect has not been observed in other species, and even in mice there is no evidence that it is a precursor event to any downstream pathological outcome such as allergic lung inflammation or asthma. As such, use of this endpoint as the basis for a TDI is not scientifically justified.

The final TDI for BPA is 5 orders of magnitude lower than estimates of safe doses of BPA established by other agencies worldwide, including the TDI of 20 μg/kg bw/day established by South Korea (Park et al., 2016), the TDI of 25 μg/kg bw/day established by Canada (Rogers, 2021), and the reference dose of 50 μg/kg bw/day established by the United States Environmental Protection Agency (US EPA, 2002). BPA has been used safely over the years for all intended uses based on these established safe dose estimates. EFSA’s final TDI is also 3 orders of magnitude lower than the TDI of 0.2 μg/kg bw/day recently proposed by the BfR (2023) based on the same set of literature evaluated by the EFSA CEP Panel. In addition, the EFSA CEP Panel noted that the final TDI is 2–3 orders of magnitude lower than dietary exposure estimates of BPA in Europeans in all age groups (EFSA CEP, 2023b). It is difficult to reconcile the basis for such a low TDI without clear evidence for such effects in human populations that have BPA exposures that are several orders of magnitude higher. Even in the absence of studies examining immunotoxicity endpoints in humans, there are no indications of adverse effects on the immune system in general observations of human populations.

Overall, the EFSA hazard assessment review process is not scientifically sound and has led to a conclusion that there are low-dose effects based on very few, lower quality experimental animal studies. These effects and the conclusions drawn are not sufficiently supported by the totality of the available evidence, which includes multiple high-quality studies not considered in EFSA’s recent review, and indicates that the t-TDI established by EFSA in 2015 is protective of human health. Future assessments that seek to develop safe dose estimates of BPA (or any substance) should include all available evidence; provide clear guidance for evaluating study quality; consider the reliability of study results; and choose endpoints that are either adverse, apical effects (or their precursors) and that are both consistent and coherent across studies in experimental animals and humans.

Declaration of conflicting interests

The authors are employees of Gradient, an independent environmental and risk science consulting firm. The work reported in this article was conducted during the normal course of employment. The authors have previously provided consulting on BPA-related issues and have given testimony on topics related to BPA at meetings with regulatory agencies, with funding provided by the American Chemistry Council. This article is the professional work product of the authors, and the opinions and conclusions offered within are not necessarily those of their employers or the financial sponsor of the work.

Contributor Information

Robyn L Prueitt, Gradient, Seattle, Washington 98101, USA.

Julie E Goodman, Gradient, Boston, Massachusetts 02108, USA.

Funding

Financial support for this work was provided by the American Chemistry Council. The financial sponsor was not involved in the design, analysis, interpretation of the evidence, or writing of this article but did review a draft of the article prior to submission for publication.

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