Regulatory background
- The substance 4,4′-isopropylidenediphenol, also known as bisphenol A (BPA; CASRN 80-05-7), is a member of the large bisphenols family of substances that share similar chemical structures and applications. Used in the manufacture of polymers and resins, BPA is commonly employed in certain plastics and epoxy resin.
- Products containing BPA encompass a wide range of applications. They vary from articles like reusable bottles and tableware, to waterpipes, sports equipment, flexible glass applications, CDs and DVDs, and many more.
- BPA has a long history of use in food contact materials. It is commonly used to produce epoxy resins that serve as the basis of coatings and varnishes for internal and external surfaces of metal food contact applications, like food and beverage cans and lids. Additionally, it is a common constituent in certain plastics including polycarbonate and polysulfone plastics with applications in food storage and food processing and production equipment, among others[RB1] .
- In April 2023, the European Food Safety Authority (EFSA) published a re-evaluation of public health risks stemming from BPA in food that established a new tolerable daily intake (TDI) of 0.2 ng/kg of bodyweight. This value is roughly 20,000 times lower than the 2015 provisional TDI of 4,000 ng/kg of body weight previously supported by the authority.
An expert letter endorses the lower TDI
- On April 9, 2024, an article co-authored by dozens of European and American scientists and clinicians appeared in Environmental Health Perspectives, a journal published by the U.S. National Institutes of Health (NIH). The communication backs the 20,000-fold lowering of the TDI for BPA by EFSA. Additionally, it criticizes the backlash against EFSA’s move that has come from national agencies, chiefly the German Federal Institute for Risk Assessment (BfR) and the U.S. FDA.
- Endorsement of the lower TDI stems from the scientists’ approval for the comprehensive EFSA reassessment behind it. They applauded EFSA’s expert panel on food contact materials, enzymes and processing aids (EFSA-CEP) for what the authors characterize as a modern approach. The panel’s new analysis, they noted, combines “a review of independent academic research findings in addition to industry and government guideline research findings.” Additionally, the authors noted that EFSA-CEP published their proposed protocol for the study and invited comment before digging into the new analysis. The panel’s approach incorporated data supporting longstanding good practice guidelines, while also incorporating data from newer, independently conducted studies via a systematic review.
- The newly published paper emphasizes the contribution that independent scientific research had to the EFSA-CEP draft scientific opinion – data not traditionally incorporated into such documents (more about this approach below). Incorporating a large dataset drawn from more than 800 studies examining BPA exposure published since 2013, the EFSA draft scientific opinion concluded by recommending the new, lower TDI for BPA.
- Soon after the EFSA-CEP report was published, EFSA also published joint reports with the European Medicines Agency (EMA) and the German Federal Institute for Risk Assessment (BfR) that detailed points of divergence. The objections of both agencies to EFSA’s scientific approach had some overlap centering around choice of endpoints, use of uncertainty factors, and the choice of the human equivalent dose (HED) factor.
CLARITY-BPA: A model for integration of independent academic research
- Aside from endorsing the process behind the new TDI, the scientists also voiced strong support for work previously completed by the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA) program. The CLARITY-BP consortium was developed by the U.S. National Toxicology Program, National Institute of Environmental Health Sciences, and the FDA. According to a 2013 explainer article in Reproductive Toxicology, CLARITY-BPA combined a “core” intramural guideline-compliant chronic toxicity study of BPA exposure in pregnant rats and their offspring. The program also handed off rodents raised under similar conditions as the core study rats to program grantees for further study.
- The grantees, independent academic researchers who were blinded as to the rats’ exposure levels, studied effects of BPA exposure on more than a dozen target tissues and organ systems, including the brain, reproductive organs, and adipose tissue, among others. To date, their work has led to 17 peer-reviewed publications.
- In addition to publication of the findings of the core study and the grantees’ work, both arms of CLARITY-BPA research were also published as a compendium in October 2021.
- As touched on above, the structure of the CLARITY-BPA consortium and research efforts combined disparate types of research: First, the core study’s guideline-compliant research was conducted for regulatory purposes in compliance with Good Laboratory Practices (GLP), which ordinarily requires the resources of governmental bodies or commercial firms, as the 2013 explainer noted. Second, the consortium engaged independent academic grantees. “The culture and funding structures of academic research generally lend themselves to smaller-scale, hypothesis-driven studies that use a variety of experimental models to identify a chemical’s effect on a variety of potential disease-related endpoints,” as that article explains. The latter type of research has not traditionally been used in chemical regulatory decision-making.
- The conveners of CLARITY-BPA, in addition to furthering the specific scientific aims of learning more about the risks of BPA in food contact materials, saw the project as representing “a potential new model for filling knowledge gaps, enhancing quality control, informing chemical risk assessment, and identifying new methods or endpoints for regulatory hazard assessments.”
- The authors of the new article endorsed the CLARITY-BPA model and recognized its contribution to the EFSA-CEP methodology for its scientific opinion. The earlier U.S. consortium work, the authors wrote, “should serve as a model for integrating 21st century academic research into a hybrid and pluralistic regulatory assessment process for identifying hazards posed by chemicals.” Such an approach would allow more agile incorporation of newer research approaches to chemical risk assessment, serving as a counter balance to “rigid guideline protocols,” the authors argued.
- More collaboration between government and academia is what these researchers value in designating CLARITY-BPA as an aspirational model. They “ argue that regulatory agencies need to incorporate 21st century science into chemical hazard identifications” using the model that CLARITY-BPA provides, combining “nonguideline academic studies in a collaborative government–academic program model.”
- The authors also make an argument for more CLARITY-BPA-style regulatory projects on the basis of cost. They refer to both cost to public health as well as financial cost. Their critique points out that cost-benefit analyses, which have traditionally guided chemical regulation, often over-emphasize industry cost while failing to account for costs to public health. Even when emphasizing financial cost, the authors repeatedly describe CLARITY-BPA as a cost-effective model for future research frameworks.
Endocrine-disrupting chemicals such as BPA present different toxicological and regulatory considerations
- BPA’s endocrine-disrupting effects have long been studied, with the Endocrine Society, a US-based medical association of endocrinologists, calling BPA one of the “most pervasive” of the phenols considered to be endocrine-disrupting chemicals (EDCs).
- A 2019 consensus statement from a group of international experts identified 10 key characteristics of EDCs to consider in hazard identification. Using BPAs as one illustration of this approach, the experts cited evidence that the substances alter hormone receptor expression, alter signal transduction in hormone-responsive cells, induce epigenetic modifications in those cells and in those that produce hormones, and alter hormone transport and circulating hormone levels. The experts found more than 100 epidemiology studies showing associations between BPA exposure and a host of adverse outcomes ranging from diabetes to infertility to neurodevelopmental problems in children. The statement also cited abundant rodent and mechanistic data regarding BPA’s endocrine-disrupting effects.
- The ECHA recognized BPA as an EDC in 2017, with a unanimous vote from the Member State Committee to support its classification as a substance of very high concern (SVHC).
- An issue with the regulation of EDCs is that their effects can be seen at low doses and are non-monotonic, meaning that the dose-response curve does not show ill effects scaling proportionately with increased doses. In its second scientific consensus statement on EDCS (EDC-2), released in 2015, the Endocrine Society noted that these attributes of EDCs “challenge classical concepts of toxicology testing, such as potency, threshold, and the establishment of ‘safe’ doses of exposure during the process of risk assessment and subsequent management.” EDC-2 goes on to note that “Standard good laboratory practice (GLP) toxicology testing and guideline studies are not sufficiently sensitive to evaluate the hazards associated with EDCs, thereby leading to insufficient protection of public and environmental health with increased medical and other costs.”
- EDC-2 further elucidated a key point about substances with non-monotonic dose-response relationships: There is no guarantee that “the lack of adverse effects at high doses also confirms safety at low doses.” This, says the society, poses problems for regulatory toxicology, since reducing exposure doesn’t have a predictable or dose-related effect on risk reduction. “In this case, it might be necessary to eliminate the hazard entirely to ensure safety,” the experts concluded.
EFSA’s approach has seen dissent from multiple national authorities
- While the scientists authoring this letter praised EFSA’s new approach, they noted that other regulatory agencies feel otherwise. Though the FDA was one of the initiators of CLARITY-BPA, it ultimately chose to reject the data generated from academic research, opting to only accept data the more traditional component of the project. The authors noted that as far back as 2008, the FDA Science Board had reviewed the FDA’s first risk assessment of BPA in food contact materials. At that time, the Board – a group of independent advisors – took issue with the FDA for not including “the large number” of non-guideline studies in formulating its risk assessment. The article criticizes the FDA for backtracking on an initiative it participated in, saying that the EFSA assessment is superior because it benefitted from the academic arm of CLARITY-BPA.
- The German BfR also voiced strong opposition to the new EU TDI and its underlying justification. German regulators complain that “conservative worst-case assumptions are used in every step of the [EFSA] assessment process… resulting in an over-conservative [TDI].” While the BfR is entitled to its divergent opinion, it will have to abide by any EU-level legislation resulting from the new safety metric. Although a TDI is simply a scientific health metric on which safety agencies can reasonably disagree, EU legislation drafted on the back of the EFSA TDI would supersede the authority of any domestic German law.
Consequences of the new TDI
- EU-level legislation stemming from the new EFSA TDI has already manifested in the form of a proposal to ban BPA in food contact materials. The Commission acknowledged that because “no such methods exist that are able to quantify the migration of BPA reliably and consistently at such very low levels,” the only way to ensure humans are not exposed to unsafe levels of BPA through their diet is to ban their presence in food packaging. The consultation on this draft act ended in early March 2024, with the Commission’s estimate for adoption in the first quarter of 2024 having come and gone. The authors of the letter also endorsed this ban.[ See AgencyIQ’s in-depth analysis of the BPA ban in food packaging here.]
- A recent report from the European Environment Agency (EEA) used the new TDI in a biomonitoring study conducted in 11 EU member states from 2017-2022. The results indicated that nearly 100% of participants in countries like Poland, the Czech Republic, and Iceland had unsafe BPA levels when using the new TDI as the key defining metric for safety.
Analysis
- EFSA’s novel approach to reassessing BPA has been supported by the European Commission, which has incorporated its findings into a ban on BPA in food packaging. However, despite the recent article from a coalition of scientists and clinicians endorsing the EFSA’s proposed TDI – and the methods that brought the agency to its conclusion – several national agencies persist in adhering to the older, higher limits.
- The Commission itself has downplayed divergences between EFSA and the BfR on BPA. When questioned whether these differences in opinion might “undermine trust in the system of science-based regulation in the EU,” the Commission assured questioners that experts from both agencies had already convened “with the aim of clarifying and resolving the divergences.” The joint report, on closer examination, does not seem to support this view. The conclusion of the report states that “it is not possible to achieve convergence for the differences of opinion between the two bodies regarding the hazard characterization for BPA. “ As noted above, a similar joint report involving the European Medicines Agency also noted – but did not resolve – points of difference.
- These types of joint reports may become more commonplace as the EU intensifies implementation of its one substance, one assessment approach (1S1A). The Commission’s recently announced 1S1A reform package routinely mentions that differences in opinion between agencies are to be resolved with a joint report presented to the Commission outlining reasons for divergence, clarifications of underlying technical issues, and proposals to remedy the divergence. Divergences in opinion on standard data formats and technical definitions, for example, are explicitly meant to be resolved this way. The BfR and EFSA make reference to this point in the final sentence of their own joint report on BPA, reaffirming their commitment to “further constructive dialogue… as foreseen by the One Substance, One Assessment approach.” [ Please see AgencyIQ’s webinar on the 1S1A reform package here.]
- The extent to which academic studies should factor into EU regulation is a question that has come up with respect to other substances beside BPA, notably glyphosate. Green NGOs, who are currently suing the Commission for extending glyphosate’s approval, are asking the body to take account of a study examining the association of glyphosate exposure with leukemia in rats. The NGOs assert that the extension of the herbicide’s approval is unwarranted without full consideration of what they call “the only long-term study ever done on the representative formulation or any formulation [of glyphosate].”
- The Commission has recently referenced this study in numerous official capacities. Commission spokesperson STEFAN DE KEERSMAECKER acknowledged that EFSA and ECHA “are aware” of the long-term study. He stated that “if in the light of the new data, ECHA or EFSA confirm that glyphosate does no longer meet the approval criteria, the Commission will act immediately to withdraw the approval.” Additionally, the EU Commission’s official page for glyphosate explicitly names the study for its potential to impact the executive’s regulatory view of the controversial herbicide.
- EFSA’s approach for evaluating BPA may play out in its assessment of other substances, especially when taken in tandem with Commission acknowledgement of outside studies potentially affecting the regulation of glyphosate. A framework under which the EU lends substantial weight to academic research may be on the horizon, with an approach to chemical assessment that considers a broader range of data that convey the latest understanding of hazards presented.
Featuring previous research by Scott Stephens.
To contact the authors of this analysis, please email Rayan Bhargava ( [email protected]) or Kari Oakes ( [email protected]).
To contact the editor of this analysis, please email Kari Oakes ( [email protected]).