As the EU is considering a ban on bisphenol A (BPA) in food packaging based on the European Food Safety Authority’s (EFSA’s) recent lowering of its tolerable daily intake (TDI) for the chemical, an international group of academic experts has penned their support for the historically comprehensive and conservative risk assessment that led to EFSA’s establishment of the new BPA TDI. The experts refute other regulatory agencies’ disagreements with EFSA’s nontraditional risk assessment process and call on institutions around the world to modernize their approaches to risk assessment for and regulation of endocrine-disrupting chemicals (EDCs).

Background

In their letter, published in Environmental Health Perspectives in March 2024, the diverse group of experts strongly endorse EFSA’s April 2023 reassessment of dietary exposure to BPA, which established a TDI for the chemical that is 20,000 times lower than what was previously effected. The commentary article also refutes other regulatory agencies’—namely, the German Federal Institute for Risk Assessment’s (BfR’s) and the U.S. Food and Drug Administration’s (FDA’s)—continued adoption of a TDI for BPA exceeding levels that are harmful to human health. The authors call for regulatory agencies to incorporate the most current science into chemical hazard identification and provide suggestions for how BPA safety reassessment should be approached.

Based on EFSA’s lowering of the TDI for BPA, in August 2023, the European Commission (EC) announced that it is planning to propose adoption of the new TDI, including a ban on its use in food packaging material. EC also intends to address the use of other bisphenols in food packaging to avoid industry replacing BPA with other harmful chemicals. At present, comments have been submitted and are under review regarding the draft regulation considering a BPA ban in food packaging.

The issue of replacing hazardous chemicals, such as BPA, with chemicals not subjected to prior testing for their hazards that are later shown to be as bad or worse than the chemicals they replaced, is referred to by the authors as “regrettable substitutions.” The authors argue that little will be accomplished by banning BPA in products if potentially even worse bisphenols are allowed to be used in products labeled “BPA-free.” At present, dozens of regrettable substitutions are being used in products labeled “BPA-free,” the authors assert. For example, bisphenol S (BPS), bisphenol F (BPF), and other structurally similar bisphenols were previously been unregulated in the EU and have already become ubiquitous environmental contaminants. BPS and BPF have since been proven to cause similar harm to that of BPA.

Arguments For and Against EFSA’s Approach, and Problems with the Traditional Risk Assessment Process

According to the Environmental Health Perspectives article, which identifies the flaws in traditional risk assessments of EDCs conducted by FDA, BfR, and other regulatory agencies, EFSA’s process for its most recent reassessment of BPA was more comprehensive than for past assessments. The authors argue that regulatory agencies, including EFSA, historically rely on studies funded by industry and studies conducted according to government guidelines, neglecting to seriously consider academic literature. In contrast, EFSA’s recent reassessment of BPA placed importance on the findings of the academic community, and was also preceded by a transparent process that included publishing the review protocol and requesting comments prior to beginning to the review.

The inclusion of nonstandard studies in EFSA’s reassessment of BPA was met by criticism from BfR and the European Medicines Agency (EMA), however. For example, BfR argued that “conservative worst-case assumptions are used in every step of the risk assessment process [by EFSA] … resulting in an over-conservative health-based guidance value (i.e., the new TDI).”

In their commentary article, the authors take the side of EFSA, and identify specific issues that need to be addressed by other regulatory agencies to bring 21^st century science into risk assessments for EDCs. Such issues include, but are not limited to:

• Accepted risk assessment assumptions do not apply to EDCs
• Hazard identification only uses high doses to predict low-dose effects, rejecting known receptor-mediated low-dose effects of EDCs
• Group assessment for chemicals like BPA and its analogues is necessary, rather than testing for and regulating individual chemicals
• Sex differences in health outcomes are ignored for EDCs or are used to reject findings about EDCs, even though such differences are a common feature of exposure to these chemicals
• Biomonitoring data is compromised because companies do not reveal all chemicals used in products
• Epigenetics and transgenerational effects are not considered
• Multiple problems with dose-response assessment
• The acceptance of the validity of thresholds for EDCs by regulators is problematic, because the assumption of a threshold for EDCs is false if background hormone levels being disrupted are already above threshold
• The effects of the route of exposure need to be assessed
• The use of cost-benefit analysis emphasizes cost to industry and ignore public health costs, and is therefore not protective of public health
• Regulatory agencies have ignored the academic studies showing BPA hazards at low doses and have assumed human exposure is negligible
• Chemicals in mixtures relevant to human exposures are not examined
• Chemical regulatory bodies in the U.S. do not err on the side of caution when it comes to food chemical safety, which is more common practice in the EU
• Failure to prevent the replacement of harmful chemicals with hazardous analogues
• Overlooking the principles of sustainable chemistry.

Proposed Model for Modernized Risk Assessment of EDCs

The authors propose the Consortium Linking Academic and Regulatory Insights on BPA Toxicity model (CLARITY-BPA model) as a cost-effective method for hazard identification based in the most current science. CLARITY-BPA was a government-academia collaboration to link a guideline study (funded by FDA) with hypothesis-driven, academic investigator studies, funded by the U.S. National Institute of Environmental Health Sciences (NIEHS). CLARITY-BPA was a comprehensive, industry-standard Good Laboratory Practice (GLP) guideline-compliant, two-year chronic exposure study of BPA toxicity. A primary objective of CLARITY-BPA was to greatly expand the range and sensitivity of outcomes examined in hazard identification studies for environmental chemicals and to examine whether academic scientists could replicate their prior findings using animals from a GLP government-controlled study.

The Case for Precaution, and Possibly Changing Tides at FDA

Cited in the article, the Endocrine Society, a group comprising more than 18,000 physicians and basic endocrine researchers, strongly endorses precaution when there is evidence that warrants it, which is the case for BPA, in the opinion of the authors. Although the authors specifically call out FDA for its failure to take such a precautionary approach to chemical regulation, they also acknowledge that the ongoing reorganization and unification of FDA’s Human Foods Program and the reassessment of its human foods priorities may signify that FDA is more likely to err on the side of caution in the future.

As U.S. states have been making their own legislative moves to more strictly regulate chemicals in foods and food contact materials over the past year due to FDA inaction, the agency and the new FDA Commissioner for Human Foods have acknowledged the need for a more aggressive food chemical safety approach. The agency has recently proposed to revoke or is considering revoking authorizations for a number of controversial food chemicals, and is making an effort to be proactive and transparent about its shift to a modernized, systematic food chemical reassessment approach.