From Evidence of Harm to Public Health Policy: Is There Light at the End of the Tunnel? Response to: “Update on the Health Effects of bisphenol A: Overwhelming Evidence of Harm”

The title of the vom Saal-Vandenberg review may inspire endocrinologists to ponder: Why another paper on the health effects of bisphenol A (BPA)? We already know that it causes harm. But such an assessment misses the central point that, despite the “overwhelming evidence of harm”, certain regulatory agencies that are supposed to be protecting the public hinder instead the development of a protective public health policy. The review shows that since the inception of the concept of “endocrine disruptors,” the industry and some agencies both in the United States and abroad keep invoking the fifteenth-century aphorism “the dose makes the poison,” ignoring basic concepts in endocrinology and statistics and manufacturing an “illusion of controversy” by time and again defending obsolete arguments. Those erroneous concepts include the notion that “relevant” dose responses are always monotonic and that similar effects should be observed in males and females (1).

As pioneers in the field of endocrine disruption and participants in the CLARITY study, we have witnessed how the application of science to protect public health has been hindered. That environmentally relevant exposures to BPA (and other endocrine disruptors) result in deleterious effects should not surprise endocrinologists and developmental biologists. In fact, these outcomes were already predicted by the Wingspread participants almost 3 decades ago (2) and have been well documented in the Endocrine Society Scientific Statement of 2009 (3). Thus, if scientific evidence is that strong, why has regulation been curtailed so easily? After having participated in numerous committees and task forces, and having testified before legislative bodies, we were exasperated when only few regulatory changes, mostly in Europe, have been applied. Thus, we welcomed the CLARITY study because it was to have closed the evidence gap between academic and regulatory studies as both were to be performed under GLP conditions, using the same animals exposed and handled in an FDA facility. Indeed, both types of studies amply confirmed what we already knew and provided even stronger evidence that nonmonotonicity is the rule. In fact, by using state of the art mathematical and statistical approaches, 1 study showed nonmonotonic dose responses with the break between low dose and higher dose responses consistently falling at the same dose point (4). Another study showed statistical correlations among the different CLARITY academic studies revealing patterns of effects across the organs whereby the largest effects occurred at the lowest doses (5). In brief, BPA effects occurred at low doses and were nonrandom, yet the FDA concluded otherwise (1).

As recognized by the FDA, linear models are a powerful tool to provide evidence of a causal relationship because they quantitatively relate the changes of a putative cause with the one of the effects. In endocrinology, nonlinearity is predominant due to multilevel, complex regulations that are a consequence of the evolutionary history of hormones and their functions. Thus, the way to reveal the presence of causation is to show the prevalence of a specific non-monotonic pattern using pertinent and robust statistical tools (4). Note that in both cases, all that is needed is good mathematics, not more “mechanistic studies.” This brings us to define our role as scientists on how to overcome the hindering efforts so eloquently revealed in the vom Saal-Vandenberg review.

Science is an activity under incessant change. Some principles are as good today as when they were first enunciated centuries ago; others are eventually discarded. This openness of science for its own sake has worked well in the long run. But when knowledge is needed to prevent diseases it should be a way to determine when “enough is enough” regarding evidence. Thus, when regulators and industries detrimentally affected by our discoveries tell us to go back to the bench to find out the molecular mechanism underlying the effect, we should think again. Postponing action stems from the assumption that molecular mechanisms reliably represent the definitive level of explanation. Proposed alternatives are pejoratively called “phenomenological.” For instance, if exposure to an endocrine disruptor results in transgenerational transmission of decreased fecundity, this evidence will not count for regulation until a “mechanism” is found. Pragmatically, this call to search for mechanisms is suspicious because (1) it represents a powerful delay stratagem, and (2) “mechanism” is not a universally acknowledged gold standard for explaining biological phenomena. In fact, biologists and philosophers have challenged the usefulness of “mechanism” to explain biological complexity and organization. Additionally, the inadequacy of the metaphoric use of the mathematical concepts of “program,” “information,” and “signal” dating from the beginning of the Molecular Biology Revolution has triggered a revival of the organicist tradition which is best suited to the study of biological complexity than the prevailing reductionist and mechanist worldview (6).

These novel perspectives suggest that the time is ripe to pause and think afresh about what constitutes a proper and rigorous explanation of complex biological phenomena. This includes invoking and articulating new, relevant principles for endocrinology. Meanwhile, endocrinologists should oppose the delaying tactic of falling into the bottomless pit of molecular mechanism, which is now epitomized by the search of “adverse outcome pathways.” Instead, we should advocate adopting the useful concept of “key characteristics” for the identification of endocrine disruptors and to characterize the hazard posed by these EDCs without waiting for more molecular details (7).

In unanticipated support of this Commentary, on October 14, 2020, the European Commission published a chemicals strategy for sustainability. It proposes “to establish legally binding hazard identification of endocrine disruptors, based on the definition of the WHO, building on criteria already developed for pesticides and biocides, and apply it across all legislation; ensure that endocrine disruptors are banned in consumer products as soon as they are identified (8).” This great step forward is the result of the efforts of scientists, journalists, politicians, and medical and scientific societies like ours. Not surprisingly, resistance from the “usual suspects” will likely soon materialize. Endocrinologists should be ready to oppose the delaying tactics armed with the proper principles and a clear understanding of when “enough is enough.”

Glossary

Abbreviation

BPA

bisphenol A

Additional Information

Disclosures: A.M.S. has received travel reimbursements from Universities, Governments, NGOs, and Industry, to speak about endocrine-disrupting chemicals. She is an unpaid member of the Science Advisory Councils of Beauty Counter and the Food Packaging Forum. Her endocrine disruptor related work has been supported by US federal agencies, Beauty Counter, and the Valspar corporation. C.S. has no conflicts to declare.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.