The 7th Food Packaging Forum (FPF) workshop on “Improving the chemical safety of food contact articles: Accelerating science and innovation” took place on October 24, 2019, in Zurich, Switzerland. The talk by Ana Soto from Tufts University School of Medicine, Boston, U.S. and Centre Cavaillès, École Normale Supérieure, Paris, France, discussed the biological mechanisms underlying non-monotonic dose-response curves (NMDRC) and explained why non-monotonicity phenomena are “useful to organisms, challenging for regulators” (FPF reported). Soto emphasized that NMDRCs are “remarkably common in endocrinology” (FPF reported) and governed by several biological mechanisms that include “receptor down-regulation and desensitization, cell- and tissue-specific receptors and cofactors, receptor selectivity, endocrine negative feedback loops, tissue interactions.”

Soto also discussed the successes and limitations of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA) project, a U.S.-based initiative to combine regulatory and academic research on health effects of bisphenol A (BPA, CAS 80-05-7) (FPF reported). CLARITY-BPA was a “collaboration of guideline-compliant studies and academic hypothesis-based studies to assess the effects of BPA,” which “went well until the final conclusions had to be drawn,” and this is where the disagreements in the interpretation of the obtained results became apparent between regulatory and academic scientists (FPF reported). Soto pointed out that academics have identified several fundamental flaws in “design, execution and interpretation” of the CLARITY-BPA project, which could limit its value for risk assessment of BPA, especially in regards to the “core study” outcomes and interpretation (FPF reported). For example, although the regulatory “core study” (FPF reported) concluded that “BPA produced minimal effects” (FPF reported), a “quantitative unsupervised analysis” carried out by academic scientists on a “set of 91 measurements” from CLARITY-BPA data produced “the most striking” NMDRCs. Soto summarized that “at all-time points, lower doses resulted in larger effects, consistent with the core study which revealed a significant increase of mammary adenocarcinoma incidence at the lowest BPA dose tested.”

Experimental studies in humans could offer another, perhaps more productive, approach to generating data that could be used in risk assessment of BPA (as opposed to animal-based studies, like CLARITY-BPA which was carried out in rats). An example is a study co-authored by John Peterson Myers from Carnegie Mellon University, U.S., and member of the FPF’s foundation board, and Angel Nadal from Universidad Miguel Hernandez de Elche, Spain, and member of the FPF’s scientific advisory board. It was published in the peer-reviewed Journal of the Endocrine Society and investigated whether BPA affects secretion of insulin or C-peptide in healthy men and women (FPF reported). The study demonstrated that administration of BPA at the “dose considered safe by U.S. regulators” (i.e., 50 µg/kg body weight) “may alter glucose-stimulated insulin response in humans,” thus lending further weight to in vitro, animal-based, and epidemiological studies that suggest association of BPA exposure with “insulin resistance, type 2 diabetes, and other metabolic diseases.”

At the end of her presentation, Soto recapitulated that “NMDRCs occur at all levels of biological organization” and “both natural hormones and endocrine disruptors produce NMDRC,” with underlying mechanisms being “well understood.” And although there could be some uncertainties remaining due to the overall complexity of the biology at hand, Soto challenged the audience by asking “do we need to know the underlying mechanisms in order to accept the existence of NMDRCs?” She used the practice of castrating domestic animals as an example of a method humans have used “since time immemorial” to stop the animals from reproducing, even though “mechanistic explanations were generated thousands of years after this practice became common.” Thus, Soto argued, “we do not need to know mechanisms in order to accept the existence of a phenomenon!”

Read more

Ana Soto (October 24, 2019). “Non-monotonic dose-responses: useful to organisms, challenging for regulators.” (YouTube; pdf)


Prins, G. S., et al. (2018). “CLARITY-BPA academic laboratory studies identify consistent low-dose Bisphenol A effects on multiple organ systems.Basic & Clinical Pharmacology & Toxicology 125: 14-31.

vom Saal, F. S. (2019). “Flaws in design, execution and interpretation limit CLARITY-BPA’s value for risk assessments of bisphenol A.Basic & Clinical Pharmacology & Toxicology 125: 32-43.

Stahlhut, R. W. (2018). “Experimental BPA exposure and glucose-stimulated insulin response in adult men and women.Journal of the Endocrine Society 2: 1173-1187.