Thresholds and Endocrine Disruptors

The concept of a threshold of adversity in toxicology is neither provable nor disprovable. As such, it is not a scientific question but a theoretical one. Yet, the belief in thresholds has led to traditional ways of interpreting data derived from regulatory guideline studies of the toxicity of chemicals. This includes, for example, the use of standard "uncertainty factors" when a "No Adverse Effect Level" (or similar "benchmark dose") is either observed, or not observed. In the context of endocrine-disrupting chemicals (EDCs), this approach is demonstrably inappropriate. First, the efficacy of a hormone on different endpoints can vary by several orders of magnitude. This feature of hormone action also applies to EDCs that can interfere with that hormone. For this reason, we argue that the choice of endpoint for use in regulation is critical, but note that guideline studies were not designed with this in mind. Second, the biological events controlled by hormones in development not only change as development proceeds but are different from events controlled by hormones in the adult. Again, guideline endpoints were also not designed with this in mind, especially since the events controlled by hormones can be both temporally and spatially specific. The Endocrine Society has laid out this logic over several years and in several publications.

Abbreviations
EDC, endocrine-disrupting chemical; EPA, Environmental Protection Agency; OECD, Organization for Economic Co-operation and Development.

Acknowledgments
The authors wish to thank Dr Joe Laakso, director of science policy for the Endocrine Society and Dr Shirlee Tan, toxicologist with Public Health—Seattle & King County for their careful review and comment on this commentary.

Additional information
Disclosures & Disclaimers
This letter was drafted in response to the commentary by Dr Brescia, "Thresholds of adversity and their applicability to endocrine disrupting chemicals". This response is submitted by the authors (Barbara Demeneix, Laura Vandenberg, Richard Ivell, and R. Thomas Zoeller) on behalf of the Endocrine Society's Endocrine-Disrupting Chemicals Expert Advisory Group and the members of this Advisory Group.
The Endocrine Society's EDC Advisory Group provides coordinated oversight and guidance on Society activities related to Endocrine-Disrupting Chemicals (EDCs) covering all relevant Society functions, including publications, education, and policy. The EDC-related positions and priorities that the Endocrine Society advocates for are described in our Position Statement on EDCs (https://www.endocrine.org/advocacy/position-statements/endocrine-disrupting-chemicals) and Position Statement on EDCs in the EU (https://www.endocrine.org/advocacy/position-statements/endocrine-disrupting-chemicals-in-the-european-union).

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

Authors and Disclosures

Barbara Demeneix¹, Laura N. Vandenberg², Richard Ivell³ and R. Thomas Zoeller^4,5

¹UMR 7221, Muséum National d'Histoire Naturelle, Département Régulation Développement et Diversité Moléculaire, Paris, France 75231; ²Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts–Amherst, Amherst, Massachusetts 01003; ³School of Biosciences, University of Nottingham, Sutton Bonington, UK; ⁴Morrill Science Center, Department of Biology, University of Massachusetts–Amherst, Amherst Massachusetts 01003; and ⁵School of Science and Technology, Örebro University, SE-701 82, Örebro Sweden

Correspondence
R. Thomas Zoeller, Biology Department, University of Massachusetts Amherst, 611 N Pleasant St, Amherst, MA 01003. E-mail: tzoeller@bio.umass.edu.

None of the authors received funding from any source for this commentary. The views expressed here are the professional opinions of the authors and do not necessarily reflect those of their employers or any agencies that have funded their work. There are no contractual relations or proprietary considerations that restrict the authors' publication or dissemination of the findings described in the manuscript.
Dr Demeneix is currently the chair of the Endocrine Society's EDC Advisory Group and is co-chair of one of its Task Force groups. Her EDC-related research has been funded by government and EU agencies and foundations. Dr Demeneix holds a patent under the name "Transgenic clawed frog embryos and use thereof as detectors of endocrine disruptors in the environment" filed in 2002 (number FR020669) and extended by a Patent Cooperation Treaty filed in 2003.
Dr Vandenberg is currently a member of the Endocrine Society's EDC Advisory Group, is co-chair of one of its Task Force groups, and a member of 2 other Task Forces. She is also a member of the US EPA's Science Advisory Board Chemical Assessment Advisory Committee and a scientific advisor (unpaid) to 2 Horizon 2020 EDC grants. Her travel has been sponsored by various government, academic, and industry groups to present findings of her research. Dr Vandenberg's EDC-related research has been funded by US government agencies, the University of Massachusetts Amherst, and nongovernmental organization including the Cornell Douglas Foundation and the Great Neck Breast Cancer Coalition.
Dr Ivell is currently a member of the Endocrine Society's EDC Advisory Group and is Editor-in-Chief of the specialty section "Reproduction" for the journals Frontiers in Physiology and Frontiers in Endocrinology. His EDC-related research has been funded by government and academic agencies.
Dr Zoeller has served on various advisory boards and panels of the US EPA, the National Institutes of Health and Pew Charitable Trusts in relation to issues of EDCs. He is currently a member of the Endocrine Society's EDC Advisory Group and is co-chair of one of its Task Force groups. His travel has been sponsored by various government, academic, and industry groups to present findings of his research. Dr Zoeller's research has been funded by government agencies in the United States and the European Union.