Editorial

Scientically unfounded precaution drives European Commissions

recommendations on EDC regulation, while defying common sense,
well-established science and risk assessment principles
We, the undersigned editors of prominent journals of pharma-
cology and toxicology, are drawing your attention to the imminent
decisions by the European Commission to enforce a regulatory
framework for so-called endocrine disrupting chemicals (EDCs).
The currently drafted framework is based on virtually complete
ignorance of all well-established and taught principles of pharma-
cology and toxicology, of opinions raised by the European Commis-
sions own competent expert authority [4], and of critical
statements made by member countries, while avoiding asking for
support from the European Commissions own scientic expert
committees.
As a statement, and as emphasized by others before, endocrine
disruption is not a toxicologically dened endpoint but a mode-
of-action that may or may not result in adverse effects. In itself,
the mode-of-action concept implies the necessary existence of a
threshold as experimentally proven for numerous other non-geno-
toxic agents including EDCs. Moreover, endocrine systems play a
fundamental role in the physiological response to changes in the
environment with the aim of keeping an organisms biology within
the homeostatic space. It is the task of toxicologists to make the
distinction between those effects that are within this adaptive
range and effects that go beyond the boundaries of this space
and thus can be called adverse. Such adverse effects can be
observed in adequately designed and performed toxicity studies.
While we agree that a concern for possible EDCs is sensible and
important, we also think that the identication and regulation of
such substances should depend on (a) the denition of adverse ef-
fects that are relevant to whole human or animal organisms and
not to isolated test systems of unknown homeostatic signicance,
and (b) on a characterization of real-life potency and therefore of
thresholds of concern.
In contrast, the currently drafted EU framework for EDCs fore-
sees a priori regulation of agents that may show presumably endo-
crine-mediated effects in some experimental system (in vitro, in
silico, in vivo. . .), and under the a priori default assumption of no
thresholds. This approach is based on a very small number of pub-
lications [1,810] that lack the required scientic robustness
needed for such an important piece of legislation that is sweeping
in nature, will set an unforeseen precedence, and nally will have
profound ramications for everyones livelihood. Furthermore, the
regulatory draft specically states that the identication of an
endocrine disruptor relies on the demonstration of an
adverse effect for which there is convincing evidence of a biologically
plausible causal link to an endocrine disrupting mode of action and for
which disruption of the endocrine system is not a secondary
consequence of other non endocrine-mediated systemic toxicity. Rele-
vance of the data to humans should be assumed in the absence of
appropriate data demonstrating non-relevance.
As all scientists should know, it is biologically and statistically
impossible to demonstrate absence of effect and thus absence
of relevance. The mere statement demonstrates the lack of atten-
tion paid by the European Commission to the weight of scientic
evidence that clearly demonstrates the presence of a threshold
for non-genotoxic compounds including EDCs [2,3,57], as well
as to the scientic detail with regard to the physiological and sta-
tistical implausibility of the approach taken. In fact, any scientist
familiar with the overwhelming biochemical complexity of life
understands that the healthy homeostasis of an organism results
from an orchestrated network of myriad thresholds for every com-
ponent substance.
On this account, a nucleus of scientists sent an open letter on
June 18 2013
1
to Prof. Anne Glover, Chief Scientic Advisor to the
President of the European Commission Manuel Barroso,
2
pointing
out the major deciencies of the drafted EU framework, and the wor-
risome ramications this draft could have for science, the economy,
and human welfare the world over.
Although some readers may shrug and think this is not impor-
tant and not their problem, it soon could be. Regulations that pro-
foundly affect human activities, that legally impose signicant
nes and even detention, should not be based on irrelevant tests
forced to be regarded as relevant by administrative dictates, and
on arbitrary default assumptions of no thresholds. Such standards
would be contrary not only to science, but to the very principles of
an enlightened governance and social contract. Not only scientists
but society itself would pay dearly if unscientic approaches were
to undermine our everyday practice of science, and the stringency
of data analysis and evaluation developed by scientic thinking
over the past centuries. In the present instance, the very credibility
of thorough and robust teaching, research, and scientic analysis is
questioned. This calls for action, and as beneciaries of public sup-
port it is the utmost responsibility of us scientists to resist and
counteract any efforts that undermine the core of science and its
continuing promise for the betterment of the human condition
and of the planet.
0009-2797/$ - see front matter 2013 Published by Elsevier Ireland Ltd.
http://dx.doi.org/10.1016/j.cbi.2013.07.001
1
Open Letter to Prof. Anne Glover (to be included in each Journals own format) of
June 18, 2013.
2
http://ec.europa.eu/commission_2010-2014/president/chief-scientic-adviser/
Chemico-Biological Interactions 205 (2013) A1A5
Contents lists available at SciVerse ScienceDirect
Chemico-Biological Interactions
j our nal homepage: www. el sevi er . com/ l ocat e/ chembi oi nt
Authors
Daniel R. Dietrich, Editor-in-Chief, Chemico Biological
Interactions
Sonja von Aulock, Editor-in-Chief, ALTEX
Hans Marquardt, Editor-in-Chief, Toxicology
Bas Blaauboer, Editor-Europe, Toxicology in Vitro
Wolfgang Dekant, Editor-in-Chief, Toxicology Letters
James Kehrer, Editor-in-Chief, Toxicology Letters
Jan Hengstler, Editor-in-Chief, Archives of Toxicology
Abby Collier, Section Editor, Chemico Biological Interactions
Gio Batta Gori, Editor-in-Chief, Regulatory Pharmacology and
Toxicology
Olavi Pelkonen, Editor-in-Chief, Frontiers in Predictive
Toxicology
Florian Lang, Editor-in-Chief, Toxins
Frank A. Barile, Editor-in-Chief, Toxicology in Vitro
Frans P. Nijkamp, Editor-in-Chief, European Journal of
Pharmacology
Kerstin Stemmer, Assoc. Editor, Toxicology in Vitro
Albert Li, Section Editor, Chemico Biological Interactions
Kai Savolainen, Editor for Europe and rest of the World, Human
and Experimental Toxicology
A. Wallace Hayes, Editor for the Americas, Human and Experi-
mental Toxicology and Editor-in-Chief, Food and Chemical
Toxicology
Nigel Gooderham, Editor-in-Chief, Toxicology Research
Alan Harvey, Editor-in-Chief, Toxicon
References
[1] L.S. Birnbaum, When environmental chemicals act like uncontrolled medicine,
Trends Endocrinol. Metab. 24 (2013) 321323.
[2] A.R. Boobis, G.P. Daston, R.J. Preston, S.S. Olin, Application of key events
analysis to chemical carcinogens and noncarcinogens, Crit. Rev. Food Sci. Nutr.
49 (2009) 690707.
[3] C.J. Borgert, E.V. Sargent, G. Casella, D.R. Dietrich, L.S. McCarty, R.J. Golden, The
human relevant potency threshold: reducing uncertainty by human calibration of
cumulative risk assessments, Regul. Toxicol. Pharmacol. 62 (2012) 313328.
[4] E.F.S.A.S. Committee, Scientic opinion on the hazard assessment of endocrine
disruptors: scientic criteria for identication of endocrine disruptors and
appropriateness of existing test methods for assessing effects mediated by
these substances on human health and the environment, EFSA J. 11 (2013)
31323216.
[5] A.H. Piersma, L.G. Hernandez, J. van Benthem, J.J. Muller, F.X. van Leeuwen, T.G.
Vermeire, M.T. van Raaij, Reproductive toxicants have a threshold of adversity,
Crit. Rev. Toxicol. 41 (2011) 545554.
[6] L.R. Rhomberg, J.E. Goodman, Low-dose effects and nonmonotonic dose-
responses of endocrine disrupting chemicals: has the case been made?, Regul
Toxicol. Pharmacol. 64 (2012) 130133.
[7] L.R. Rhomberg, J.E. Goodman, L.T. Haber, M. Dourson, M.E. Andersen, J.E.
Klaunig, B. Meek, P.S. Price, R.O. McClellan, S.M. Cohen, Linear low-dose
extrapolation for noncancer heath effects is the exception, not the rule, Crit.
Rev. Toxicol. 41 (2011) 119.
[8] D.M. Sheehan, No-threshold dose-response curves for nongenotoxic chemicals:
ndings and applications for risk assessment, Environ. Res. 100 (2006) 9399.
[9] L.N. Vandenberg, T. Colborn, T.B. Hayes, J.J. Heindel, D.R. Jacobs Jr., D.H. Lee, T.
Shioda, A.M. Soto, F.S. vom Saal, W.V. Welshons, R.T. Zoeller, J.P. Myers,
Hormones and endocrine-disrupting chemicals: low-dose effects and
nonmonotonic dose responses, Endocr. Rev. 33 (2012) 378455.
[10] R.T. Zoeller, T.R. Brown, L.L. Doan, A.C. Gore, N.E. Skakkebaek, A.M. Soto, T.J.
Woodruff, F.S. Vom Saal, Endocrine-disrupting chemicals and public health
protection: a statement of principles from the endocrine society,
Endocrinology 153 (2012) 40974110.
A2 Editorial / Chemico-Biological Interactions 205 (2013) A1A5
RE: Draft regulation on endocrine active chemicals June 18, 2013
Dear Prof. Glover,
We, the undersigned are writing to draw your attention to
imminent decisions by the European Commission to set a regula-
tory framework for so-called endocrine disrupting chemicals. We
are concerned that the approach proposed could rewrite well-
accepted scientic and regulatory principles in the areas of toxicol-
ogy and ecotoxicology without adequate scientic evidence
justifying such a departure from existing practices.
First of all, we want to emphasize that endocrine disruption is
not a toxicological endpoint, but one of many mechanisms which
may cause adverse effects. In addition, we recognize that such a
policy initiative is highly technical and complex and requires an
understanding of the modes of action for endocrine disruption
and their signicance. It also implies the in-depth involvement
not only of toxicological disciplines but also of environmental sci-
ences and thus requires scientic input from experts in this area.
The undersigned are concerned that the Commissions scientic
committees have so far not been consulted by the Commission
when drafting such regulations. What is even more disturbing is
that, where a scientic advisory body such as EFSA has been con-
sulted, critical elements of this bodys opinion are ignored. For
example, in assessment of chemicals with endocrine activity, EFSA
supported a substance specic risk assessment approach integrat-
ing exposure and adverse effects instead of developing horizontal
criteria for dening whether a substance is an endocrine disrup-
tor. Development of horizontal lists ignores the long-standing
principle that an assessment of a substance should be based on
data obtained from toxicity testing on this specic substance and
derived information on potency.
If the Commission will adopt a policy stating that it is impossi-
ble to dene a safe limit or threshold for a substance with classied
as endocrine disruptor, this would reverse current scientic and
regulatory practices and, more importantly, ignore broadly devel-
oped and accepted scientic development and accepted knowledge
regarding thresholds of adversity. Moreover, the latter approach
may not only apply to potential EDCs but rather would apply to
all chemical substances and thus nullify decades of experience
and repeatable observations in exposureresponse relationships
in pharmacology and toxicology and well-established and widely
proven procedures in hazard and risk assessment.
It also appears that the Commission will propose that identica-
tion of an in vitro effect without a causal relationship to adversity
in an intact organism may be sufcient to classify a substance as an
endocrine disruptor. This would not only represent a rewriting of
the rules and accepted practices of toxicology, which rely on well-
dened adverse effects observed in adequately performed studies,
but also would be contrary to all accumulated physiological
understanding.
This leaves us concerned that there is neither a scientic basis
nor broad support by scientists established in risk assessment be-
hind the approach of setting horizontal criteria and the lists of con-
rmed and suspected endocrine disruptors.
We have noted your important interventions on the need for
scientic evidence to be at the heart of EU policy and are therefore
writing to urge your review of the emerging policy to ensure that
the opinion of relevant scientic committees and member states
authorities are taken into account.
The following individuals are supporting this initiative:
Antero Aitio, Dr. Med. Sc., Professor h.c., former scientist/medi-
cal ofcer at the International Programme on Chemical Safety,
World Health Organization; former team leader, Finnish Institute
of Occupational Health; former Unit Chief of the Monographs Pro-
gramme, International Agency for Research on Cancer
Herman Autrup, Professor, PhD ATS, President International Un-
ion of Toxicologists, former member SCHER, AFC-Panel of EFSA,
Institute of Public Health, University of Aarhus, Denmark
Susan, Barlow, Ph.D., former member of EFSA Scientic Com-
mittee (20032012), Brighton, UK
Diane Benford, Dr., member, chair CONTAM Panel of EFSA, Head
of Chemical Risk Assessment Unit, Food Standards Agency, London,
UK
Ole J. Bjerrum, DMSc, Professor of Pharmacology, University of
Copenhagen, Denmark
Sir Colin Berry, Prof. Emeritus of Pathology, Queen Mary, Uni-
versity of London, UK
Bas J. Blaauboer, Prof. Dr., Doerenkamp-Zbinden Chair on Alter-
natives to Toxicity Testing, Institute for Risk Assessment Sciences,
Division of Toxicology, Utrecht University, The Netherlands
Hermann M. Bolt, Prof. Dr. med., Dr. rer. nat., Chair of the Scien-
tic Committee for Occupational Exposure Limits, SCOEL (DG
Employment), Leibniz Research centre for Working Environment
and Human Factors (IfADo) at the TU Dortmund, Germany
Alan Boobis, Prof., OBE, PhD, FSB, FBTS, member CONTAM Panel
of EFSA, centre for Pharmacology & Therapeutics, Department of
Medicine, Imperial College London, UK
Christopher J. Borgert, Ph.D., President & Principal Scientist,
Applied Pharmacology and Toxicology, Inc., Research Assistant Sci-
entist, Department of Physiological Sciences, College of Veterinary
Medicine, Gainesville, FL, USA
Alexander Brkle, Prof. Dr., Chair of Molecular Toxicology
Department of Biology, University of Konstanz, Germany
Michle Bouchard, Ph.D., Associate Professor, Head of the Chair
in Toxicological Risk Assessment and Management and Head of the
Biomarker Unit of the Xenobiotics and Nanoparticles Platform,
Department of Environmental and Occupational Health, Faculty
of Medicine, University of Montreal, Canada
Thomas Colnot, Ph.D., ERT, CiS Toxicology, Castro, Chile
Brian Cummings, Ph.D., Assistant Professor, Department of
Pharmaceutical and Biomedical Sciences, University of Georgia,
Athens, GA, USA
Slawomir Czerczak, Prof. Dr., Chair for Group of Experts for
Chemical Agents of Polish Intersectoral Commission for MAC and
MAI Values, Head of Department of Chemical Safety, Nofer Insti-
tute of Occupational Medicine Lodz, Poland
Gisela H. Degen, Prof. Dr., member SCCS, Leibniz Research cen-
tre for Working Environment and Human Factors (IfADo) at the TU
Dortmund, Germany
Wolfgang Dekant, PhD, Professor of Toxicology, former member
SCHER, CSTEE, member SCHENIHR, Department of Toxicology, Uni-
versity of Wrzburg, Germany
Lennart Dencker, Prof. Dr., Department of Pharmaceutical Bio-
sciences, Uppsala University, Uppsala, Sweden
Daniel Dietrich, Prof. Dr., Ph.D., Professor of Human and Envi-
ronmental Toxicology, Member of SCENIHR, Former Chair of the
OECD Endocrine Disruption and Ecotoxicology EDTA-VMG Non-
Animal of the OECD, Member Presidential Expert Group AOAC, Fac-
ulty of Biology, University of Konstanz, Germany
Daniel R. Doerge, Ph.D., National Center for Toxicological
Research, Jefferson, AR, USA (afliation is given for identication
purposes only)
Eugenia Dogliotti, Dr., Member CONTAM Panel of EFSA, Istituto
Superiore di Sanit, Environment & Primary Prevention Dept., Unit
of Molecular Epidemiology, Roma, Italy
Editorial / Chemico-Biological Interactions 205 (2013) A1A5 A3
Jose L. Domingo, Professor and Director, Laboratory of Toxicol-
ogy and Environmental Health, School of Medicine, Universitat
Rovira i Virgili, Reus, Spain
Johanna Fink-Gremmels, Prof. Dr., Utrecht University, Faculty of
Veterinary Medicine, Institute for Risk Assessment Sciences,
Division Toxicology, Veterinary Pharmacology, Pharmacotherapy
and Toxicology, Utrecht, The Netherlands
Hermann Fromme, Prof. Dr., Department of Chemical Safety and
Toxicology, Bavarian Health and Food Safety Authority, Munich
Corrado Galli, Pof. Dr., Dean, Faculty of Pharmaceutical Sciences,
Lab. Toxicology, Department of Pharmacological and Biomolecular
Sciences, University of Milan, Italy
David Gott, Dr., member ANS Panel of EFSA, Head of Toxicology
Team, Chemical Risk Assessment Unit, Food Standards Agency,
London, UK
Gio Batta Gori, DSc, MPH, ATS, Editor, Regulatory Toxicology
and Pharmacology
Bettina Grasl-Kraupp, Prof. Dr., ERT, Institute for Cancer Re-
search - Medical University of Vienna, Austria
Helmut Greim, Prof. Dr., member RAC ECHA, former chair MAK
Commission, former chair SCHER, former member CSTEE, member
SCHER, Technische Universitt Mnchen, Senatskommission der
DFG zur Prfung gesundheitsschdlicher Arbeitsstoff, Freising,
Germany
Heidrun Greim, Dr., Wissenschaftliches Kommissionssekretariat
der Stndigen Senatskommission der DFG zur Prfung ges-
undheitsschdlicher Arbeitsstoffe, Karlsruher Institut fr Technol-
ogie (KIT), Abteilung Lebensmittelchemie und Toxikologie,
Institut fr Angewandte Biowissenschaften, Freising- Weihenste-
phan, Germany
G.M.M. Groothuis, Prof. Dr., Professor in Drug Metabolism and
Toxicology, Department of Pharmacy, Groningen Research Institute
of Pharmacy, Division Pharmacokinetics, Toxicology and Targeting,
University of Groningen, The Netherlands
Helen Hkansson, Professor, Head of Unit, Karolinska Institutet,
Institute of Environmental Medicine, Environmental Health Risk
Assessment Unit, Stockholm, Sweden
Steen Honor Hansen, Prof. D.Sc., Analytical Biosciences,
Department of Pharmacy, Faculty of Health and Medical Sciences,
University of Copenhagen, Denmark
Wolfgang Heger, Dr., Umweltbundesamt, Berlin, Germany
Bjrn Hellman, Ph.D., Professor of Toxicology, Department of
Pharmaceutical Biosciences, University of Uppsala, Sweden (aflia-
tion is given for identication purposes only)
Jan G. Hengstler, Prof. Dr., Leibniz Research Centre for Working
Environment and Human Factors, IfADo, Dortmund, Germany
Magnus Ingelman-Sundberg, PhD, BSc.Med, Professor and
Section Head, Vice Dean (Recruitment), Karolinska Institutet, Sec-
tion of Pharmacogenetics, Department of Physiology and Pharma-
cology, Stockholm, Sweden
Colin Janssen, Prof. Dr., former member CSTEE, member SCHER,
Ghent University, Department Applied Ecology and Environmental
Biology, Laboratory of Environmental Toxicology and Aquatic Ecol-
ogy, Ghent, Belgium
Risto Juvonen, PhD, School of Pharmacy Faculty of Health Sci-
ences University of Eastern Finland, Kuopio, Finland
James Kehrer, Professor and Dean, Faculty of Pharmacy & Phar-
maceutical Sciences, Katz Centre for Pharmacy & Health Research,
University of Alberta, Edmonton, AB, Canada
Hannu Kiviranta, Ph.D., Unit head, National Institute for Health
and Welfare/Department of Environmental Health/Chemical Expo-
sure, Kuopio, Finland
Hannu Komulainen, Research professor, former member SCHER,
National Institute for Health and Welfare, Department of Environ-
mental Health, Kuopio, Finland
Hans Lepper, Dr., Bayerisches Landesamt fr Gesundheit und
Lebensmittelsicherheit, SG K3: Forschungskoordination/Zentrals-
telle Risikoanalyse, Erlangen, Germany
Beatriz Silva Lima, Prof. Dr., Lisbon University, Faculty of Phar-
macy, Lisbon, Portugal
Jan Linders, Dr., member SCHER, formerly National Institute for
Public Health and the Environment (RIVM), The Netherlands
Marcello Lotti, MD, Professor, University of Padua, Medical
School, Padua, Italy
Marina Marinovich, Prof. Dr., Faculty of Pharmaceutical Sci-
ences, Lab. Toxicology, Department of Pharmacological and Biomo-
lecular Sciences, University of Milan, Italy
Angelo Moretto, Prof. Dr., Department of Biomedical and Clini-
cal Sciences, Universit degli Studi di Milano, Milano, Italy
Paquale Mosesso, Associate Professor of Genetics, member ANS
Panel of EFSA, Department of Ecological and Biological Sciences,
University of Tuscia, Viterbo, Italy
Mikko Nikinmaa, Prof. Dr., Department of Biology, University of
Turku, Finland
Marc Pallardy, Prof. Dr., INSERM UMR 996, University Paris-Sud,
Faculty of Pharmacy, Chatenay-Malabry, France
Markku Pasanen, Prof. Dr., University of Eastern Finland, Faculty
of Health Sciences, School of Pharmacy, Kuopio, Finland
Olavi Pelkonen, Professor of Pharmacology, Department of
Pharmacology and Toxicology, University of Oulu, Oulu, Finland
Hannu Raunio, Prof. Dr., University of Eastern Finland, Faculty of
Health Sciences, School of Pharmacy, Kuopio, Finland
Ivonne M.C.M. Rietjens, Prof. dr. ir., Professor in Toxicology,
member ANS Panel of EFSA, Wageningen University AFSG/Division
of Toxicology, Wageningen, The Netherlands
Konrad Rydzynski, Prof. Dr. med., Coordinator of the European
Network of Excellence ECNIS (Environmental Cancer Risks, Nutri-
tion and the Individual Susceptibility), member SCENIHR, Director
of the Nofer Institute of Occupational Medicine, Lodz, Poland
Edward V. Sargent, Dr., MPH, PhD DABT, Adjunct Full Professor,
School of Public Health, Rutgers University, NJ, USA
Tinaa Santonen, MD, PhD, MSc in Applied Toxicology TeamLeader,
Chemical Safety, Finnish Institute of Occupational Health, Finland
Josef Schlatter, Dr., member of EFSA Scientic Committee,
Zrich, Switzerland
Dieter Schrenk, MD PhD, Professor of Toxicology, member CON-
TAM Panel of EFSA, Food Chemistry and Toxicology University of
Kaiserslautern, Germany
Richard M Sharpe, Prof. Dr., MRC Centre for Reproductive
Health, The Queens Medical Research Institute, University of Edin-
burgh, Scotland, UK
Andrzej C Skladanowski, PhD, Prof. Dr., Medical University of
Gdansk Intercollegiate Faculty of Biotechnology UG-MUG, Depart-
ment of Molecular Enzymology, Gdansk, Poland
Ralf Stahlmann, Prof. Dr. med., Institut fr Klinische Pharmakol-
ogie und Toxikologie, Charit Universittsmedizin Berlin, Germany
Frank M. Sullivan, BsC (Hons), FBTS, formerly UK Specialist in
Reproductive Toxicology
James A. Swenberg, DVM, PhD, DACVP, KenanDistinguishedProfes-
sor of Environmental Sciences and Engineering, Gillings School of Glo-
bal Public Health, University of North Carolina, Chapel Hill, NC USA
Emanuela Testai, Dr., former member SCHER, CSTEE, member
SCENIHR, Istituto Superiore di Sanit, Environment & Primary Pre-
vention Dept., Mechanisms of Toxicity Unit, Roma, Italy
Jouko Tuomisto, MD, PhD, Professor emeritus, Department of
Environmental Health, THL (National Institute for Health and Wel-
fare), Kuopio, Finland
N.P.E. Vermeulen, Prof. Dr., AIMMS/LACDR-Section of Molecular
Toxicology, Dept. of Chemistry & Pharmaceutical Sciences, VU Uni-
versity, Amsterdam, The Netherlands
A4 Editorial / Chemico-Biological Interactions 205 (2013) A1A5
Marco Vighi, Prof. Dr., former member SCHER, Department of
Earth and Environmental Sciences, University of Milano Bicocca,
Milano, Italy
Matti Viluksela, Prof. Dr., former member SCHER, National Insti-
tute for Health and Welfare Department of Environmental Health,
Kuopio, Finland and University of Eastern Finland Department of
Environmental Science Kuopio, Finland
Wolfgang Vlkel, PD Dr., ERT, Bayerisches Landesamt fr
Gesundheit und Lebensmittelsicherheit, Sachgebiet Chemikaliensi-
cherheit und Toxikologie/Biomonitoring, Mnchen, Germany
J.C. Vos, Dr., Dept. of Chemistry & Pharmacochemistry, AIMMS-
Section of Molecular Toxicology, Vrije Universiteit, Amsterdam,
The Netherlands
Wojciech Wasowicz, Prof. Dr., President of the Polish Society of
Toxicology, Nofer Institute of Occupational Medicine, Lodz, Poland
Professor Anne Glover CBE,
Chief Scientic Adviser to the President of the European Commission
Berlaymont 08/039,
Rue de la Loi 200,
B-1049 Brussels,
Belgium
Available online 4 July 2013
Editorial / Chemico-Biological Interactions 205 (2013) A1A5 A5
Policy Decisions on Endocrine Disruptors Should Be
Based on Science Across Disciplines: A Response to
Dietrich et al.
A. C. Gore, J. Balthazart, D. Bikle, D. O. Carpenter, D. Crews, P. Czernichow,
E. Diamanti-Kandarakis, R. M. Dores, D. Grattan, P. R. Hof, A. N. Hollenberg,
C. Lange, A. V. Lee, J. E. Levine, R. P. Millar, R. J. Nelson, M. Porta, M. Poth,
D. M. Power, G. S. Prins, E. C. Ridgway, E. F. Rissman, J. A. Romijn,
P. E. Sawchenko, P. D. Sly, O. Sder, H. S. Taylor, M. Tena-Sempere, H. Vaudry,
K. Wallen, Z. Wang, L. Wartofsky, and C. S. Watson
Division of Pharmacology and Toxicology, The University of Texas, Austin, Texas 78712 (A.C.G.);
University of Lige, GIGA Neurosciences, B-4000 Lige, Belgium (J.B.); VA Medical Center and University
of California, San Francisco, San Francisco, California 94143 (D.B.); Institute for Health and the
Environment, University at Albany, State University of New York, Albany, New York 12222 (D.O.C.);
Section of Integrative Biology, The University of Texas, Austin, Texas 78712 (D.C.); Professor Emeritus of
Pediatrics, University of Paris, 75006 Paris, France (P.C.); Medical School University of Athens, Sotiria
Hospital, Athens 115 27, Greece (E.D.-K.); Department of Biological Sciences, University of Denver,
Denver, Colorado 80208 (R.M.D.); Department of Anatomy, University of Otago, North Dunedin 9016,
New Zealand (D.G.); Icahn School of Medicine at Mt Sinai, New York, New York 10029 (P.R.H.); Beth
Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts 02115 (A.N.H.);
University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota 55455 (C.L.); University of
Pittsburgh Cancer Institute and Magee Womens Research Institute, Pittsburgh, Pennsylvania 15213
(A.V.L.); Wisconsin National Primate Research Center, Madison, Wisconsin 53715 (J.E.L.); UCT/MRC
Receptor Biology Unit, University of Cape Town, Cape Town, South Africa (R.P.M.); Department of
Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210 (R.J.N.);
Hospital del Mar Institute of Medical Research and School of Medicine, Universitat Autnoma de
Barcelona, 080041 Barcelona, Spain (M.Porta); Uniformed Services University of the Health Sciences,
Bethesda, Maryland 20814 (M.Poth); Department of Biosciences, Universidade do Algarve, 8005139
Faro, Portugal (D.M.P.); Department of Physiology and Biophysics, University of Illinois, Chicago, Illinois
60612 (G.S.P.); Department of Medicine, University of Colorado School of Medicine, Denver, Colorado
80208 (E.C.R.); Department of Biochemistry and Molecular Genetics, School of Medicine, University of
Virginia, Charlottesville, Virginia 22908 (E.F.R.); Division of Medicine, Academic Medical Center,
University of Amsterdam, 1012 WX Amsterdam, The Netherlands (J.A.R.); Laboratory of Neuronal
Structure and Function, The Salk Institute, La Jolla, California 92037 (P.E.S.); Queensland Childrens
Medical Institute, University of Queensland, Royal Childrens Hospital, Brisbane, Queensland 4000,
Australia (P.D.S.); Karolinska Institutet at Karolinska University Hospital Solna, 171 76 Stockholm,
Sweden (O.S.); Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of
Medicine, New Haven, Connecticut 06510 (H.S.T.); Department of Cell Biology and Physiology,
University of Crdoba, 14071 Crdoba, Spain (M.T.-S.); Institut National de la Sant et de la Recherche
Mdicale U982, University of Rouen, 76821 Rouen, France (H.V.); Department of Psychology and Yerkes
National Primate Research Center, Emory University, Atlanta, Georgia 30322 (K.W.); Department of
Psychology and Neuroscience, Florida State University, Tallahassee, Florida 32306 (Z.W.); Department of
Medicine, Washington Hospital Center, Washington, DC 20010; and Department of Biochemistry and
Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555 (C.S.W.)
(Endocrinology 154: 39573960, 2013)
ISSN Print 0013-7227 ISSN Online 1945-7170
Printed in U.S.A.
Copyright 2013 by The Endocrine Society
Received September 14, 2013. Accepted September 14, 2013.
Abbreviations: EDC, endocrine disrupting chemical; UNEP, United Nations Environment
Programme; WHO, World Health Organization.
E D I T O R I A L
doi: 10.1210/en.2013-1854 Endocrinology, November 2013, 154(11):39573960 endo.endojournals.org 3957
W
e are writing as scientists and editors of leading
peer-reviewed journals that have published impor-
tant contributions in the study of endocrine disrupting
chemicals (EDCs). By signing this editorial, we affirmthat
regulatory decisions on EDCs should be made based on
the best available science and expertise that involves,
among others, reproductive biology, endocrinology, med-
icine, genetics, behavior, developmental biology, and tox-
icology (1). (For a complete list of Signatories and their
Disclosures, see Supplemental Table 1 published on The
Endocrine Societys Journals Online web site at
http://end.endojournals.org.)
Thousands of published studies have revealed the health
effects of EDCs on wildlife and laboratory animals and,
moreover, have shown associations of EDCs with effects in
humans. Many of these studies have been reviewed recently
by The Endocrine Society, the United Nations Environment
Programme (UNEP) and World Health Organization
(WHO), andother independent scientists (25). The conclu-
sions presented in each of these documents are extraordi-
narilyconsistent: like hormones, EDCs are active at very low
doses and can induce a range of adverse health outcomes,
many of which are not examined in traditional toxicology
assays (1). In sum, these reports point to the conclusion that
EDCs pose a global health threat.
Arecent editorial signed by a number of editors of tox-
icology journals argues for the status quo in the regulation
of EDCs (6), despite the large volume of evidence indicat-
ing that current regulations are ineffective in protecting
human populations from these chemicals (47). As the
UNEP/WHOreport notes, the incidence of chronic disease
is nowgreater thanthat of communicable disease; many of
these diseases have an endocrine basis. Both experimental
animal and epidemiology studies provide plausible causal
links between EDCs and many of these diseases; for some,
the data are sufficiently robust (8).
The dismissive approach to endocrine disruption sci-
ence put forth by Dietrich et al (6) is unfounded, as it is
neither based on the fundamental principles of how the
endocrine system works and how chemicals can interfere
with its normal function, nor does it consider the conse-
quences of that interference. Their letter also ignores a
growing and rigorous body of literature on both endoge-
nous hormonal and exogenous EDC effects.
Basic scientists, clinical investigators, and physicians
understand that the endocrine systems functions and re-
sponses change remarkably across the life cycle. Of par-
ticular concern is incontrovertible evidence, published
more than a half century ago (9, 10), that there are critical
life stages, especially during early development, whenhor-
mones dictate the differentiation and development of tis-
sues. Any perturbation of the delicate hormonal balance,
whether due to the absence of natural hormones or the
presence of exogenous hormones, can have irreversible
effects on endocrine-sensitive organs. EDCs are known to
upset this delicate balance.
Dietrich et al (6) also misrepresent the state of science
on thresholds, stating that the evidence clearly demon-
strates the presence of a threshold for nongenotoxic com-
pounds including EDCs. Dietrich et al assert that their
position constitutes common sense and that the Euro-
pean Commissions approach departs from common
sense. Theydonot, however, provide scientific support for
this position. Instead, they list several references (1115)
that, upon examination, do not contain data supporting
their assumption but rather simply assert that the assump-
tion is true. They also fail to address the considerable lit-
erature that speaks against that assumption (eg, Refs 16
20). Finally, they argue that structuring regulation upon
the assumption of no threshold will set an unforeseen
precedence [sic]. This is simply and demonstrably not
true. The assumption of no threshold has been widely
used, for many years, in the regulation of genotoxic car-
cinogens, often based on in vitro data. We believe extend-
ingthis precedent toEDCs is supportedbythe science (19).
Furthermore, we hold that common sense dictates that
policies, particularly those in which public health is at stake,
should be based on scientific evidence obtained from the
worlds leading researchers and should derive from a more
evolved, modernunderstandingof thescience, ratherthanon
older, outdatedconcepts anddatataught inclassrooms 20or
more years ago. The European Commission policy, by that
standard, does represent common sense.
Further, the US National Academy of Sciences has con-
cluded that because of the range of susceptibility to environ-
mental chemicals across the population, such as that from
age, preexisting conditions, and genetic variation, and be-
causetherearedocumentedexposures tomultiplechemicals,
including EDCs, in the population, it is more appropriate to
consider lack of thresholds at a population level (16).
Many toxicologists have developed rigorous research
programs on EDCs that incorporate endocrinological
principles, including two former presidents of the Society
of Toxicology, Cheryl Walker and Linda Birnbaum. They
and many other toxicologists do work in this area and
report results that have contributed to the breadth and
depth of concern about EDCs as a global public health
threat. The ad hominem attacks in Dietrich et al (6) do
nothing to advance science or opportunities to protect
public health; we refer readers totwoadditional responses
to their editorial that support this point of view (21, 22).
We need the fields of toxicology, endocrinology and other
stakeholders to work together to address these issues, not
engage in recriminations.
3958 Gore et al Editorial Endocrinology, November 2013, 154(11):39573960
Policymakers in Europe and elsewhere should base their
decisions onscience, not onassumptions basedonprinciples
that arose out of research on chemicals that are not EDCs.
The letter by Dietrich et al does the European Commission,
science, including the field of toxicology, and most impor-
tantly, public health, a profound disservice.
Acknowledgments
The following is the list of signatories. The complete list of their
affiliations and disclosure information is provided in Supple-
mental Table 1.
Signatories
Journal Editors-in-Chief:
1. Prof. Jacques Balthazart, PhD, Frontiers in
Neuroendocrinology
2. David O. Carpenter, MD, Reviews on Environmental Health
3. Paul Czernichow, MD, Hormone Research in Pediatrics
4. Donald B. DeFranco, PhD, Molecular Endocrinology
5. Robert M. Dores, PhD, General and Comparative
Endocrinology
6. Andrea C. Gore, PhD, Endocrinology
7. David Grattan, PhD, Journal of Neuroendocrinology
8. Stephen R. Hammes, MD, PhD, Editor-in-Chief elect,
Molecular Endocrinology
9. Patrick R. Hof, MD, Journal of Comparative Neurology
10. Carol Lange, PhD, Hormones and Cancer
11. Jon E. Levine, PhD, Frontiers in Neuroendocrinology
12. Deborah M. Power, PhD, General and Comparative
Endocrinology
13. Professor Robert P. Millar, PhD, FRSE,
Neuroendocrinology
14. E. Chester Ridgway, MD, MACP, Endocrine Reviews
15. Johannes A. Romijn, MD, PhD, European Journal of
Endocrinology
16. Peter D. Sly, MBBS, FRACP, MD, DSc, Reviews on En-
vironmental Health
17. Hubert Vaudry, PhD, DrSci, Frontiers in Neuroendo-
crine Science; also Senior Editor, Journal of Neuroendo-
crinology; Associate Editor, Hormone and Metabolic Re-
search; Associate Editor, General and Comparative
Endocrinology; Associate Editor, Peptides
18. Kim Wallen, PhD, Hormones and Behavior
19. Leonard Wartofsky, MD, MACP, Journal of Clinical En-
docrinology and Metabolism
20. Cheryl S. Watson, PhD, Endocrine Disruptors
Journal Associate Editors
1. ke Bergman, PhD, Archives of Environmental Contam-
ination and Toxicology; Environmental Science and Pol-
lution Research
2. Daniel Bikle, MD, PhD, Endocrinology
3. Barbara A. Cohn, PhD, Endocrine Disruptors
4. David Crews, PhD, Endocrine Disruptors; Journal of
Experimental Zoology; Ecological Genetics and
Physiology; Sexual Development; Epigenetics
5. Peter L. DeFur, PhD, Endocrine Disruptors
6. Evanthia Diamanti-Kandarakis, MD, PhD, European
Journal of Endocrinology
7. Anthony N. Hollenberg, MD, Endocrinology
8. Susan Jobling, PhD, Endocrine Disruptors
9. Jun Kanno, MD, PhD, Environmental Health Perspectives
10. Carolyn Klinge, PhD, Endocrine Disruptors
11. B. Paige Lawrence, PhD, Endocrine Disruptors
12. Adrian V. Lee, PhD, Endocrinology
13. J. P. Myers, PhD, Endocrine Disruptors
14. Randy J. Nelson, PhD, Hormones and Behavior
15. Miquel Porta, MD, MPH, PhD, Journal of Epidemiology
& Community Health; European Journal of Clinical
Investigation; European Journal of Epidemiology
16. Merrily Poth, MD, Journal of Clinical Endocrinology
and Metabolism
17. Gail S. Prins, PhD, Endocrinology; Andrology
18. Emilie F. Rissman, PhD, Endocrinology
19. Paul E. Sawchenko, PhD, Journal of Comparative
Neurology
20. Olle Sder, MD, PhD, Hormone Research in Pediatrics
21. Ana M. Soto, MD, Progress in Biophysics and Molecular
Biology
22. Shanna Swan, PhD, Endocrine Disruptors
23. Hugh S. Taylor, MD, Endocrinology
24. Manuel Tena-Sempere, MD, PhD, Endocrinology
25. Frederick vom Saal, PhD, Endocrine Disruptors
26. Zuoxin Wang, PhD, Hormones and Behavior
27. Wade V. Welshons, PhD, Endocrine Disruptors
28. R. Thomas Zoeller, PhD, Endocrine Disruptors
Additional Signatories
1. Benson T. Akingbemi, PhD
2. Koji Arizono, PhD
3. Scott M. Belcher, PhD
4. Fiorella Belpoggi, PhD
5. Carl-Gustaf Bornehag, PhD
6. Jean-Pierre Bourguignon, MD, PhD
7. Terry R. Brown, PhD
8. Ernesto Burgio, MD
9. Terrence J. Collins, PhD
10. D. Andrew Crain, PhD
11. Barbara Demeneix, PhD
12. Rodney R. Dietert, PhD
13. Loretta Doan, PhD
14. Thea M. Edwards, PhD
15. Mariana F. Fernandez, PhD
16. R. William Field, PhD, MS
17. Linda C. Giudice, MD, PhD
18. Louis J. Guillette, PhD
19. Y. Leon Guo, MD, PhD, MPH
doi: 10.1210/en.2013-1854 endo.endojournals.org 3959
20. Tyrone Hayes, PhD
21. Andrea Hinwood, PhD
22. C. Vyvyan Howard, MB, ChB, PhD, FRCPath
23. Eric R. Hugo, PhD
24. Patricia Hunt, PhD
25. Taisen Iguchi, PhD
26. Richard J. Jackson, MD, MPH, AIA(Hon), ASLA(Hon)
27. Patricia Joseph-Bravo, PhD
28. Hans Laufer, PhD
29. Duk-Hee Lee, MD, PhD
30. Rachel Morello-Frosch, PhD, MPH
31. Jane Muncke, PhD
32. Angel Nadal, PhD
33. David O. Norris, PhD
34. Jrg Oehlmann, PhD
35. Nicolas Olea, MD, PhD
36. Edward F. Orlando, PhD
37. Vasantha Padmanabhan, PhD
38. Paola Palanza, PhD
39. Stefano Parmigiani, PhD
40. Donald W. Pfaff, PhD
41. Beverly S. Rubin, PhD
42. Joan V. Ruderman, PhD
43. Arnold Schecter, MD, MPH
44. Toshi Shioda, MD, PhD
45. Martin Scheringer, PhD
46. Niels E. Skakkebaek, MD
47. Howard M. Snyder III, MD
48. Carlos Sonnenschein, MD
49. Richard W. Stahlhut, MD, MPH
50. Laura Vandenberg, PhD
51. Catherine VandeVoort, PhD
52. Martin Wagner, PhD
53. Hong-Sheng Wang, PhD
54. Bernard Weiss, PhD
55. Teresa Woodruff, PhD
56. Tracey Woodruff, PhD
Address all correspondence and requests for reprints to: An-
drea C. Gore, PhD, Editor-in-Chief, Endocrinology, Gustavus,
Louise Pfeiffer Professor of Pharmacology, Toxicology, The Uni-
versity of Texas at Austin, Austin, Texas 78712. E-mail:
andrea.gore@austin.utexas.edu.
References
1. American Society of Human Genetics, American Society for Repro-
ductive Medicine, Endocrine Society, Genetics Society of America,
Society for Developmental Biology, Society for Pediatric Urology,
Society for the Study of Reproduction, Society for Gynecologic In-
vestigation. Assessing chemical risk: societies offer expertise. Sci-
ence. 2011;331:1136.
2. Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, et al. Endo-
crine-disrupting chemicals: an Endocrine Society scientific state-
ment. Endocr Rev. 2009;30:293342.
3. Vandenberg LN, Colborn T, Hayes TB, et al. Hormones and en-
docrine-disrupting chemicals: low-dose effects and nonmonotonic
dose responses. Endocr Rev. 2012;33:378455.
4. Zoeller RT, Brown TR, Doan LL, et al. Endocrine-disrupting chem-
icals and public health protection: a statement of principles fromthe
Endocrine Society. Endocrinology. 2012;153:40974110.
5. Bergman A, Heindel JJ, Jobling S, Kidd KA, Zoeller RT, eds. State
of the Science of Endocrine Disrupting Chemicals2012. An As-
sessment of the State of the Science of Endocrine Disruptors Pre-
pared by a Group of Experts for the United Nations Environment
Programme and World Health Organization. Geneva, Switzerland:
United Nations Environment Programme and the World Health Or-
ganization; 2013.
6. Dietrich DR, Aulock SV, Marquardt H, et al. Scientifically un-
founded precaution drives European Commissions recommenda-
tions on EDC regulation, while defying common sense, well-estab-
lished science and risk assessment principles. Chem Biol Interact.
2013;205:A1A5.
7. Vandenberg LN, Colborn T, Hayes TB, et al. Regulatory decisions
on endocrine disrupting chemicals should be based on the principles
of endocrinology. Reprod Toxicol. 2013;38:115.
8. Birnbaum LS. Environmental chemicals: evaluating low-dose ef-
fects. Environ Health Perspect. 2012;120:A143A144.
9. Phoenix CH, Goy RW, Gerall AA, Young WC. Organizing action of
prenatally administered testosterone propionate on the tissues me-
diating mating behavior in the female guinea pig. Endocrinology.
1959;65:369382.
10. Wallen K. The Organizational Hypothesis: reflections on the 50th
anniversary of the publication of Phoenix, Goy, Gerall, and Young
(1959). Horm Behav. 2009;55:561565.
11. Boobis AR, Daston GP, Preston RJ, Olin SS. Application of key
events analysis to chemical carcinogens and noncarcinogens. Crit
Rev Food Sci Nutr. 2009;49:690707.
12. Borgert CJ, Sargent EV, Casella G, Dietrich DR, McCarty LS,
Golden RJ. The human relevant potency threshold: reducing uncer-
tainty by human calibration of cumulative risk assessments. Regul
Toxicol Pharmacol. 2012;62:313328.
13. Piersma AH, Hernandez LG, van Benthem J, et al. Reproductive
toxicants have a threshold of adversity. Crit Rev Toxicol. 2011;41:
545554.
14. Rhomberg LR, Goodman JE, Haber LT, et al. Linear low-dose ex-
trapolation for noncancer health effects is the exception, not the
rule. Crit Rev Toxicol. 2011;41:119.
15. Rhomberg LR, Goodman JE. Low-dose effects and nonmonotonic
dose-responses of endocrine disrupting chemicals: Has the case been
made? Regul Toxicol Pharmacol. 2012;64:130133.
16. vom Saal FS, Sheehan DM. Challenging risk assessment. Forum
Appl Res Public Policy. 1998;13:1118.
17. Sheehan DM, WillinghamE, Gaylor D, Bergeron JM, Crews D. No
threshold dose for estradiol-induced sex reversal of turtle embryos:
how little is too much? Environ Health Perspect. 1999;107:155
159.
18. Sheehan DM, vom Saal FS. Low dose effects of hormones: a chal-
lenge for risk assessment. Risk Policy Rep. 1997;4:3139.
19. Sheehan DM. No-threshold dose-response curves for nongenotoxic
chemicals: findings and applications for risk assessment. Environ
Res. 2006;100:9399.
20. Welshons WV, Thayer KA, Judy BM, Taylor JA, Curran EM, vom
Saal FS. Large effects from small exposures. I. Mechanisms for en-
docrine-disrupting chemicals with estrogenic activity. Environ
Health Perspect. 2003;111:9941006.
21. Grandjean P, Ozonoff D. Transparency and translation of science in
a modern world. Environ Health. 2013;12:70.
22. Bergman A, Andersson AM, Becher G, et al. Science and policy on
endocrine disrupters must not be mixed: a reply to a common
sense intervention by toxicology journal editors. Environ Health.
2013;12:69.
3960 Gore et al Editorial Endocrinology, November 2013, 154(11):39573960