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Science-based regulation of endocrine disrupting chemicals 
in Europe: which approach?

Endocrine disruptors are defined by WHO as “exogenous  a resolution adopted by the European Parliament on  Lancet Diabetes Endocrinol 2016
compounds or mixtures that alter function(s) of the  June 8, 2016. This resolution stresses that the criteria  Published Online 
June 13, 2016 
endocrine system and consequently cause adverse  can only be carried out on the basis of scientific data  http://dx.doi.org/10.1016/
effects in an intact organism, or its progeny, or (sub) related to the endocrine system, independently of  S2213-8587(16)30121-8
populations”.1 European Union (EU) laws on pesticides  any other consideration, particularly economic ones. 
(plant protection products regulation [PPPR]) and  Also, it calls on the Commission to immediately adopt 
biocide products regulation (BPR), enacted in 2009  hazard-based scientific criteria for the determination of 
and 2012, respectively, place restrictions on the use  endocrine-disrupting properties.
of active substances with severe forms of toxicity, 
At the time of publication, the EC has not released 
including carcinogenicity, mutagenicity, reproductive  the endocrine disruptor criteria and continues to justify 
toxicity, and endocrine disruption. Chemicals with such  this delay with reference to a controversy within the 
properties will in the future not receive authorisation  scientific community.5 However, we have recently 
for placement on the market as active substances in  shown that the controversy is not about the basics of 
pesticide or biocide products. Compared with earlier  endocrine disruptor science, but rather is the result of a 
EU law, these legal provisions are innovative in two  lack of distinction between hazard identification and risk 
respects: first, for the first time, pesticides and biocides  assessment (which is not required for the identification 
with endocrine-disrupting properties are regulated;  of endocrine disruptors as defined in the laws on 
second, those with severe toxicities are regulated  pesticides and biocides).2 Very recently, this confusion 
solely on the basis of hazard identification, and not by  was resolved, and a consensus among the scientists 
risk assessment, as previously. Hazard identification  engaged in the previous debate has emerged, with all 
pinpoints a potential threat to health (eg, a chemical),  involved now accepting that the regulatory decision-
which is further analysed in a process of hazard  making required in EU laws on pesticides and biocides 
characterisation in terms of additional features such as  involves hazard identification.6 We have also shown 
species sensitivities, dose-response relationships, and  that endocrine disruptors can be identified through a 
others. Risk assessment relates the likelihood that an  scientific strategy analogous to that implemented for 
effect occurs to exposures experienced under different  carcinogens by the International Agency for Research 
circumstances.2 This development requires that scientific  on Cancer (IARC; part of WHO).2 The first step in risk 
criteria for the identification of endocrine disruptors  assessment is to identify whether a chemical or a mixture 
are developed, and the European Commission (EC) was  belongs to a given class of hazards, such as carcinogens. 
obliged by law to publish such scientific criteria within  IARC identifies carcinogens and categorises the degree 
the context of PPPR and BPR by 2013. 
of confidence in this identification without regard to 
Commercial interests have strongly argued against  potency. No one would suggest making the definition 
hazard-based cut-off criteria for endocrine disruptors,  of carcinogens dependent on an impact assessment, and 
which resulted in the EC conducting an impact  the same should apply to endocrine disruptors.
assessment before defining the endocrine disruptor 
Although a great deal is known about how hormones 
criteria.3  Inevitably, this challenge has delayed the  affect health and disease, there remains much to 
publication of criteria to such an extent that Sweden  learn. Similarly, we know a great deal about how 
and other EU member states brought a case against  some manufactured chemicals can cause adverse 
the EC for not establishing the criteria. In December,  effects in human beings, farm animals, and wildlife by 
2015, the European Court of Justice judged that the EC  interfering with hormones.7 Researchers have shown 
acted unlawfully in failing to publish the criteria, and  that endocrine disruptors can produce epigenetic 
that an impact assessment was not necessary for their  modifications and transgenerational effects.8 Such 
development.4 This judgment has been followed by  scientific evidence must be considered appropriately 
www.thelancet.com/diabetes-endocrinology   Published online June 13, 2016   http://dx.doi.org/10.1016/S2213-8587(16)30121-8 
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Comment
with respect to its implications for human health  active substances (figure). Such categories, based on 
today and for future generations. Robust science at  level of evidence, are consistent with those used in the 
the leading edge allows us to discriminate among the  EU for carcinogens, mutagens, and reprotoxicants, 
known, the possible, and the unknown. Therefore,  which are hazards of equivalent concern to endocrine 
the decision taken by the EC should be based on  disruptors. Moreover, option 3 provides the necessary 
what we know now, and allow incorporation of new  characteristics that will allow for incorporation of new 
information as it becomes available.
data as it becomes available, which might trigger revised 
In a roadmap that the EC released in 2014 to define  categorisations (figure). The majority of responders 
the parameters of impact assessment, four different  to the public consultation initiated by the EC about 
options for defining regulatory criteria for endocrine  endocrine disruptor identification criteria were clearly in 
disruptors were proposed.9 The first does not provide  favour of option 3.10 The Endocrine Society, the world’s 
defining criteria, and is therefore not operable. Two  largest organisation devoted to research on hormones 
options (labelled 2 and 3) rely on the WHO definition of  and the clinical care of endocrine disorders, also 
endocrine disruptors; option 2 defines a single category  supports this option.11 An assessment of the strength of 
of endocrine disruptors, whereas option 3 further  the evidence has also been used in studies on the cost of 
identifies suspected endocrine disruptors and endocrine- managing health consequences of endocrine disruptors 
in the EU; with more than 99% probability, this cost 
A
exceeds €160 billion per year.12 
ED identification
The last option (option 4; figure) uses a binary 
EC roadmap option 3:
Different strength of 
definition (endocrine disruptors or non-endocrine 
evidence for fulfilling 
e
the WHO/IPCS definition 
disruptors) and incorporates potency as a criterion. 
The idea of including potency was initiated by UK 
Endocrine disruptor 
of evidenc
and German authorities. Mindful of the potential 
Suspected endocrine disruptor
Revision or confirmation of
Level 
category based on further 
economic effect on industry  of regulating substances 
Endocrine-active substance
studies including potency
with ED properties in a hazard-based system, the stated 
 
Endocrine-inactive substance  
intention was to only assign the endocrine disruptor 
identifier to substances of high potency and where the 
B
endocrine disruptor property is a prominent feature of 
the hazard profile.13 Potency, however, is not mentioned 
EC roadmap option 4: 
WHO/IPCS definition to 
in the accepted WHO definition1 and has been deemed 
identify ED (hazard 
identification) and inclusion 
irrelevant for the identification of endocrine disruptors.2 
of potency as element of 
hazard characterization 
Potency is quite complex to apply as a criterion and 
Potency
Endpoint X
scientifically indefensible because a single chemical 
Endocrine 
Most sensitive endpoint used?
disruptor 
Cut-off criterion for ED
might seem differently potent depending on the 
Endpoint Y
identification?
endpoint and the testing conditions (figure). Potency 
Endocrine-
Predictive for any in-vivo 
inactive
condition?
is measured by a dose-response function; however, 
Endpoint Z
substance  
Endpoint N
the variability of the response and the corresponding 
2014–16
Summer
2017
likelihood of overlooking effects are what make 
2016
Onwards
potency so complicated. Historically, diethylstilbestrol 
Figure: Two proposed options for identification of EDs in the European 
and thalidomide are notable examples. These drugs 
Union 
In a 2014 roadmap, the European Commission has proposed criteria for ED 
were prescribed for pregnant women without any 
identification through four options; here we show option 3 (A) and option 4 (B). 
adverse effects being noted. However, the children of 
From summer, 2016, EDs will be identified based on one option or the other. 
Option 3 identifies endocrine-inactive substances and three ED categories based 
treated women showed adverse effects—either at the 
on the level of evidence; it allows for further revision based on new scientific 
time of birth, or several years later. In these cases, the 
information. Option 4 uses potency as a criterion and identifies only one ED 
category; its application implies further questions about selected endpoints, 
prediction of negligible potency from some in-vivo 
cutoff criteria, and predictive value. In panel B, the four symbols arbitrarily denote 
testing gave physicians the confidence to prescribe 
different levels of potency of a given chemical depending on the studied endpoint. 
ED=endocrine disruptor. IPCS=International Programme on Chemical Safety.
these drugs, but they were tragically missing crucial 

www.thelancet.com/diabetes-endocrinology   Published online June 13, 2016   http://dx.doi.org/10.1016/S2213-8587(16)30121-8

Comment
data for developmental issues. In a recent position  Society for organisational support and reimbursement of travel expenses related 
statement about EU regulation of endocrine disruptors,  to meetings about incorporation of endocrine science data into the regulatory 
management of endocrine-disrupting chemicals. 
the Endocrine Society recommended the exclusion  1  WHO. Global assessment of the state-of-the-science of endocrine 
of potency from identification criteria.11 Similarly, the 
disruptors. WHO/PCS/EDC/02.2. http://www.who.int/ipcs/publications/
new_issues/endocrine_disruptors/en/ (accessed June 2, 2016).
consensus statement from the scientists engaged  2  Slama R, Bourguignon JP, Demeneix B, Ivell R, Panzica GC, Kortenkamp A, 
in the previous debate over scientific principles for 
Zoeller RT. Scientific issues relevant to setting regulatory criteria to identify 
endocrine disrupting substances in the European Union. Env Health Perspect 
the identification of endocrine disruptors states that 
2016; published online April 25. DOI:10.1289/EHP217.
potency considerations have no place in the hazard  3  Horel S. A toxic affair: how the chemical lobby blocked action on endocrine 
disrupting chemicals. Brussels: Corporate Europe Observatory, 2015. 
identification process for endocrine disruptors.6
http://corporateeurope.org/food-and-agriculture/2015/05/toxic-affair-
how-chemical-lobby-blocked-action-hormone-disrupting (accessed June 
The current scientific consensus on the relevance 
2, 2016).
of the WHO definition of endocrine disruptors,1  4  European Parliament resolution of 8 June 2016 on endocrine disruptors: 
state of play following the judgment of the General Court of the European 
the irrelevance of potency for the identification of 
Union of 16 December 2015 (2016/2747(RSP). http://www.europarl.
endocrine disruptors,
europa.eu/sides/getDoc.do?pubRef=-//EP//TEXT+TA+P8-TA-2016-
2,6 and the inapplicability of impact 
0270+0+DOC+XML+V0//EN&language=EN (accessed June 8, 2016)
assessment studies to provide scientific definition of  5  European Commission. EC Commissioner Andriukaitis, Statement to the 
endocrine disruptors
European Parliament Plenary, Feb 2, 2016—Commission statement - 
2,11 all point to the same conclusion. 
Commission action to comply with Judgement in case T-521/14: Sweden vs 
As scientists, we believe that science provides all 
the Commission. https://ec.europa.eu/commission/2014-2019/
andriukaitis/announcements/ep-plenary-commission-statement-
necessary arguments towards implementation of 
commission-action-comply-judgement-case-t-52114-sweden-vs-
relevant criteria to identify endocrine disruptors. Such 
commission_en (accessed June 2, 2016).

BfR. Scientific principles for the identification of endocrine disrupting 
criteria are consistent with an option already formulated 
chemicals – a consensus statement. Outcome of an international expert 
meeting organized by the German Federal Institute for Risk Assessment 
by the EC: option 3 of the EC roadmap. Public health 
(BfR). Communication 011/2016. http://www.bfr.bund.de/en/publication/
urgently deserves science-based regulations.
bfr_opinions_2016-196132.html (accessed June 2, 2016).

UNEP/WHO. State of the science of endocrine disrupting chemicals. 
Geneva: World Health Organization, United Nation Environmental 
*Jean-Pierre Bourguignon, Rémy Slama, Åke Bergman, 
Program, 2013. http://www.who.int/ceh/publications/endocrine/en/index.
html (accessed June 2, 2016).
Barbara Demeneix, Richard Ivell, Andreas Kortenkamp, 

Skinner MK, Manikkam M, Guerrero-Bosagna C. Epigenetic 
transgenerational actions of endocrine disruptors. Reprod Toxicol 2011; 
GianCarlo Panzica, Leonardo Trasande, R Thomas Zoeller
31: 337–43. 
Pediatric Endocrinology, CHU Liège and Neuroendocrinology Unit,  9  European Commission. Roadmap-defining criteria for identifying 
GIGA Neurosciences, University of Liège, B4000 Liège, Belgium 
endocrine disruptors in the context of the implementation of the plant 
protection product regulation and biocidal products regulation. Brussels: 
(J-PB); Inserm, CNRS and University Grenoble Alpes, IAB Joint 
European Commission, 2014. http://ec.europa.eu/smart- regulation/
Research Center, Team of Environmental Epidemiology, Grenoble, 
impact/planned_ia/docs/2014_env_009_endocrine_disruptors_en.pdf 
France (RS);
(accessed June 2, 2016).
 Swedish Toxicology Sciences Research Center, 
10  European Commission. Report on public consultation on defining criteria 
Södertälje, Sweden  (ÅB); UMR CNRS/MNHN 7221, Department 
for identifying endocrine disruptors in the context of the implementation 
RDDM, Muséum National d’Histoire Naturelle, Paris, France (BD); 
of the plant protection product regulation and biocidal products 
School of Biosciences & School of Veterinary Medicine and 
regulation. Brussels: European Commission, 2015. http://ec.europa.eu/
health/endocrine_disruptors/docs/2015_public_consultation_report_e n.
Science, University of Nottingham, Nottingham ,UK (RI); Brunel 
pdf (accessed June 2, 2016).
University London, Institute of Environment, Health and 
11  Endocrine-disrupting chemicals in the European Union Endocrine Society, 
Societies, Uxbridge, UK (AK); Department of Neuroscience, 
2015. https://www.endocrine.org/~/media/endosociety/files/advocacy-
and-outreach/position-statements/2015/position_statement_edc_eu.pdf 
University of Torino, and Neuroscience Institute Cavalieri 
(accessed June 2, 2016).
Ottolenghi, Orbassano, Italy (GP); Departments of Pediatrics, 
12  Trasande L, Zoeller RT, Hass U, et al. Estimating burden and disease costs of 
Environmental Medicine and Population health, New York 
exposure to endocrine-disrupting chemicals in the European Union. 
J Clin Endocrinol Metab 2015; 100:1245–55. 
University School of Medicine, New York, NY, USA (LT); and 
13  BfR. German Federal Institute for Risk Assessment). Joint DE – UK position 
University of Massachusetts, Biology Department, Amherst, MA, 
paper. Regulatory definition of an endocrine disrupter in relation to 
USA (RTZ) 
potential threat to human health. Proposal applicable in the regulatory 
context of Plant Protection Products, Biocidial Products, and Chemicals 
xxxxxxxxxxxxx@xxx.xx.xx
targeted within REACH. May 16, 2011. http://www.bfr.bund.de/cm/343/
BD is a cofounder of the company WatchFrog, , a producer of fluorescent 
regulatory_definition_of_an_endocrine_disrupter_in_relation_to_
amphibian larvae for detection of chemicals. The other authors declare no 
potential_threat_to_human_health.pdf (accessed June 5, 2016)
competing interests. J-PB, RS, BD, RI, GCP, LT, and RTZ thank the Endocrine 
www.thelancet.com/diabetes-endocrinology   Published online June 13, 2016   http://dx.doi.org/10.1016/S2213-8587(16)30121-8 
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