Endocrine Disruptors:
From Scientific Evidence to
Human Health Protection
Brussels, 2 April 2019
Presentation by
Pr. Barbara DEMENEIX
MNHM/CNRS
Policy Department Citizens’ Rights and Constitutional Affairs
Responsible Administrator: Martina SCHONARD [email protected]
Dr. Rémy SLAMA
Inserm
The opinions expressed here are the sole responsibility of the authors and do not
necessarily represent the official position of the European Parliament nor of the
authors’ institutions.
Conflicts of interest statement
The authors declare no financial conflict of interests.
Barbara Demeneix is a cofounder of Watchfrog S.A., a
company involved in the development of tests to identify
endocrine disruptors. She receives no financial
compensation for any activity related to her work with the
company.
Outline
The
endocrine
system
Key
concepts
of
Endocrine
Disruption
Adverse
effects
expected
from EDs
How
frequent is
ED
exposure
in the EU?
Estimated
population
impact of
EDs
Current
regulation
of EDs in
the EU
Extent of the issue
(Science)
Management
(Policy)
I. Scientific evidence
regarding the health
effects of Endocrine
Disruptors (EDs) in the EU
• What is the endocrine system and why is it so
sensitive to disruption?
• What are endocrine disruptors (EDs) ?
• Health effects shown by epidemiology or by
animal experimentation
• Population impact
Hormones act at very low doses and
harmonise our body functions from
conception onwards
Corresponds
to the
dilution of a
drop of
water in an
Olympic
swimming
pool
Hormones act at extremely low
(nanomolar) concentrations.
Thyroid hormone has different roles in
different time periods and can act non-
linearly at very low concentration
Roles of thyroid hormone:
Maternal thyroxine
concentration (picomol/l)
In adults:
Controls body temperature
Controls heart and breathing rates
Mood, anxiety, concentration
Metabolism
…
During development:
Growth
Fetal brain development
IQ
Offspring c
ort
ex
volu
me (
cm
3)
(Korevaar, Lancet Diab Endo, 2016)
Definition of endocrine disruptors
(WHO, 2002)
An endocrine disruptor is an exogenous
substance or mixture that alters function(s)
of the endocrine system
and consequently causes adverse health
effects in an intact organism, or its progeny
or (sub)populations.
EDs act according to several modalities
and can increase the risk of many
(multifactorial) diseases
• Thyroid axis
• Testosterone
• Oestrogen
Aromatasefunction
Endocrine disruption modalities
Endocrine disruptor
Steroid hormones
• PPARs receptors
• Hormone synthesis, transport, metabolism
• Other Nuclear Receptors
• Membrane receptors
• Metabolic hormones (insulin…)
EDs act according to several modalities
and can increase the risk of many
(multifactorial) diseases
• Thyroid axis
• Testosterone
• Oestrogen
Aromatasefunction
Endocrine disruption modalities
Endocrine disruptor
Steroid hormones
• PPARs receptors
• Hormone synthesis, transport, metabolism
• Other Nuclear Receptors
• Membrane receptors
• Metabolic hormones (insulin…)
Neurodevelopment, mood, cardiac function, metabolism…
Puberty, malformations,fecundity disorders
Metabolic disorders (insulin resistance, diabetes…)
Growth and overweight disorders, bone development
Cancers of hormone sensitive organs (breast, prostate, testis…)
Health endpoints
Oestrogen-related factors likely
associated with breast cancer risk
Estrogenic drugs:DES/diethylstilboestrol (intra-uterine or adult exposures)
Hormonal substitution therapy (adulthood)
Tamoxifen (anti-oestrogen anti cancer drug)
Synthetic oestrogen-like chemicals:DDT (following early-life exposure)
Bisphenol A (likely)
Total xenoestrogenic burden
Reproductive life factors related to
oestrogen exposure:Low number of pregnancies
Early menarche, late menopause
Short total breastfeeding duration
BREAST
CANCER
RISK
Other examples of presumed or very
likely adverse effects of EDsCompound Use Adverse effect
Organophosphate
pesticides (e.g.
chlorpyrifos)
Plant protection
products
Thyroid homeostasis Very likely
Mercury Neurotoxicity Certain
Paracetamol Drug Altered testicular
function following
intra-uterine
exposure
Very likely
Bisphenol A Food, food
contact material,
consumer
products…
Growth and
overweight
Anxiety, hyperactivity
disorders
Likely to very likely
DEHP (phthalate) Food, food
contact
material…
Thyroid and
testicular functionsVery likely
Brominated flame
retardants (PBDEs)
Consumer
products
Lower IQ, thyroid
functionVery likely
How cumulative effects of mixtures
can affect health outcomes
Chemical C
Chemical B
Chemical A
Cumulative effects
Synergy
Effect of bisphenol A alone
A dose of ≅10-5 M is required to
lower testosterone level by 50%
(Gaudriault, EHP, 2017)
How cumulative effects of mixtures
can affect health outcomes
Chemical C
Chemical B
Chemical A
Cumulative effects
Synergy
Effect of bisphenol A alone
A dose of ≅10-5 M is required to
lower testosterone level by 50%
Effect of BPA with 7
other compoundsDose lowering testosterone
by 50% is divided by 10(Gaudriault, EHP, 2017)
ED exposure is ubiquitous and
continuous in the EU population
France
Spain
Greece
Norway
Lituania
Overall
Bradford
(Haug et al, Env Int, 2018)
Butyl-parabenBisphenol A
Ethyl-paraben Triclosan
Propylparaben Methylparaben (DEHP metabolite)
Oxy-benzone
phthalate
Estimated costs (B€) associated to the health
effects of ED exposure per year in the EU
Neurodevelopment
Obesity and diabetes6%
Cancer0.5%
Reproductive disorders5%
Total estimated cost (EU) most probably above €22 billion.Most likely estimate: €163 billion.
(Trasande, Andrology, 2016)
II. Regulation of
Endocrine Disruptors in
the EU
• General principles and aims
• Sector-specific regulations
• 12 recommendations
Regulation of chemicals in the EU
Some general principles
Probably >22,000 chemicals currently marketed in the EU (source:
ECHA/REACH)
The responsibility of the identification of hazards and risks
generally lies with the producer/seller of the product
Regulations often have a compound by compound logic
Regulations are usually sectorial
However, a few overarching concepts and principles exist
E.g., categories of substances warranting specific consideration
are defined:
• CMR (carcinogens, mutagens, reprotoxicants), PBT (Persistent,
bioaccumulative, Toxic), vPvB (very Persistent, very Bioaccumulative),
EDs (endocrine disruptors)…
CLP
directive
(hazard
definition
and
labelling)
(2008)
Defines
CMR substances
Overarching regulations and plans
7th
Environ-
mental
Action Program
(EAP)
(2013)
EU
Strategy
on EDs
(1999)
Commu-
nication
towards a
compre-
hensive EU
framework
on EDs
(2018)
REACH regulation
(2006)
Chemicals,
excluding
in
particular
cosmetics,
drugs,
pesticides
…
Defines
PBT and
vPvB
substances
ED-related overarching principles
7th Environmental Action Programme (7th EAP, 2013)
The Union has agreed to achieve, by 2020, the objective that chemicals are
produced and used in ways that lead to minimisation of significant adverse effects
on human health and the environment …
Efforts need to be stepped up to ensure that, by 2020, all relevant substances
of very high concern, including substances with endocrine-disrupting
properties, are placed on the REACH candidate [SVHC] list. [art. 50]
2018 (EC) communication toward a comprehensive EU
framework on EDs
The EU… approach on EDs…should be based on the application of the
precautionary principle and aim at minimising overall exposure of humans
and the environment to EDs, paying particular attention to exposures during
important periods of development of an organism, such as foetal development and
puberty.
5 regulatory steps to protect health
Sector
1. Definition of
EDs
2. Guidance
document
3. Tests 4. Test
requirements
5. Risk
management
logic
Pesticides Y Y
I
I Y
Biocides Y Y I Y
REACH
chemicalsN
N NY
Cosmetics N N N N
Food
additivesN
N NN
Food
packagingN
N NN
Workers’
regulationsN
N NN
How to minimise overall exposure of
humans and the environment to EDs?
A simple view of an efficient regulation
Workers’ protection
Cosmetics
Food additives
Food contact materials
Toys’ safety directive
Drinking water directive
Water framework dir.
Medical
devices
Drugs
Consumers’ goods
Media-oriented
regulations Air qualitySoil
Waste
Usage-oriented
regulations
Plant Protection Products (PPPR)
Biocides (BPR)
Overarching regulations and plans
CLP
directive
(hazard
definition
and
labelling)
(2008)
Defines
CMR substances
7th
Environ-
mental
Action Program
(EAP)
(2013)
EU
Strategy
on EDs
(1999)
Commu-
nication
towards a
compre-
hensive EU
framework
on EDs
(2018)
REACH regulation
(2006)
Chemicals,
excluding
in
particular
cosmetics,
drugs,
pesticides
…
Sector-specific regulations: the
example of the plant protection products
regulation (PPPR, 2009)
5 regulatory steps to protect health
1. Definition of EDs 2. Guidance document 3. Tests 4. Test requirements 5. Risk
management logic
Definition of
EDs valid in
the context of
plant
protection
products as
of 2018
ECHA/EFSA
guidance
document (2018)
Existing
tests allow to
cover some
(but not all)
ED
modalities
Few tests are
required in the
plant protection
products
homologation
dossiers
Plant
protection
products
containing EDs
should not be
authorized
(PPPR, 2009)
Sector-specific regulations: the
example of REACH chemicals
5 regulatory steps to protect health
1. Definition of EDs 2. Guidance document 3. Tests 4. Test requirements 5. Risk
management logic
No definition
of EDs
legally valid –
WHO
definition
used in
practice
No legally valid
guidance
document
Existing
tests allow to
cover some
(but not all)
ED
modalities
Very limited
requirements
when it comes
to ED action
identification in
homologation
dossiers
Rather
complex and
lengthy
management
logic
(“authorization
list”)
13 EDs currently on the SVHC list. Scientific evidence suggests that
there are more than 13 EDs on the market. All EDs are unlikely to be on
REACH SVHC list by 2020 as required by the 7th EAP.
Overview of the framework regarding
protection from ED health effects
I: Insufficient/needs reinforcement. N: None or very limited. Y: Yes, satisfying existing regulation.
5 regulatory steps to protect health
Sector
1. Definition of EDs 2. Guidance
document
3. Tests 4. Test
requirements
5. Risk
management
logic
Plant prot.
productsY Y
I
I Y
Biocides Y Y I Y
REACH
chemicalsI I I I
Cosmetics N N N N
Food
additivesN N N N
Food
packagingN N N N
Workers’
regulationsN N N N
Medical
devicesY N N Y
Overview of the framework regarding
protection from ED health effects
I: Insufficient/needs reinforcement. N: None or very limited. Y: Yes, satisfying existing regulation.
5 regulatory steps to protect health
Sector
1. Definition of EDs 2. Guidance
document
3. Tests 4. Test
requirements
5. Risk
management
logic
Plant prot.
productsY Y
I
I Y
Biocides Y Y I Y
REACH
chemicalsI I I I
Cosmetics N N N N
Food
additivesN N N N
Food
packagingN N N N
Workers’
regulationsN N N N
Medical
devicesY N N Y
Main conclusions There is consensus regarding the scientific definition of EDs and the fact
that EDs are a threat to human health (and the environment).
Not everything is known regarding the exact number of EDs or their total
impact – just like for carcinogens – which would justify to have a regulation
defining several categories of EDs according to the current level of
evidence (as for carcinogens)
The EU aim of minimising overall exposure of humans and the
environment to endocrine disruptors is scientifically justified
The plant protection and biocidal products regulation are the most
advanced in terms of consideration of the risks incurred by EDs
However, even in this sector, the regulation does not allow application of the
risk management logic set forth (too limited test requirements)
The existing EU regulations do not appear to allow attaining the aim set by
the EC regarding the minimisation of ED exposure
Lack of coherence both within- and between sectors
Unlikely that all EDs will be placed by 2020 on REACH SVHC list
Simple changes could be done to make the EU regulations related to
chemicals more fit to this purpose (see list of 12 recommendations)
http://www.europarl.europa.eu/thinktank/fr/document.html?reference=IPOL_STU(2019)608866
Recommendations (1) – Policy goal Policy goal: Endocrine disruptors (EDs) are one of the main classes
of health hazards and are of similar concern to CMRs, PBT and vPvB
substances. Consequently, in order to better protect human health
and the environment, on which our health depends, the EU should
develop a set of trans-sectorial and harmonized regulations to
minimize human and environmental exposure to endocrine
disruptors.
Attaining this goal requires a) a cross-sectorial (“horizontal”) definition
of EDs with three categories according to the level of evidence; b) a
guidance document explaining how to apply the definition on the
basis of tests results and scientific literature, and identify EDs; c)
tests covering all ED modalities; d) legal requirements to make these
tests compulsory in application dossiers; e) risk management
measures aiming to minimize ED exposure, which may distinguish
sectors with very likely human exposure from those for which
exposure is rare.
Recommendations (2) ED identification Currently the ED definition is limited to PPRs and biocides. EU
regulation should define EDs across sectors. As for other hazards, e.g.
CMRs, this requires distinguishing 3 categories according to the level of
evidence: known (category 1A), presumed (1B) and suspected (2) EDs.
Guidance document: A guidance document, based on the current PPR/
biocide one, should be developed to explain how EDs should be identified based
on the cross-sectorial definition, including REACH chemicals, cosmetics, food
contact materials and food additives. The current logic requiring a weight of
evidence approach based on biological plausibility linking the adverse effect and
the endocrine activity should be maintained.
Test development: urgently need accelerated test development and
validation... Enhance use of academic publications when assessing ED
properties.
Test requirements: insufficient data requirements to efficiently identify EDs in
any sector, including for pesticides and REACH chemicals. Increased means
should be allocated for the control of substance application dossiers. More
ambitious objectives should be set for the numbers of chemicals examined each
year for their ED properties in national and EU agencies
Recommendations (3) – Global
management of EDs Management of EDs across sectors (1): EDs should be recognized as a class of
hazard of equivalent concern to carcinogens, mutagens and reprotoxicants in all
sectors and not only for pesticides and REACH chemicals, but also cosmetics, toys,
food additives and food contact materials.
Management of EDs across sectors (2): In order to minimize ED exposure among
EU citizens, the EU should move towards an identical management of EDs across all
sectors for which ED use is very likely to entail population exposure. This includes in
particular plant protection products, biocides, food contact materials and additives,
consumer goods, cosmetics and toys. Established scientific facts show that (a)
hormones act at extremely low doses; (b) EDs are expected to also act at low doses,
and this is proven for the most studied EDs; (c) there are methodological limitations to
the approaches typically used to identify so-called safe thresholds in regulatory
toxicology and (d) the approaches commonly used to identify these safe thresholds
generally do not consider cumulative effects of combined exposures. Hence, one
option to protect human health and make the EU regulation more coherent across
sectors would be to apply a logic similar to that already in use for pesticides, i.e. that
substances identified as known or presumed EDs should not be authorized (“no
exposure” logic) in products with general population exposure. For the cosmetic sector
specifically, a logic similar to that applied for CMRs should be used for EDs, consisting
in banning known, presumed and suspected EDs in cosmetics.
Recommendations (4) – Management of EDs in
specific sectors; research needs Management of EDs in specific sectors (1) - Media-oriented regulations: The
oestrogenic, androgenic, thyroid, steroid (E, A, T, S) loads of food and drinking water
should be evaluated and monitored, and the implementation of limit values for E, A, T,
S activities should be considered, bearing in mind that such endocrine activity may be
indicative of adverse effects.
Management of EDs in specific sectors (2) - Occupational exposures:
Occupational exposure limits should be set for EDs.
Surveillance of production, use and exposure to EDs: Data on ED production, use
of EDs across sectors should be gathered by the industry and relevant actors and
made available at fine geographic and temporal scales. Monitoring known, presumed
and suspected EDs (banned or still in use) in human populations (human
biomonitoring) should be implemented in a harmonized way at the EU scale, including
among pregnant women and children.
Research priorities: The current scientific knowledge, accumulated over the last 30
years, is sufficient to justify the above-mentioned recommendations. However, in order
to identify new EDs, develop new tests and better quantify their population impacts, six
areas of research are flagged: (i) Epigenetic effects of EDs; (ii) Concern beyond the
current generation; (iii) ED effects on the microbiome, an essential component of
physiological and immune responses (iv) Green (safe) chemistry; (v) Novel ED
modalities (vi) Characterization of dose-response functions for ED effects in humans.
Acronyms
BPR: Biocidal Products Regulation (2012)
CMR: Carcinogen, Mutagen or Reprotoxic substance
ED: Endocrine Disruptor
EU: European Union
PBT: Persistent, Bioaccumulative, Toxic
PPPR: Plant Protection Products Regulation (2009)
REACH: (2006)
SVHC: Substance of Very High Concern
vPvB: Very Persistent and very Bioaccumulative
Additional slides
Dossier
evaluation
Inclusion
in SVHC
list
Inclusion in
Annex XIV(authorisation list)
Application for
authorization
Preparation of
Annex XV
dossier
Placement in
Annex XVII
Simplified restriction procedure for CMR substances with
consumer use (no dossier)CMR substances
with consumer
use (art. 68/2)
Authorization
decision (EC)
No application
for authorization
Restric
tion
under
REACH
Currently 197
substances*Currently 43
substances*
EC
*As of 20 Jan. 2019
After
sunset
date
Industry
Production is
limited or
banned
Currently 69
substances*
Request for
further
information
Preparation
of restriction
dossier
Normal restriction procedure Draft opinion,
consultation
(ECHA)
Restriction
decision (EC)
Authorisation
procedure
Restriction
procedures
Industry
provides
information
CMR: Carcinogen, Mutagen, Reprotoxicant
EC: European Commission
ECHA: European Chemicals Agency
SVHC: Substance of Very High Concern
Authorisation and restriction
procedures under REACH
Sector-specific regulations: cosmetics (2006)
5 regulatory steps to protect health
1. Definition of EDs 2. Guidance document 3. Tests 4. Test requirements 5. Risk
management logic
No definition
of EDs
No legally valid
guidance
document
Very limited
requirements
when it comes
to ED action
identification in
homologation
dossiers
No
management
logic specific to
EDs
(while
carcinogens
and suspected
carcinogens
are not
authorized)
Definition of EDs (“scientific criteria”)
valid in the context of plant protection
products (EC, 2018)
An active substance, safener or synergist shall be considered as
having endocrine disrupting properties that may cause adverse
effect in humans if [...] it …meets all of the following criteria…:
it shows an adverse effect in an intact organism or its progeny,
which is a change in the morphology, physiology, growth,
development, reproduction or life span of an organism, system or
(sub)population that results in an impairment of functional
capacity, an impairment of the capacity to compensate for
additional stress or an increase in susceptibility to other influences;
it has an endocrine mode of action, i.e. it alters the function(s) of
the endocrine system;
the adverse effect is a consequence of the endocrine mode of
action.
ED timeline
Rachel Carson’s « Silent Spring » book. Warning about DDT and PCB effects
Wingspread conference (USA) defines endocrine disruption
First effects of in utero exposure to oestrogen-like drug DES identified
Weybridge ED conference (UK) convened by the EC
EU strategy on Endocrine Disruptors
REACH chemicals regulation (EU)Plant Protection Products Regulation (PPPR)
Biocidal Products Regulation (BPR)
Scientific criteria to identify EDs in biocides
7th Environmental Action Programme
ECHA/EFSA ED guidance document
Scientific criteria to identify EDs in PPPs
EC communication: « Minimise
ED exposure »
Definition of EDs (“scientific criteria”)
valid in the context of plant protection
products (EC, 2018)
An active substance, safener or synergist shall be considered as
having endocrine disrupting properties that may cause adverse
effect in humans if [...] it …meets all of the following criteria…:
it shows an adverse effect in an intact organism or its progeny or
in (sub)populations, which is a change in the morphology,
physiology, growth, development, reproduction or life span of an
organism, system or (sub)population that results in an impairment
of functional capacity, an impairment of the capacity to
compensate for additional stress or an increase in susceptibility to
other influences;
it has an endocrine mode of action, i.e. it alters the function(s) of
the endocrine system;
there is a biologically plausible link between the adverse effect and
the endocrine activity.
WHO definition of EDs 2002:
“An endocrine disrupter is an exogenous substance or mixture that
alters function(s) of the endocrine system and consequently
causes adverse health effects in an intact organism, or its progeny
or (sub)populations.”
An adverse effect is defined as:
“a change in the morphology, physiology, growth, development,
reproduction or life span of an organism, system or
(sub)population that results in an impairment of functional
capacity, an impairment of the capacity to compensate for
additional stress or an increase in susceptibility to other
influences.”
EDs act according to several modalities
and can increase the risk of many
(multifactorial) diseases
• Thyroid axis Neurodevelopment, mood, cardiac function, metabolism…
• Testosterone Puberty, malformations,fecundity disorders
• Oestrogen
Aromatasefunction
Metabolic disorders (insulin resistance, diabetes…)
Growth and overweight disorders, bone development
Cancers of hormone sensitive organs (breast, prostate, testis…)
Health endpointsEndocrine disruption
modalities
Endocrine disruption
Steroid hormones
• PPARs receptors
• Hormone synthesis, transport, metabolism
• Other Nuclear Receptors
• Membrane receptors
• Metabolic hormones (insulin…)
Terms of reference of the report (extracts)
The scope of the study is to give a clear and simple overview to the non-expert
reader an analysis of possible effects of endocrine disruptors on human health,
the ways to eliminate its adverse effects on humans. Assessment whether the
current regulatory framework in the EU is sufficient in protecting human health
from the currently known effects of EDs should be carried.
The perceived inconsistency in establishing of a causal link between an exposure
to the EDs and diseases may be inevitable due to insuperable methodological
issues. The study should address the issue of methodology of such assessment
and suggest how to bring about scientific results which are comparable.
The study should address issues raised during the Hearing of the Committee on
petitions on Endocrine disruptors. Differing views have been expressed on the
impact of EDs on human health and the study should reflect those in its findings.
Further to that, the study should assess:
The approved criteria for ED Identification under EU Regulations on Plant
Protection Products and on Biocidal Products
The EU’s Guidance document for the implementation of the New Criteria on
Endocrine Disruptors for Biocides and Pesticides
Lastly, the study should suggest to the European Parliament ways of achieving
higher protection of human health, supported by scientific evidence, and suggest
future research topics which could increase the possibility of bringing about
evidence-based liaison between the EDs and health defects or chronic diseases.
Parallel between carcinogens and EDs
Carcinogens Endocrine Disruptors
Overarching definition valid in all
sectors (CLP regulation, 2008)
3 categories defined according to
the level of evidence (certain,
presumed, suspected)
No definition legally valid in all
sectors in the EU (only for
pesticides)
No distinction according to level
of evidence
Uncertainties regarding the exact number of substances, the total population
impact, some of their fine scale mechanism of action…
Not authorized in plant protection products
Category of chemicals not
authorized in cosmetics
No provision for this category of
chemicals in cosmetics