Endocrine Disruptors: Human Health Protection

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.

mailto:[email protected]@ep.europa.eu

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…)




• Thyroid axis

• Testosterone

• Oestrogen

Aromatasefunction

Endocrine disruption modalities

Endocrine disruptor

Steroid hormones

• PPARs receptors





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)


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



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.


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

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)



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.”




• 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





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

Endocrine Disruptors: Human Health Protection

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