Aktuelle Entwicklungen bei der gesundheitlichen Bewertung von
endokrin aktiven Substanzen
Gisela H. Degen
Leibniz Institut für Arbeitsforschung an der TU Dortmund (IfADo)
– previous Chair of ’AK CM‘ of Subcommittee III in the AGS
– Expert / Member of the EU Scientific Committee of Consumer Safety (SCCS)– Member of EFSA Scientific Committee on Hazard assessment of EDs
Ardeystr. 67 ● D-44139 Dortmund ● www.ifado.de
Arbeitstagung Umweltmedizin-/hygiene – Essen 12. Okto ber 2017
Endokrin aktive Substanzen - ein Spezialfall ?
���� Toxikologie als Brücke zwischen Wissenschaft und Regulation
� Endokrines System; Definitionen (EAS or Endocrine Disruptor ?)
• Wie können Chemikalien damit interferieren ?
� Besorgnis - Beispiele (Wildlife, Human)
� Diethylstilbestrol als ‘proof of principle‘
• Dosis-Effekt-Beziehungen & mode of action
� Bereiche der Regulation
• Hazard vs. Risk-based
� Diskussion zu ‘ED Criteria‘
� Resume
• Tierversuche unverzichtbar; Risiko-Kommunikation !
Endokrine RegelkreiseHypothalamus und Hypophysen Achse
Hormone & Zielorgane
und weitere ??
Nebenniere,
Pankreas
Endokrines System
Schilddrüse,
Gonaden,
Mamma,
Knochen
Degen GH, 2004 Bundesgesundheitsbl
DOI 10.1007/s00103-004-0893-5
Sexualhormone :
Endokrine Regulation
und Angriffspunkte
(A-D) für Interferenzen
durch Chemikalien
(synth., natürliche)
In vitro Tests zur
� Rezeptor-Bindung
und ‚Aktion‘
� Steroidbiosynthese
Endokrin aktive Substanzen: Modes of Actiona) Interaktion mit Hormon-Rezeptoren (agonistic, antagonistic )
b) Interferenz mit Hormon-Biosynthese, Metabolismus oder Transport
e.g. Aromatase-Inhibitoren, Enzyminduktoren, Thyroidperoxidase Inhibitoren, Agentien die an SHBG oder andere Transportproteine binden
Resultieren aus zellulären Effekten (a or b)auch funktionale Veränderungen in vivo ??
Fig. from Schug T et al. 2016
Some EAC‘s (natural, synthetic)
acting via sex hormone receptors
asagonists / antagonists
Fig. from Schug T et al. 2016
origin of a hazard ?potency, exposure &
kinetics !
Definitionen: ENDOCRINE DISRUPTOR & more
� WHO/IPCS definition(s) 2002
“An endocrine disrupter is an exogenous substance or mixturethat alters function(s) of the endocrine system and consequentlycauses adverse health effects in an intact organism, or its progeny, or (sub)populations.”
“A potential endocrine disrupter * is an exogenous substance ormixture that possesses properties that might be expected to lead toendocrine disruption in an intact organism, or its progeny, or(sub)populations.”
� Adversity ? WHO + 2009, BfR Workshop
“A change in morphology, physiology, growth, reproduction, developmentor lifespan of an organism which results in impairment of functional capacityor impairment of capacity to compensate for additional stress or increasedsusceptibility to the harmful effects of other environmental influences”.
* endocrine active substances (EAS): not all are EDs ......
‘Endocrine Disruptors‘ und ...
adverse Effekte auf
Wildtiere ?
– Vögel (DDT)
– Alligatoren (p,p‘-DDT/DDE)
– andere Reptilien (???)
– Fische (Estrogens)
– marine mammals (PCB‘s)
– marine snails (TBT)
div. Effekte .......
Aspekte: Bioakkumulation (Nahrungskette), Exposition, Ökosystem ...
adverse Effekte beim Menschen ?
– die „Spermienkrise“– Hypospadien– Hodenkrebs– Brustkrebs– neuroendokrine &– immunologische
Veränderungen – Obesity ?
. . . . .
* Stoffe mit Wirkungen auf ..
– Rezeptoren: AR, ER, AhR, RxR;
– Steroidhormonbiosynthese
und/oder
– Schilddrüsenhormonsystem
– . . .
Sind Endokrine Disruptoren (EDCs*) in der Umwelt verantwortlich für ...
Die „Xenoestrogen
Hypothese“ ...
Mechanisms / Mode of Action
Main concern: developmental exposurecan lead to disease later in life ... � Example of Diethylstilbestrol
Pharmaka in der Schwangerschaft
Diethylstilbestrolhochpotentes Estrogenund Anti-Androgen
–> „DES-Töchter“„DES-Söhne“
Danazol – potentes Androgen; bei 200 mg und mehr–> Virilisierung bei einem
Teil der Mädchen **
AminogluthetimidInhibitor der Aromatase–> Pseudohermaphoditism
bei Mädchen *
*LeMaire et al 1972 **Brunskill 1992 cited in Hotchkiss K et al. (2008)
KONZEPT: irreversible Effekte bei Exposition in
kritischen Entwicklungsstadien
Abbildung aus
Fabricius ab Aquapendente, De Formato Foetu, 1624
Herzog August Bibliothek Wolfenbuettel
Diethylstilbestrol (DES) a potent hormone,
prescribed as a drug*to pregnant womenin the 1950-1970
in several countries ...
* DES doses: initially 5 mg /day,
then up to 25 mg / day
Golden RJ et al. (1989) Crit Rev. Toxicol
28(2): 109-227
Goodman A et al. (2011) N Engl J Med
364(22): 283-4
Hoover RN et al. (2011) N Engl J Med
365:1304-1314Evidence shows that endocrine disruption follows
„normal ““““ rules for dose-effect relationships !
Studies in rodents
• female/male offspring
• Dose-effect relationships
• mechanistic studies (ER)
Diethylstilbestrol (DES) Proof of principle
Diethylstilbestrol
OH
HO
„DES-Mütter ““““ (Ges. Dosis: 1,4 -18 g)
moderat ⇑ Brustkrebsrisiko ?
Pränatale (in utero) Exposition
� „DES-Töchter ““““:
Adenosis (häufig),
Karzinome Cervix u. Vagina (Risiko 1:1000)
Brustkrebsrisiko ⇑ bei > 40 J
� „DES-Söhne:Kryptorchismus ⇑, Hypospadien
keine sign. höhere Hodentumorinzidenz
hochpotentes Estrogenund Anti-Androgen
Studies in rodents
• Dose-effect relationships
• mechanistic insights (ER)
Bereiche der Regulation & Endokrin aktive Stoffe
� FOOD: Ingredients, Preservatives, Contaminants ...
EFSA BfR; SKLMEuropean Food Safety Authority
� Non-Food: Cosmetics, Toys, etc.
SCCS BfR committeeScientific Committee for Consumer Safety
� OccupationSCOEL AGS; MAKS C for Occupational Exposure Limits
� EnvironmentSCHER UBAS C on Health and Environmental Risks
Regulation: Hazard or Risk Assessment ?
European & National
Bisphenol ADaidzein, Genistein
Parabene, Zearalenon
Parabene, org. UV Filter Phthalate,
‘Botanicals‘
Alkylphenole, MetallePharmaka (OC) ...
Tributylzinn; POPs; ....
Biozide, Pflanzenschutz, & REACH
Herkunft? man-made / natural
Elemente einer toxikologischen Risikobewertung
HazardIdentification
HazardCharacterization
Dose-response relations
Risk Characterization
ExposureAssessment
to inform Risk Management !Risk = Hazard x Exposure� Mode of Action (MoA)
various routes & sources; timing
OECD Guidance ... Conceptual Framework (CF) for Testing and Assessment
of Endocrine Disrupting Chemicals
Level 1: desirable and non-test information (phys-chem/in silico)
Level 2: in vitro assays providing data about selected
endocrine mechanism(s)/pathway(s)
Level 3: in vivo assays providing data about selected endocrine
mechanism(s)/pathway(s) [oestrogen-, androgen-, thyroid-
mediated modes of action]
Level 4: in vivo assays providing data on adverse effects
on endocrine relevant endpoints (apical tests)
Level 5: in vivo assays providing more comprehensive data
on adverse effects on endocrine relevant endpoints over
extensive parts of the lifecycle of the organisms
OECD (2012) Guidance document on standardized test guidelines for evaluating chemicals for endocrine disruption.
Series on Testing and Assessment no. 150, ENV/JM/MONO(2012)22 pp. 385-387http://search.oecd.org/officialdocuments/displaydocumentpdf/?cote=env/jm/mono%282012%2922&doclanguage=en
Screen:
Haz.Id.
in vitro
in vivo
Test:
Hazard
Char.
Hazard or Risk based approach ?
* Scientific Opinion on the hazard assessment of endocrine disruptors:Scientific criteria for identification of endocrine disruptors and appropriateness of existing test methods for assessing effects mediated by these substances on human health and the environment. EFSA J2013; 11(3):3132 84 pp document – available at: www.efsa.europa.eu/efsajournal
� In rodent models (potential) endocrine disruptors, of natural or synthetic origin, can be identified and characterized according to criteria such as hormonal activity and adversity of effects.
� A possible impact of EAS on human health will depend upon (internal) exposure - at critical windows of susceptibility.
� Endocrine disrupters should be treated like most ot her chemicals of concern, i.e. be subject to risk assessment and not only to hazard assessment.
� Risk assessment - taking into account hazard and expo sure predictions - makes best use of available informatio n to inform on risk and level of concern for the purpose of risk management decisions .
Some conclusions*
Hazard or Risk based approach ?
� endorses WHO/IPCS definitions of a potential … / an ED
� Criteria for identification of an ED: … the presence of
i) an adverse effect in an intact organism or a (sub)population;ii) an endocrine activity;
andiii) a plausible causal relationship between the two.
� lists examples of past and present practices for assessing risk from substances used as cosmetic ingredients:
�
Memorandum on Endocrine DisruptorsSCCS/1544/14 adopted on 16 dec 2014
Preservatives (Biocides), UV Filter, Fragrances, others
Available at: http://ec.europa.eu/health/scientific_committees/consumer_safety/opinions/index_en.htm
SCCS opinions* on the safety of parabens
are / have been “ignored“:
Campaigns (...) misinform and scare consumers !
Despite SCCS:
Some cosmetic companies advertise their
products as “free of parabens“
marketing versus science
“Replacements“: Methylisothiazolinone (P94)
can cause real problems in consumers !
opinions SCCS 1548/15 and 1557/15
GHD‘s personal view:
* Parabens: SCCP/0873/05, SCCP/0874/05, SCCP/1017/06, SCCP/1183/08,
SCCS/1348/10, SCCS/1446/11, SCCS/1514/13
A Decade of Discussions on Parabens
1st June 2015 in Brussels: EU Conference on Endocrine DisruptorsCriteria for Identification and Related Impacts
http://ec.europa.eu/health/endocrine_disruptors/events/ev_20150416_en.htm
• general consensus on the WHO/IPCS Definition of an ED ...
Activities as of mid 2016
Impact Assessment Report (2016) on 4 options to define ED for PPP & BP regulation*
http://ec.europa.eu/health/endocrine_disruptors/impact_assessment/index_en.htm
11-12 April 2016 in Berlin: Expert Meeting on Endocrine DisruptorsBfR communication No. 10/2016, 4 May 2016 and Report at:
http://www.bfr.bund.de/cm/349/scientific-principles-for-the-identification-of-endocrine-disrupting-chemicals-a-
consensus-statement.pdfSolecki R et al. 2016/7 Arch Toxicol DOI 10.1007/s0024-016-1866-9
15 June 2016: Draft Commission regulations under the Biocidal and Plant
Protection Products legislation + Communication from the Commission to the
European Parliamant and the Council – all documents at:
http://ec.europa.eu/health/endocrine_disruptors/policy/index_en.htm
EU Roadmap activities: ... need to harmonize guidance on the regulation of EDs
“It is expected that the consensus reached will serve as an important basis for the development of regulatory ED criteria.“
Divergent Views on ...
Hazard or Risk-based approach * ?
� Thresholds ?
(Mechanisms; MoA)
� Non-monotonous Dose-
Effect Relations
(biol. or adverse effect)
� LOW Doses – in Relation to
Exposure (and ROUTE?)
* Testai E, Galli C, Dekant W, Marinovich M, Piersma AH, Sharpe RM (2013)
A plea for risk assessment of endocrine disrupting chemicals. Toxicology 314: 51-59
** Autrup H, Barile FA, Blaauboer B, Degen GH, Dekant W, Dietrich D, et al. (2015)
Principles of pharmacology and toxicology govern also effects of chemicals on the
endocrine system. Toxicol Sci 146: 11-15
Zusammenfassung
Ardeystr. 67 ● D-44139 Dortmund ● www.ifado.de
� Endokrines System; Definitionen (EAS or Endocrine Disruptor ?)
• Wie können Chemikalien damit interferieren ?
� Besorgnis - Beispiele (Wildlife, Human)
� Diethylstilbestrol als ‘proof of principle‘
• Dosis-Effekt-Beziehungen & mode of action
� Bereiche der Regulation
• Hazard vs. Risk-based
� Diskussion zu ‘ED Criteria‘
� Resume
• Tierversuche unverzichtbar; Risiko-Kommunikation !
Vielen Dank für ihre Aufmerksamkeit !
Diskussion – Fragen ?