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 ?