role of the cro on the horizon 2025 - cw-presentations.com · cro and tomorrow’s issues – c....

CRO and tomorrow’s issues – C. Cavaignac & D. Baudiffier

1st Chemical Watch Expo: REACH into the FutureCélia Cavaignac & Damien Baudiffier – 25/04/2017

Role of the CRO on the horizon 2025 How can the CRO bring proactive approaches

regarding tomorrow’s issues?


I - State of the art - REACH 2018 : issues and deadlines

II - Towards new testing strategies - Integration in the global chemical assessment | Role of the CRO

Synopsis

Polymers

Mixture effects

Endocrine Disruptors


I - State of the art - REACH 2018 :Issues and deadlines


(Consultants)

I - State of the art - REACH 2018 : Issues and deadlines

REACH: Which actors? What purposes? - Position of a CRO among these actors

European Commission

Members States

Pivotal role, issues an opinionDecision

Participate in the EC decisionsand in the work of the ECHA

Chemical industriesSubstances production

Data providers

Contract ResearchOrganizationData producers

MinistriesNational Agency

Academic ResearchLaboratories

(Consultants)



REACH: Data to provide in ecotoxicologyTests carry out either by applicants or by CRO

Annex VII1 – 10 t/year

Annex VIII10 – 100 t/year

Annex IX100 – 1000 t/year

Annex X> 1000 t/year

Short term toxicity on freshwater aquatic invertebrate (Daphnids) (OECD 202*)Alga or Lemna sp growth

inhibition test (OECD 201*, 221*)Ready Biodegradability

(OECD 301*, 310*)Water solubility (OECD

105*) & partition coefficient (n-octanol/water) (OECD 107*, 117*)

Fish acute toxicity tests (OECD 203*, 236*)Activated Sludge,

Respiration Inhibition Test (OECD 209*)Hydrolysis as a function of

pH (OECD 111*),Adsorption - Desorption using a batch equilibrium method (OCDE 106*)

Long term toxicity test on invertebrate (OECD 211*), Fish, (OECD 210*)Biodegradation

simulation test: surface water, soils, sediments (OECD 304A, 314)Bioaccumulation in

Fish(OECD 305*) Short term toxicity on soil

organisms: invertebrates (OECD 207*, 235*), plants (OECD 208*, 227*), microorganisms (OECD 216*, 217*)

Long term toxicity on soil and sediment organisms (OECD 222*) Long term toxicity/avian

reproduction test (OECD 206)

ANNEX VII

ANNEX VIII

ANNEX IX

ANNEX X

* Tests currently offered by RRCo



REACH: Data to provide in ecotoxicology

Annex VII1 – 10 t/year

















ANNEX VII

ANNEX VIII

ANNEX IX

ANNEX X


TesTs carry ouT eiTher by applicanTs or by cro



REACH: Data to provide in ecotoxicologyAnnex VII1 – 10 t/year

















ANNEX VII

ANNEX VIII

ANNEX IX

ANNEX X




REACH: REACH - Ecotoxicology data to provideAnnex VII1 – 10 t/year


















Do these tests answer to all the current problematics?Are they applicable and appropriate to all the substances?

? ? ? ?



What could happen after REACH 2018?

2018

1-100 t/year

Last data procurement, Last REACH dossiers registration

Studies still ongoing, Feedback from the ECHA on tests proposals, Request from the ECHA on supplementary data set

New problematics ? Polymers, mixture effects, endocrine disruptors

Feedback from the ECHA on dossier submitted for REACH 2018



REACH on the horizon 2025

REACH 2018 is simply “the end of the beginning”

Companies have to keep their registration dossier up to date

ECHA and MS will continue to evaluate dossiers and substances

Risks from the most dangerous substances will continue to be

managed

Emergence of new problematics : polymers, mixtures effects,

endocrine disruption

How REACH can evolve on the horizon 2025?


II - Towards new testing strategies?– Integration in the global

chemical assessment | Role of the CRO


II - Towards new testing strategies?

Polymers

Definition : Under REACH, molecule that contains a sequence of at least 3 monomer units, which are covalently bound to at least one other monomer unit or other reactant

exempted from registration and evaluation under REACH may however still be subject to authorization and restriction manufacturers and importers of polymers may still be required to

register the monomers or other substances used as building blocks of the polymer



Polymers after REACH 2018?

Towards a REACH integration? How to test the effects on polymers? How to test their biodegradability?

Test the worst case? Which tests to integrate?

Learn from what already exists in the other regulations?

Other regulations, e.g. ASTM regulationAdapted tests on biodegradability of polymers, e.g. long-term assay

Towards new environmental fate and ecotoxicityassays?

Integration intoREACH?



Polymers after REACH 2018?

Towards a REACH integration? How to test the effects on polymers? How to test their biodegradability?

Test the worst case? Which tests to integrate?

Learn from what already exists in the other regulations?

Other regulations, e.g. ASTM regulationAdapted tests on biodegradability of polymers, e.g. long-term assay

Towards new environmental fate and ecotoxicityassays?

Integration intoREACH?

Development and realization of assays by CRO



Mixtures effect

Definition : “mixture or solution composed of two or more substances”

Current situation : “Regarding mixture effects in REACH regulation (CLP), regulatory texts encourage computation rules at the expense of tests on mixtures which can potentially be synergistic”



Mixtures effect after REACH 2018, mesocosm studies and Whole Effluent Assessment (WEA)

Increasing recognition by regulators that there are limitations to the substance-specific approach for assessing and controlling the environmental fate and effects of effluents

Measure of the combined effects of all the components in a complex effluent, such as synergistic, additive or antagonistic effects

Towards more holistic techniques such as whole effluent assessment (WEA) to supplement existing approaches

Application to complex mixtures into REACH?



Mesocosm studies as a tool for mixture effects

Reproduction

Environmentalfate

Acute toxicity Chronic toxicityReproduction

Genotoxicity Endocrine disruption?

RRCo – Experimental Hall Artificial River Layout


II – Towards new testing strategies?

Perspectives

WEA No current EU-wide

legislation Only national

specific regulation, e.g. US, Sweden

Towards an integration intoREACH – Mesocosmstudies as a tool for mixture effects

WEA Integration into

OSPAR regulation, which is a veryspecificregulation

Development of integrative testing strategies and realization of assays by CRO



Endocrine Disruptors "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" (WHO, 2002)



Endocrine Disruptors mechanisms of action

(1) Interaction with nuclear receptors: Estrogen receptors : Vitellogenin induction by Endocrine Disruptors

agonists Androgens receptors : Stickleback Spiggin induction

Endocrine Disruptors biomarkers exposure

(2) Independant mechanisms of receptors: Alteration in the activity of P450 cytochromes P450 implied in hormonal

metabolism: catabolism and steroidogenesis (biosynthesis)



Endocrine Disruptors after REACH 2018?

Only for substances on CoRAP and SVHC lists Towards an integration from the annex 7? Towards a standardized testing strategy Which tests? Which OECD guidelines? Additional

tests? Limiting factors: ED are not directly tested but their

mechanisms of action, which is complicated. A Solution: integration in Adverse Outcome

Pathways (AOP).



Integrative approaches and PE - AOPs, from mechanisms of action to adverse effects

Definition

“An AOP is an analytical construct that describes a sequential chain of causally linked events at different levels of biological organization that lead to an adverse health or ecotoxicologicaleffect”

(OECD, 2012)



AOP concept : contraction of existing concepts Characterize, organize and define cause-and-effect relationships

(from Ankley et al., 2010)

To link a molecular mechanistic effect to an observable effect at the individual or population level.






Academic laboratoriesCRO

Academic laboratoriesCRO






Who is ready to realize all steps of an AOP ?



AOP - Objectives Support chemical risk assessment based on mechanistic

reasoning; Improve decision-making in regulatory ecotoxicology.

Perspectives

OECD guidelines: biomarkers identification and integration into an AOP



AOP - Example

Plasma:reduced

circulating E2

Hepathocyte:reduced VTG

production

Ovary:Impaired

oocyte Dev.

Female:Decreased

spawning & fecundity

Population:Decliningtrajectory

AndrogenReceptor:agonism

Plasma:reduced

GtH

Theca:reduced

T synthesis

Granulosa:reduced E2

synthesis

Aromatase:inhibition



Testing strategies for EDCs based on AOPs

Plasma:reduced circulatin

g E2

Hepathocyte:reduced VTG

production

Ovary:Impairedoocyte

Dev.

Female:Decreased

spawning & fecundity

Population:Decliningtrajectory

AndrogenReceptor:agonism

Plasma:reduced

GtH

Theca:reduced

T synthesis

Granulosa:reduced E2

synthesis

Aromatase:inhibition

CALUX-AR

in vitro tests aromatase (aro-GFP)

Measurements E2, VTG

Fertility/Development assay

Development of relevant biomarkers and realization of assays : Academics or CRO



Testing strategy for EDCs integrating into AOPs concept

First step : screening in vitro• CALUX-ER /CALUX-AR (Chemical Activated Luciferase gene eXpression):

detection of endocrine distrupting potencies

• Aromatase assay

Second step : in vivo relevant « endpoint »• Changes in genes and protein expression

• Gonad histology

Third step : Adverse effect• Apical / Adverse Effect : fertility, F1 generation



Conclusion

Endocrine Disruption

Screening in vitro

In vivo endpoint Adverse effect

AOP

Mixture effect

Mesocosmstudies

Environmentalfate

Ecotoxicity

WEA

Polymer Long-term

biodegradability Case-by-case

ecotoxicity

Otherregulation

Testing strategy :



Role of a CRO on the horizon 2025European Commission

Members States




Data providers


Ministries

National Agency

Task force proposition of new testing strategies


(Consultants)

(Consultants)



Role of a CRO on the horizon 2025European Commission

Members States




Data providers


MinistriesNational Agency

Coordination Funding

for new testing strategies?


(Consultants)

(Consultants)


Conclusion REACH 2018 deadline appears unrealistic for the end of the

“standardized” tests.

REACH 2018: “The end of the beginning”

Additionally we notice emerging issues: polymers, mixtures, ED;

How REACH could evolve with new tests on the horizon 2025?

Mutual proactivity between industrials and CROs is required to anticipate these issues and suggest tests.

Should we start new tests validation on these issues? With which organisations? Which funding? By which deadlines?

CRO = source of proposals, REACH tests and apart from REACH for emerging issues? Regulating anticipation


Contact

Célia [email protected]

Damien [email protected]


Vielen Dank für Ihre Aufmerksamkeit

role of the cro on the horizon 2025 - cw-presentations.com · cro and tomorrow’s issues – c....

Documents