CRAC-HCF 2020 Virtual Forum

Nov 16 - Dec 10, 2020

Organizers：REACH24H Consulting Group / Helsinki Chemicals Forum

Partners：United Nations Environment Programme / Organization for Economic Cooperation and Development/
European Chemicals Agency / China Petroleum and Chemical Industry Federation/ China Chemical Safety Association/
VEGA HUB / China Crop Protection Industry Association / China Chamber of Commerce for I/E of Foodstuffs, Native
Produce and Animal Products, Flavor and Fragrance Branch / Pesticide Industry Association of Shandong Province /
Anhui Provincial Pesticide Industry Association/ Crop Protection Coalition / China Cleaning Industry Association /
Zhejiang Health Products & Cosmetics Industry Association / Chinese Industry Association for Antimicrobial Materials
& Products/ China Council for the Promotion of International Trade , Chemical Industry Branch / Italy China Chamber
of Commerce/ Foreign Agriculture Cooperation Public Information Service Platform / Centro REACH/China Association
of Fragrance Flavor and Cosmetic Industries

Media Partners：Xinhua News Agency / AGROPAGES / China Environment News / ChemLinked / Bloomberg / Japan
Chemical Daily / Pesticide Market News

Global Product QINGDAO NUOCHENG CHEMICAL

Towards a More
Sponsors： Charles River
Compliance SAFETY TECHNOLOGY CO., LTD

Synergic Future
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Introduction to the Risk
Assessment of Plant Protection
Products in the European Union
Dr Jean Lou Dorne-Senior Scientific Officer
European Food Safety Authority
Scientific Committee and Emerging Risks Unit

Towards a More
Synergic Future
Contents

1 Principles of Chemical Risk Assessment

2 Risk Assessment of Plant Protection Products

in the European Union

3 Open Source Tools for Chemical Risk Assessment

4 Conclusions and Future Perspectives

2
1 Principles of Chemical Risk Assessment

Organisations should not aim at

‘increase trust’
rather aim to demonstrate
Trustworthiness

Information should be
 Accessible
 Intelligible
 Useable
 Assessable

Professor David Spiegelhalter

EFSA 3rd scientific Conference September
2018

3
 1 From Question to Answer

Risk
Management

Risk Communication
Consumers
Risk Opinion

Media Assessment
Industry
Scientific Community

4
 1 Chemical Risk Assessment

– Starts with problem formulation : Question to answer, resources, timelines, data available
- Fit for purpose
– Uses tiered approaches depending on data available, time and resources

Step 1
Identify toxic effects
Hazard Identification
Quantify toxic effects: - Dose
Step 2 response
- Reference Point
Hazard Characterisation
- Reference value

Step 3
Occurrence x Consumption
Exposure Assessment

Step 4 Hazard vs Exposure: Risk

Risk Characterisation
5
 1 Deriving Reference Points and Reference Values
 Reference Points: most often from animal studies

• NOAEL: No observed-Adverse-Effect-Level
• BMDL: Benchmark Dose

 Reference Values:

• Chronic exposure
-Acceptable Daily Intake (ADI) - regulated Chemicals e.g. pesticides
-Tolerable Daily or weekly Intake -contaminants

ADI/TDI *mg/kg b.w/day)=NOAEL or BMDL/100 Fold-UF 100-fold uncertainty factor (UF)

Species Human
Differences Variability

10 10
• Acute exposure : Acute Reference Dose KINETICS DYNAMICS KINETICS DYNAMICS

6
1 Hazard assessment of chemicals: Data-based and Data Poor

7
 1 Mapping Level of knowledge and Tiering Principles

Risk
Hazard
Exposure Assessment Hazard identification Characterisation
Tier characterisation

Occurence Consumption TK TD TK TD
Default values e.g. Default values
Semi-Q in silico
0 Default values No data No data TTC Qualitative
Read across
In silico
In silico in silico
In silico in silico
Point estimates Point estimates in food Limited Basic TK
1 data NOAEL e.g. Semi-quantitative
categories data Read across
Read across Default UF
Semi-Q
NOAEL/
Dossier in silico BMDL e.g. Quantitative
Measured data Measured in some
2 data Dossier Data ADME data Default Deterministic/ Probabilistic
food categories
Qttve in silico
UF
Dossier
Dossier and/or MoA/AOP, Epi data, PB-PK
Large measured Full patterns -food and/or lit. e.g. Quantitative
3 lit. (in vitro, model, OMICs, BBDR, BMDL,
dataset categories (in vitro, in Full probabilistic 8
OMICs, Epi) CSAF
vivo)
1 Dealing With Chemical Mixtures

• Harmonised Guidance
• Whole Mixture approach and Component-based approaches
• Includes interactions

• Problem Formulation
• Exposure and Hazard Assessment
• Risk Characterisation

• Reporting Table
• Human Health, Animal Health and Environment

• Implementation: Technical Reports

• Human Health
• Animal Health 9
 2 Risk Assessment of Plant Protection
Products in the European Union

EU Legislative
Framework for Plant
Protection Products
(PPP)
“The purpose of this Regulation
is to ensure a high level of
protection of both human and
animal health and the
environment and at the same
time to safeguard the
competitiveness of Community
agriculture.”

10
 2 EU assessment and approval decision of the active pesticide substance

• Active substance
• Reg. 1107/2009 Submission

Periodic • Rapporteur MS
• EU DUAL regulatory Renewals Risk
Assessment • EFSA Peer-Review
system for pesticides
Decision
• EU approval
• Key Actors :
MS assessment and pre-marketing authorisation of each formulation
 Member States
 EFSA •PPP dossier •PPP dossier
Submission
•PPP dossier
Submission Submission

 EU approval •Member State •Member State

•Member State
Risk
Assessment
•Zonal process Risk
Assessment
•Zonal process Risk
Assessment
•Zonal process

•MS PPP authorisation •MS PPP authorisation

Decision •MS PPP authorisation Decision Decision

11
 EFSA Pesticide Unit and
2 PPR Panel Activities
Scientific Panel on Plant  Opinions
Protection Product and their
 Guidance documents
Residues (PPR) &
methodological development  Ad-hoc mandates

Provides Conclusions and

Coordinates the Peer Review Technical reports for single
of active substances active substances to support
the EU decision-makers
Pesticides Steering Network
Pesticides Monitoring
Network

 MRL Reasoned Opinions

Maximum Residue Levels
&
Consumers risks  Annual reports: CODEX &
residues monitoring 12
 2 Peer review process for PPPs

Dossier
1. Commenting phase
submission

PEER REVIEW 2. Evaluation of

comments
EFSA, Rapporteur MS,
Other MSs,
EU Commission,
3. Expert’s consultation
Notifier, Public
EFSA
Conclusion

EFSA Risk
Assessment Commission +MSs
Standing Committee on Plants,
EFSA Animals, Food and Feed
D/RAR Approval/Non Approval
Draft/Review
Assessment
Report National authorisation PPP by
13 MSs
2 EFSA Scientific Assessment of PPPs
• Substance ID Classification (CLP)
• Hazard assessment Hazard approval
criteria
• Phys-chem. Properties
• Env. Fate properties (Eco)Toxicologi
cal profile:
CMR,
• Hazard characterisation Endocrine
• Exposure assessment effects, PBT,
POP
• Risk characterisation
Risk based
approval
criteria 14
 2 Peer Review Process : Toxicological data

• New data requirements

• GLP status
• Analytical methods
• Toxicokinetics and comparative metabolism
• Phototoxicity/photomutagenicity
• Genotoxicity testing
• Toxicological profile of metabolites and impurities
• Endocrine disruptive properties
• Proposals for classification and labelling
• Literature search
• Panel recommendations

15
 2 Peer Review Process : Ecotoxicological data

• Mammals
• Aquatic organisms
• Bees
• Soil Organisms
• Risk assessment for uses in protected structures
• PPR Opinion on Non-Target Terrestrial Plants
• Aspects of the new data requirements
• Evaluation and validity of studies (performed using older versions of test
guidelines) using the criteria from latest version
• Literature data for the risk assessment

16
 2 Renewal Assessment Report

All RMS Comments EFSA

available
Evidence
Discussed
and
Presented

Mandatory GLP studies + RMS evaluation, Comments, Critical concerns,

Scientific literature + Updates are responses, Data gaps
other evaluations highlighted meeting reports, Validated
MSs views endpoints

17
 2 Relevant Outputs

• Conclusions on Pesticides*
• Identity and Phys/Chem properties
• Mammalian Toxicology & non dietary
health risks
• Residues & Consumers risks
• Environmental Fate and Behaviour
• Ecotoxicology & environmental risks

• Reasoned Opinions on MRLs & Annual reports

• Residues & Consumers risks

*Some conclusions are limited to one or more areas

18
2 PPR Panel and Methodological updates :
Guidance documents
Guidance
Documents
ready for
Risk
Managers
Panel or EFSA guidance decision on
Panel • Hearings enforcement
Scientific • Networking
opinion • Mandatory public
Preliminary
• Hearings consultation
work by EFSA
• Optional
• Grants & public
procurements consultation
Need
identified • External
report
• PPR Panel
• Pesticides
Steering
Network
19
 2 PPR Panel : Key activities

Human Health
• Cumulative Assessment of Pesticides
• Use of epidemiological studies in PPP risk assessment
• Residue definition for dietary risk assessment
• Dermal absorption
• Developmental neurotoxicity testing strategy including AOP development
• Endocrine Active substances
• Comparative in vitro metabolism

Environmental Fate
• Persistence in soil
• Environmental exposure including non-dietary by-standers and resident exposure

Ecotoxicology including
• Aquatic including sediment and modelling
• Terrestrial: vertebrates, bees and other arthropods, in-soil organisms, terrestrial plans
20
 2 Proposed Adverse Outcome pathways
Parkinson’s disease
Molecular Initiating Event  Key events cascade  Adverse outcome

21 21
 3 Open Source Tools for Chemical Risk Assessment
Inventory of EFSA’s chemical RA since
OpenFoodTox: EFSA’s Open Source Toxicological DB its creation in 2002

Easy Reference and Crisis

5000 Substances
• Crisis: Free, Quick, Easy access to EFSA’s
Chemical Hazards Data
• Tool for stakeholders

Avoid duplication of efforts

2,000 Scientific outputs
International Harmonisation and
Data Sharing
• OECD Harmonised Templates
• Data sharing

22
 3 Open FoodTox : Content

Substance Identity : CAS, IUPAC, SMILES etc.

Chemical Information  Single Substances (e.g. flavourings)
 Group of Substances (e.g. mixture/formulation)

 Opinions/Conclusions on Pesticides/Statements
EFSA Outputs Title, Publication date, link etc.

Genotoxicity
Reference Points
Toxicological  Human and Animal health and Ecological RA
Information Reference Values
 Regulated products: e.g. ADI for pesticides
 Nutrients: e.g DRV for vitamins and minerals
 Contaminants: TDI for acrylamide
23
 3 Downloading OpenFoodTox

https://zenodo.org/record/3693783#.Xs0DSzozZeU

24
 3 Micro-strategy Tool for OpenFoodTox

https://www.efsa.europa.eu/en/microstrategy/openfoodtox

25
3 Micro-strategy Tool 2 for OpenFoodTox

26
 3 Future of OpenFoodTox 2.0 2020-2022

Collect new properties

• Physico-chemical properties, TK data, bioaccumulation etc
• Summary exposure estimates
• Intermediate effects (mechanistic data)

New and updated OECD harmonised Templates

• Design template for Weight of evidence, biological relevance and uncertainty
• Update mechanistic (OHT 201) and TK template

Link OpenFoodTox with modelling platforms

• QSAR models e.g VEGA
• Published EFSA values and Predicted values

27
 3 Future of OpenFoodTox 2.0 2020-2022

Chemical Information Structure

Exposure Physico-chemical
properties
Summary Exposure
EFSA Outputs

Genotoxicity
Toxicological Information Toxicokinetics vitro vivo
Toxicodynamics vitro vivo

Models implemented in VEGA

Modelling Platform www.vegahub.eu

New Approach Methodologies (NAMs)

28
3 OpenFoodTox and QSAR models

29
 3 Connecting Exposure, Dosimetry and Effects
What the body does to the chemical What the chemical does to the body
Toxicokinetics Toxicodynamics
External Toxic
dose Effect

External Internal Toxic

dose dose Effect

External Internal Target organ Toxic

dose dose Dose Effect

External Internal Target organ Target organ Toxic

dose dose Dose metabolism Effect

External Internal Target organ Target organ Target organ Toxic

dose dose dose metabolism responses Effect 30
 3 TK Plate: Example of Open Source Models

• International Cooperation (2016-2020)

 State of the art Workshop – JRC, National and international bodies (US-EPA, FDA, EFSA, RIVM,HSE, etc)
 OECD Guidance document: Use of TK/PB-K models in RA (2020)

31
3 Open source PBK models in 4 Fish species@EFSA

32
3 Open source PBK models for farm animal species@EFSA

33
 3 Quantitative in vitro in vivo extrapolation in humans

 New data requirements for pesticides (283/284 2013) :

Compare in vitro metabolism rat/human

 Collaborative case studies with national/international (2016-2020):

1. Use of human in vitro metabolism data and QIVIVE models in RA
2. Prediction of human kinetics for EFSA relevant compounds (e.g. pesticides, contaminants)

 Guidance on use of human in vitro metabolism studies to be developed by Pesticide panel (2021)

 Takes into account difference in metabolism for human risk assessment

34
 3 Connecting metabolism and variability in humans

In vitro metabolism In vivo variability/Uncertainty

35
 3 Building a TK Platform for species of relevance

External Internal Target organ Target organ

dose dose dose metabolism

Physiological
Data Internal Dose
TK parameters
Tissue residues
Reverse dosimetry

Species-specific TK
Interspecies Differences
Human Variability
TKTD modelling

Chemical Specific – Sensitivity

Data Uncertainty
Exposure
Physico-chemical
Metabolism
36
4 Conclusions and Future Perspectives

• Risk Assessment
-Fit for purpose, Tiered approaches and weight of evidence
-Pesticides : Peer review process, re-evaluation, MRL settings, monitoring

• Open source Tools support risk assessment

-OpenFoodTox: over 5000 chemicals, new properties and in silico models
-TKPlate: Open source TK and TK TD models

• Future perspectives
-Further development open source tools: range of test species + case studies
-Implement tools in RA and Train staff and RA community

• New speciality section in EUROTOX: IN2TOX (In vitro in silico)

-Support dissemination of in silico in vitro methods in risk assessment 37
 Integrating State Of The Art Methods And Data Streams

Exposure Dosimetry Reference Risk

Point

In vitro

OpenFoodTox
and MATRIX
OMICs

AOP/MoA
Epidemiological In Silico
Data 38
 Acknowledgements

 EFSA Staff: Jose Tarazona, Jose Cortinas-Abrahantes, Jane Richardson, Luca Pasinato,
Tobin Robinson, Djien Liem, Georges Kass

 OpenFoodTox and QSAR models

1.S-IN : Vicenza, Italy; 2.Istituto Mario Negri, Milan, italy,
3.Molecular networks, Germany; 4. JRC, Ispra

 TK Platform
1.Laser Analytica, Paris, France; 2. INERIS, Paris, France;3.Radboud University, Niemigen, The Netherlands 4.
Open Analytics, Antwerp, Belgium

 TK/TD
1.ANSES, Paris, France; 2. ISS, Rome, Italy; 3.University of Utrecht, Utrecht, The Netherlands; 4.University of
Bretagne, Brest, France

39
 Acknowledgements

 EFSA Staff: Jose Tarazona, Jose Cortinas-Abrahantes, Jane Richardson, Luca Pasinato, Tobin
Robinson, Djien Liem, Georges Kass

 OpenFoodTox and QSAR models

1.S-IN : Vicenza, Italy; 2.Istituto Mario Negri, Milan, italy,
3.Molecular networks, Germany; 4. JRC, Ispra

 TK Platform
1.Laser Analytica, Paris, France; 2. INERIS, Paris, France;3.Radboud University, Niemigen, The Netherlands
4. Open Analytics, Antwerp, Belgium

 TK/TD
1.ANSES, Paris, France; 2. ISS, Rome, Italy; 3.University of Utrecht, Utrecht, The Netherlands; 4.University
of Bretagne, Brest, France

 DEB Models
1.Center for Ecology and Hydrology , UK; 2. Technico Lisboa, Lisbon, Portugal; 3.Akvaplan Niva, Tromso,
Norway
40
Thanks a lot !

Questions ?
Towards a More
Synergic Future