Cosmetics Europe LRSS Programme 2016-20
Transcript of Cosmetics Europe LRSS Programme 2016-20
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Objectives of CE Research
To deliver tools & strategies for animal-free safety assessment
Accurate
Robust
Efficient
…ultimately accepted by regulators…
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Our Systematic Rationale
Exposure
• Exposure upon use
Local effects
• Skin, eye irritation
Penetration, Metabolism, Excretion
• Skin penetration, metabolism
• Bioavailability at systemic target site
Systemic Effects
• Sensitization, genotoxicity
• (Sub-) chronic toxicity
Safety Assessment
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Current LRSS Situation
LRSS = triple package
❶Develop non-animal methods & testing strategies to be used for safety assessment of cosmetics ingredients / chemicals
❷Show that safety assessment – thus probabilistic & realistic assessment – is possible on a broad spectrum of effects / likelihoods including systemic toxicity
❸Advocate for the regulatory acceptance of data generated with such alternative methods
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Current LRSS Situation
5 task forces
1. Eye Irritation
2. Genotoxicity
3. Skin tolerance
4. Bioavailability & Metabolism / ToxicoKinetics (TK)
5. Mode of Action / ToxicoDynamics (TD)
Well advanced combination of
alternative methods towards reg.
accep. Systemic
toxicity…
…based on
non-animal
methods only
Discussed for
decades
Many attempts
to achieve this
But so far not
accepted
Big
challenge
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AAT Strategic Roadmap
2013
Skin Irritation Eye Irritation Genotoxicity
Acute Toxicity
2016
Eye Irritation Genotoxicity
Skin sensitization
Exposure / ADME
Systemic Toxicity
2020
Sensitization
Systemic Toxicity
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Evolution of Genotoxicity Requirements
Ames
MLA
MN
Ames
MN
High Sensitivity
Low false
positive ratio
Reduced costs
2003 2004 2014
3D Comet
3D MN
SCCS Notes of guidance – in vitro battery:
Skin assays
accepted follow-
up option
Successful Validation is prerequisite for maintaining status quo!
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Genotoxicity
Strategy supported by SCCS and OECD
Drastically less false positives by 2-assay strategy
Evaluation of tier 2 assays progressing Finalize validation of 3D skin model assays in 2016
Support validation of Hen’s Egg micronucleus test as viable option to follow-up on orally exposed ingredients
Goal to have 2 assays/strategy approved by scientific/regulatory community in 2017/18
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Metabolism
Immunology
Chemistry
Penetration
Chemical reactivity
Protein modification
Cellular response
Organ response
In vivo response
Integrated assessment
Expert systems
in silico tools
Skin Sensitization - OECD “Adverse Outcome Pathways“ -
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Metabolism
Immunology
Chemistry
Penetration
Chemical reactivity
Protein modification
Cellular response
Organ response
In vivo response
Three in vitro assays validated DPRA, KeratinoSens, hCLAT
Additional 13 assays evaluated Six methods prioritized (incl. DPRA, KeratinoSens and hCLAT)
Promising prediction models being assessed e.g. Support Vector Machines, Bayesian models …
Skin Sensitization - OECD “Adverse Outcome Pathways“ -
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Metabolism
Immunology
Chemistry
Penetration
Chemical reactivity
Protein modification
Cellular response
Organ response
In vivo response
Researching
assays
Skin Sensitization - OECD “Adverse Outcome Pathways“ -
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Overview Skin Sensitization
Achievements
Assays developed / validated / evaluated
Clear roadmap
Status
6 OECD-submitted data interpretation procedures (DIP‘s) evaluated
Assay optimization & data integration
Characterize & expand applicability domain
Challenges (2017-2020)
Potency determination
Testing strategy finalization
Regulatory acceptance
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Paradigm shift
*adapted from P. Price (US EPA), “Using in vitro data in quantitative risk assessments”
QIVI
VE
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Strategy Systemic Toxicity
Hazard Identification
- Toxicodynamics -
Mechanistic predictions
Exposure
- Toxicokinetics -
Systemic exposure predictions
Safety Assessment
Combined evaluation & extrapolation
Fusion • Concentration response data
• Modelling
- Case Studies -
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Systemic Toxicity - Status
• SEURAT-1 final event 4 Dec. 2015
• SEURAT-1 level 3 case studies Proof-of-concept, TTC, Read-across framework, ab initio
• Differential planning vs. public programs
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Toxicokinetics / ADME - Objectives
Internal exposure
• For read-across and
ab initio risk assessments
• Enable internal TTCs
Guidance for in vitro assays
(concentrations, target organs)
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Toxicokinetics / ADME - Principles
• Topical exposure
• Local concentrations in different organs
• Metabolism
• Distribution
• Excretion
• Organ-specific toxicity
• Reactive metabolite formation or detoxification
• PK profile, Cmax, AUC
Fate of a chemical after exposure via different routes
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Toxicokinetics / ADME - Status
In silico models
Partition/ diffusion
coefficients
Lipid binding
Solubility
Skin penetration (non-viable skin)
Metabolism in ex vivo
skin
Metabolism, stability in
S9
Protein binding
(Physico-) chemical properties
In silico models
Bioavailability & Metabolism
• 50 compounds tested Q3/2016
• In silico models 2017
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Toxicokinetics / ADME - Way Forward
Internal TTC
PBPK ADME Model
Read across / ab initio concepts
In silico
Skin Penetration
Prediction Models
ADME
in vitro Toolbox • intestinal absorption
• liver metabolism
• in vitro biokinetics
• plasma protein binding
Static & Dynamic
3D Skin & Liver
Models
Exposure
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Toxicodynamics - Objectives • Discriminate between specific and non
specific adversities and low toxicity
• Determine perturbed biological
pathways for repeat dose toxicity
• Establish quantitative points of
departure for use in risk assessment
(linked to kinetics)
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Mode of Action
Ontology (2016-2019)
Bio-/ Chemo-
informatics Data (2016-2019)
Toxicogenomics (2017-2019)
Toxicodynamic
AssayToolbox (2016-2020)
Toxicodynamics Building Blocks
Quantify dose which can
alter biological pathway(s)
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Toxicodynamics Building Blocks
Mode of Action
Ontology
(2016-2019)
Bio-/ Chemo-
informatics Data
(2016-2019)
Toxicogenomics
(2017-2019)
Toxicodynamic
AssayToolbox (2016-2020)
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Toxicodynamics Building Blocks - Mode of Action Ontology -
Mode of Action
Ontology
(2016-2019)
Bio-/ Chemo-
informatics Data
(2016-2019)
Toxicogenomics
(2017-2019)
Toxicodynamic
AssayToolbox (2016-2020)
Knowledge-based grouping of chemical features associated with repeat dose toxicity into categories, tie to a putative mode of toxicity (or not)
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Toxicodynamics Building Blocks - Toxicogenomics -
Mode of Action
Ontology
(2016-2019)
Bio-/ Chemo-
informatics Data
(2016-2019)
Toxicogenomics
(2017-2019)
Toxicodynamic
AssayToolbox (2016-2020)
Front line screen for broad characterization of hazard
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Toxicodynamics Building Blocks - Toxicodynamic Assay Toolbox -
Mode of Action
Ontology
(2016-2019)
Bio-/ Chemo-
informatics Data
(2016-2019)
Toxicogenomics
(2017-2019)
Toxicodynamic
Assay Toolbox (2016-2020)
In vitro assays for generating toxicodynamic data Address identified gaps Source of targeting testing
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Toxicodynamics Building Blocks - Bio-/ Chemo-informatics Data -
Mode of Action
Ontology
(2016-2019)
Bio-/ Chemo-
informatics Data
(2016-2019)
Toxicogenomics
(2017-2019)
Toxicodynamic
AssayToolbox (2016-2020)
Informatics and integration/visualization needs of toxicity and ADME data for analysis via case studies
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Fusion & Safety Assessment - Case Studies / Modelling / Evaluation -
Case Studies as Guiding Principle
• Concentration response data / modelling
• Quantitative in vitro-in vivo extrapolation
(QIVIVE)
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1. IDENTIFY USE SCENARIO
TIER 2: APPLICATION
TIER 0: IDENTIFY USE SCENARIO, CHEMICAL OF
CONCERN AND COLLECT EXISTING
INFORMATION
TIER 1: HYPOTHESIS
FORMULATION
2. IDENTIFY MOLECULAR STRUCTURE
3. COLLECT EXISTING DATA
4. IDENTIFY ANALOGUES, SUITABILITY ASSESSMENT AND EXITING DATA
5. SYSTEMIC BIOAVAILABILITY (PARENT VS. METABOLITE(S), TARGET ORGANS, INTERNAL CONCENTRATION)
6. MOA HYPOTHESIS GENERATION (WEIGHT OF EVIDENCE BASED ON AVAILABLE TOOLS)
7A. TARGETED TESTING 7B. BIOKINETIC REFINEMENT (IN
VIVO CLEARANCE, POPULATION, IN VITRO STABILITY, PARTITION)
8. POINTS OF DEPARTURE, IN VITRO IN VIVO EXTRAPOLATION, UNCERTAINTY ESTIMATION, MARGIN OF SAFETY
9. FINAL RISK ASSESSMENT OR SUMMARY ON INSUFFICIENT INFORMATION APPROACH
EXIT TTC
EXIT INTERNAL
TTC
EXIT AB INITIO
EXIT READ ACROSS
(Adapted from Berggren et al. 2016. Publication in preparation)
Systemic Toxicity Workflow
7A. TARGETED TESTING 7B. BIOKINETIC REFINEMENT (IN
VIVO CLEARANCE, POPULATION, IN VITRO STABILITY, PARTITION)
8. POINTS OF DEPARTURE, IN VITRO IN VIVO EXTRAPOLATION, UNCERTAINTY ESTIMATION, MARGIN OF SAFETY
9. FINAL RISK ASSESSMENT OR SUMMARY ON INSUFFICIENT INFORMATION APPROACH EXIT AB INITIO
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SA Paradigm = the common matrix to TK and TD TFs
There are some
direct links easy to
draw
And some others
less obvious
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Conclusions – Highlights since 2015
• OECD acceptance of eye irritation RhT tests
• OECD/SCCS acceptance of genotoxicity strategy
• SEURAT-1 case studies
– SCCS: positive reception of TTC for systemic toxicity
– ECHA: positive reception of NAMs (as supporting evidence in read-across)
• Cosmetics Europe LRSS roadmap largely planned