in vitro data and in silico models for predictive toxicology
TRANSCRIPT
In Vitro Data and In Silico Models for Predictive Toxicology
The SEURAT project
Elisabet Berggren European Commission, Joint Research Centre / COACH
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• Cluster of seven collaborative projects • 50 million Euro investment • Co-financed by EC and Cosmetics Europe • Over 70 research partners • 16 countries plus EC • 6 year programme
Seurat-1: towards replacement of in vivo repeated dose systemic toxicity testing
http://www.seurat-1.eu/
2 1 0 3 4 5 6 years
2nd PoC , 1st PoC updated
SEURAT-1 case study descriptions
2nd PoC Kick-off
Kick-Off Meeting Final Report
COACH
SEURAT-1 MAIN SEURAT-2
GC WG
DA WG JRC
SA WG
MoA WG
BK
WG
Data Ware- house
T&M Cat. 3rd PoC
1st PoC
The SEURAT-1 Roadmap
SEURAT-1 Annual Meeting
SEURAT-1 Annual Report
SC W
G
WE ARE HERE
http://www.seurat-1.eu/
The SEURAT strategy is to adopt a toxicological
mode-of-action framework to describe how
any substance may adversely affect human health,
and to use this knowledge to develop
complementary theoretical, computational and
experimental (in vitro) models that predict
quantitative points of departure needed for safety
assessment.
SEURAT - The Strategy
www.seurat-1.eu
Scientific Tools
Chemical
Cells exchange
… development underpinned by mode-of-action rationale
Bioreactors for engineering tissues
Models to link in vitro to in vivo biokinetics
Database on cosmetics ingredients and properties Genetically engineered reporter-gene cell lines Multi-scale models of organ toxicity
Protocols for stably differentiated iPSC Project data and protocol warehouse
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Adverse Outcome Pathway:
Structure the information in order to be able to PREDICT adverse health effects
Molecular Initiating Events
Key Events
Adverse Outcomes
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Level 1, KNOWLEDGE: Adverse Outcome Pathway (AOP) constructs
Level 3, APPLICATION: Predictive systems to support regulatory safety assessment
SEURAT-1 Proof of Concept on three levels:
Level 2, PREDICTION: Integrated systems including in vitro and computational methods to predict toxicity
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Visit AOP Wiki (https://aopkb.org) to explore currently mapped AOPs, improve them or add new ones.
Structure the AOP information in collaboration with the rest of the world
http://wiki.toxbank.net/wiki
ToxBank Wiki
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For the first time ever hiPS-derived hepatocytes was used for repeated dose toxicity studies (Holmgren et al. (2014) in Drug Metab. Disp., 42(9): 1401-1406
Development of an in vitro drug‐induced liver fibrosis model
Differentiation of stem cell-derived hepatocytes
A flavor of highlights from the SEURAT-1 projects
(MTX = Methotrexate) Spheroids with co-cultured HepaRG and Hepatic Stellate Cells showing accumulation of collagen
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Liver cell toxicity reporters to identify hepatotoxicant-induced cellular stress responses
A flavor of highlights from the SEURAT-1 projects 2
A toxicity reporter platform based on BAC (Bacterial Artificial Chromosome) engineering of the human HepG2 cells (Wink et al (2014) in Chem.Res. Toxicol., 27: 338-355.)
Prediction of steatosis through repeated dose exposure to 3D HepaRG system combined with
Biokinetic modelling
COSMOS database
o Open-access
o High-quality toxicity data (quality
controlled, curated structures)
o User-friendly query builder (chemical
name, structure, toxicity data)
o 44,765 unique chemical structures
o 12,538 toxicity studies for 1,660
compounds across 27 endpoints
Webinar and tutorial:
http://www.cosmostox.eu/what/COSMOSdb/
http://cosmosdb.cosmostox.eu/
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Models are Freely Available Through COSMOS KNIME WebPortal and Space
Documentation, user guidance, web tutorials
JRC, Ispra, June 2013
Scientific Tools
Chemical
Cells exchange
… how to translate them into solutions for safety assessment?
Safety Assessment Working Group
TTC One conceptual framework - three case studies:
Pieces of evidence and initial considerations
· Purpose of the assessment
· Exposure context· Expert knowledge and judgement based on existing evidence / data
General adversities Organ specific adversities
Toxicodynamics
· Target organ: full assessment based on
Adverse Outcome Pathway (AOP)1
· Non-target organ: limited assessment
Toxicokinetics
Assessment of ADME properties
Overall Assessment (including uncertainties and knowledge gaps)
Use of prediction for pre-defined purpose (with consideration of
acceptable uncertainty)
Improve assessment if necessary
1) The steps in the AOP (molecular initiating event, key events) will be assessed using a
selection of tools including in silico predictions and in vitro tests.
Hypothesis generation
regarding mode of action
Toxicodynamics
· Many biological targets (based on chemi-
cal structure, e.g. alkylating agents)
· Specific targets present in many cells /
tissues / organs (e.g. AhR-pathway)
Type of adversity
Definition of relevant dose range
Determination of point of departure
Evaluation
Result
AB INITIO
I. Chemical similarity of compounds that do not require metabolic transformation to exert a potential adverse human health effect
II. Chemical similarity involving metabolic transformation resulting in exposure to the same/similar proximal toxicant
III. Chemicals with general low or no toxicity
IV. Distinguishing chemicals in a structurally similar category with variable toxicities based on Mode of Action hypothesis
Four different scenarios
Final Reporting
You are all welcome Register at: http://www.seurat-1.eu/
Horizon 2020 project: EUToxRisk21 Starting this autumn will continue what SEURAT-1 started.
Thanks for the attention!