Computational Approaches to Predict Repeat-Dose Toxicity ... · Prediction of Human Repeated Dose...
Transcript of Computational Approaches to Predict Repeat-Dose Toxicity ... · Prediction of Human Repeated Dose...
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Computational Approaches to Predict Repeat-Dose Toxicity: Lessons Learned
from Cosmetic Ingredients: Introduction
Mark Cronin, Liverpool John Moores University, England
Chihae Yang, Altamira LLC, Columbus OH
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Global Cosmetics Industry
• A major employer
– 1.5 million people directly and indirectly employed in the EU cosmetics industry
– More than 25,000 scientists
• EU cosmetic industry worth over €70 billion
• Many products, much innovation
– Soap, shampoo, hair dyes, toothpaste, make-up etc…
• Cosmetics give us self-confidence, well-being and sometimes even health
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Cosmetics Ingredients Have a
Diverse Chemical Space
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Toxicity is Not Acceptable,
But Neither is Animal Testing
• Cosmetics are a vanity product ….
• Decades of public opinion and pressure
• European Union Cosmetics Regulation
– No testing on products
– No further testing on ingredients
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Toxicity is Not Acceptable,
But Neither is Animal Testing
• Cosmetics are a vanity product ….
• Decades of public opinion and pressure
• European Union Cosmetics Regulation
– No testing on products
– No further testing on ingredients
How are we going to ensure safety of
existing and new cosmetics ingredients?
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Aims to derive a concentration that causes no effect
Effect(s)
Dose
50%
0%
100%
NOEL
LOEL
NOEL = No Observed
Effect Level
“Traditional” Method of Identifying Hazard:
In Vivo Repeat Dose Toxicity Testing
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Aims to derive a concentration that causes no effect
Effect(s)
Dose
50%
0%
100%
NOEL
LOEL
NOEL = No Observed
Effect Level
“Traditional” Method of Identifying Hazard:
In Vivo Repeat Dose Toxicity Testing
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Alternatives to In Vivo Toxicity Testing
• Biological: In vitro, molecular biology • Computational: In silico, (Q)SAR, read-across, PBPK, TTC
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Alternatives to In Vivo Toxicity Testing
For the systemic toxicological endpoints of repeated dose toxicity, carcinogenicity and reproductive toxicity, the time
horizon for full replacement could not be estimated
• Biological: In vitro, molecular biology • Computational: In silico, (Q)SAR, read-across, PBPK, TTC
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European SEURAT-1 Research Initiative
Towards the replacement of in vivo repeated dose systemic toxicity testing
€ 25 million funding from both the European Commission and Cosmetics Europe, 2011-2015
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Models For Toxic Effects:
Linking Chemistry, Modelling and Safety
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Basis of Toxicity Prediction
Intrinsic Hazard Bioavailability
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Basis of Toxicity Prediction
Intrinsic Hazard Bioavailability
Positive
Prediction of Effect
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Basis of Toxicity Prediction
Intrinsic Hazard Bioavailability
Positive
Dose Required to
Achieve an Effective
Concentration
Prediction of Effect
Prediction of ADME
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Basis of Toxicity Prediction
Intrinsic Hazard Bioavailability
Positive
Dose Required to
Achieve an Effective
Concentration
Prediction of Effect
Prediction of ADME
Exposure
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Basis of Toxicity Prediction
Intrinsic Hazard Bioavailability
Positive
Dose Required to
Achieve an Effective
Concentration
Prediction of Effect
Prediction of ADME
Exposure Assessment of Risk
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The Project
Integrated In Silico Models for the Prediction of Human Repeated Dose Toxicity of COSMetics to Optimise Safety
6.7 Mio EUR ◦ 14 Partners EC FP7 – Cosmetics Europe
COSMOS is an EU project developing methods for determining the safety of cosmetic ingredients for humans, without the use of animals, using computational models.
www.cosmostox.eu
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In Silico Models
Project
New Toxicological Databases
Threshold of Toxicological Concern (TTC)
PBPK and In Vitro – In Vivo Extrapolation
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This Session:
Lessons Learnt from Cosmetics
• Databases, Tools and TTC Approach Applied To Chemicals In Cosmetics Products – Chihae Yang
• Role of Bioavailability in Risk Assessment of Cosmetic Ingredients: Kinetics, Permeation, and Metabolism – Elena Fioravanzo
• Adverse Outcome Pathways (AOPs) for Target Organ Effects: The Role of Structural Alerts and Chemotypes for Liver Toxicity to Group Compounds and Apply Read-Across – Mark Cronin
• Applying Databases and Tools from COSMOS to the Scientific Needs of US FDA’s CERES Project - Kirk Arvidson
• US EPA’s ToxCast, Tox21, and COSMOS Projects: Cheminformatics Approaches to Creating Data Linkages and Synergies – Ann Richard
• Questions and Discussion