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

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

Cosmetics Ingredients Have a

Diverse Chemical Space

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

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?

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

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

Alternatives to In Vivo Toxicity Testing

• Biological: In vitro, molecular biology • Computational: In silico, (Q)SAR, read-across, PBPK, TTC

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

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

Models For Toxic Effects:

Linking Chemistry, Modelling and Safety

Basis of Toxicity Prediction

Intrinsic Hazard Bioavailability

Basis of Toxicity Prediction

Intrinsic Hazard Bioavailability

Positive

Prediction of Effect

Basis of Toxicity Prediction

Intrinsic Hazard Bioavailability

Positive

Dose Required to

Achieve an Effective

Concentration

Prediction of Effect

Prediction of ADME

Basis of Toxicity Prediction

Intrinsic Hazard Bioavailability

Positive

Dose Required to

Achieve an Effective

Concentration

Prediction of Effect

Prediction of ADME

Exposure

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

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

In Silico Models

Project

New Toxicological Databases

Threshold of Toxicological Concern (TTC)

PBPK and In Vitro – In Vivo Extrapolation

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