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London, November, 2014

Ovanes MekenyanLaboratory of Mathematical Chemistry

University “Prof. As. Zlatarov”, Bourgas, Bulgaria

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BURGAS

“Assen Zlatarov”UNIVERSITY

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The best town for living in Bulgaria for 2013-14

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The need of alternative testing strategies avoiding animal use

Timeline

Regulatory Acceptance

in vivo

Enormous annual use of experimental animals worldwide

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The need of alternative testing strategies avoiding animal use

Timeline

Regulatory Acceptance

in vivo

United States, 2010

>100 million

Canada, 2009

>3.3 million

United Kingdom, 2012

>4.1 million

peta.org

Enormous annual use of experimental animals worldwide

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The need of alternative testing strategies avoiding animal use

Timeline

Regulatory Acceptance

in vitroin vivo

Development of highly reliable in vitro test

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The need of alternative testing strategies avoiding animal use

Computational In silico testing

Timeline

Regulatory Acceptance

in vitroin vivo in silico

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Global regulations for chemical risk assessment

REACH -Registration, Evaluation, Authorisation and Restriction of Chemicals

ChAMP - The Chemical Assessment and Management Program

CSCL - Japanese Chemical Substances Control Law

Chemicals Management Plan

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QSAR and read-across methods used for submissions to the ECHA for existing substances at or above 1000 tpa*

(2011 ECHA report)

Read acrossQSAR env = environmental endpoint; hh = human health endpoint

*H. Spielmann et al. ATLA 39, 481–493, 2011

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Global Scientific centers for alternative testing strategies

2NTP Interagency Center for the Evaluation of Alternative Toxicological Methods/Interagency Coordinating Committee on the Validation of Alternative Methods3Japanese Center for the Validation of Alternative Methods

1European Center for the Validation of Alternative Methods

4Korean Center for the Validation of Alternative Methods

NICEATM2

USAECVAM1

EUJaCVAM3

JapanKoCVAM4

KoreaHealth Canada

They shared common activities on utilization of alternative to Animal testingby cooperation in a single organization:

International Cooperation on Alternative Test Methods(ICATM)

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Global Scientific centers for alternative testing strategies

2NTP Interagency Center for the Evaluation of Alternative Toxicological Methods/Interagency Coordinating Committee on the Validation of Alternative Methods3Japanese Center for the Validation of Alternative Methods

1European Center for the Validation of Alternative Methods

4Korean Center for the Validation of Alternative Methods

NICEATM2

USAECVAM1

EUJaCVAM3

JapanKoCVAM4

KoreaHealth Canada

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Scientific areas of LMC

•Applying molecular modeling for predicting toxicity of chemicals

Analyzing chemical structures

Explaining interaction mechanisms

Developing models

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Scientific areas of LMC

•Applying molecular modeling for predicting toxicity of chemicals

•Building information technologies for implementation of the models

Analyzing chemical structures

Explaining interaction mechanisms

Developing models

Integrating modelson software platforms

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Scientific areas of LMC

•Applying molecular modeling for predicting toxicity of chemicals

•Building information technology for implementation of the models

•Metabolism simulation

In silico simulation of metabolism

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Scientific areas of LMC

•Applying molecular modeling for predicting toxicity of chemicals

•Developing information technology for implementation of the models

•Metabolism simulation

In silico simulation of metabolism

in vivo/ in vitrorat metabolism

Predicting metabolic activation of chemicals

Identifying toxic metabolites

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Scientific areas of LMC

•Applying molecular modeling for predicting toxicity of chemicals

•Developing information technology for implementation of the models

•Metabolism simulation

In silico simulation of metabolism

Skinmetabolism

Predicting metabolic activation of chemicals

Identifying toxic metabolites

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Scientific areas of LMC

•Applying molecular modeling for predicting toxicity of chemicals

•Developing information technology for implementation of the models

•Metabolism simulation

In silico simulation of metabolism

Biodegradation

Identifying stable degradants

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Major scientific achievements of LMC

•OECD QSAR TOOLBOX

Global systems for hazard assessment

Freeware system developed with the scientific and financial assistance of:

and

DEVELOPED by

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Download statistics of QSAR Toolbox by registered users worldwide

Software for grouping chemicals into categories and filling gaps in (eco)toxicity data needed for assessing the hazards of chemicals

Category concept and read-across

TOXIC?ICG50=?

TOX

ICIT

Y (I

GC

50

)

logKow

No data

Software for grouping chemicals into categories and filling gaps in (eco)toxicity data needed for assessing the hazards of chemicals

Category concept and read-acrossTO

XIC

ITY

(IG

C5

0)

logKow

Aldehyde – “Schiff base former”

Collecting Analogs - Aldehydes “Schiff base formers”

Predicted ICG50 – 1.52x102 mg/L

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Major scientific achievements of LMC

Global systems for hazard assessment

Hazard Evaluation Support System Integrated Platform

Supported by the New Energy and Industrial Technology Development Organization

JAPAN

HESS SYSTEM - JAPAN

DEVELOPED by

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Major scientific achievements of LMC

Global systems for hazard assessment

Hazard Evaluation Support System Integrated PlatformFor predicting repeated dose toxicity

Supported by the New Energy and Industrial Technology Development Organization

JAPAN

HESS SYSTEM - JAPAN

DEVELOPED by

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Major scientific achievements of LMC

Simulating metabolism

Predicting fate and hazard accounting for metabolism

LMC products

Simulation of metabolism

Human Health – Skin metabolism

Protein conjugate

Phase II reactions

Reactive species

Simulation of metabolism

Human Health – Liver S9

Cl

Cl

O

Cl

OH

Cl

O

Mutagenic metabolite

Simulation of metabolism

Biodegradation

CH2

O

O

O OH

CH2 OH

OH

CH2

HO

O OH

O

Stable degradant

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Trainings on QSAR Toolbox and OASIS models

Major scientific achievements of LMC

ECHA

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Trainings on QSAR Toolbox and OASIS models

Tokyo

Major scientific achievements of LMC

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Sydney

Trainings on QSAR Toolbox and OASIS models

Major scientific achievements of LMC

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Canberra

Trainings on QSAR Toolbox and OASIS models

Major scientific achievements of LMC

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Madrid

Trainings on QSAR Toolbox and OASIS models

Major scientific achievements of LMC

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Barcelona

Trainings on QSAR Toolbox and OASIS models

Major scientific achievements of LMC

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Bern

Trainings on QSAR Toolbox and OASIS models

Major scientific achievements of LMC

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Ottawa

Trainings on QSAR Toolbox and OASIS models

Major scientific achievements of LMC

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Trainings on QSAR Toolbox and OASIS models

Major scientific achievements of LMC

Oxford

Regulatory agencies – major partners of LMC

Industrial companies – major partners of LMC

Let’s Take a Break We’ll Back in 5 Mins

“Assen Zlatarov”UNIVERSITY

BourgasBULGARIA

Laboratory of Mathematical Chemistry

“Assen Zlatarov”UNIVERSITY

BourgasBULGARIA

Laboratory of Mathematical Chemistry

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Instead of conclusion

Ones I`ve got a phone call from an old lady begging me to cure the tumor of her cat…

at that moment I understood that even with QSAR I am helping to save animals.