Animal Welfare Perspective on Pathway- based Approaches to ... · in the 21st century: A vision and a strategy: “envisions a new toxicity-testing system that evaluates biologically

Advancing AOPs for Regulatory Applications | March 2 – 7, 2014 | Somma Lombardo, Italy Predictive Toxicology Summit | May 22 – 23, 2012 | Boston, MA

Advancing AOPs for Regulatory Applications | March 2 – 7, 2014 | Somma Lombardo, Italy

Animal Welfare Perspective on Pathway-

based Approaches to Safety Assessment

Catherine Willett, PhD Director, Regulatory Testing Risk Assessment and Alternatives The Humane Society of the United States [email protected]

Molecular initiating

event

Intermediary steps

Adverse Outcome

Advancing AOPs for Regulatory Applications | March 2 – 7, 2014 | Somma Lombardo, Italy Advancing AOPs for Regulatory Applications | March 2 – 7, 2014 | Somma Lombardo, Italy

Outline

• The scientific need for a new approach to toxicology

• Animal cost, in terms of numbers, suffering

• Opportunity for a better approach

• Precedents for a pathway-base approach

• Current programs and projects in AOP development

• What’s needed for the future?

• Involvement of the HSUS

• The Human Toxicology Project Consortium


The argument for a new approach

Pharmaceuticals: o 92% of drug candidates fail in clinical studies o “The average drug developed by a major pharmaceutical company

costs at least $4 billion, and it can be as much as $11 billion” (Forbes 2012)

o Need to assess novel chemistries (i.e. nanomaterials)

Industrial chemicals: o Growing concern over lack of data (> 10K chemicals worldwide) o Large-scale regulatory programs: REACH (EU, China, S.Korea)

Pesticides: o Registration requires the use of approximately 10,000 animals, millions

of USD, and many years (decades) o Need to identify “greener” chemistries

Cosmetics: o European Cosmetics Directives ban on animal testing o Consumer concern over safety and animal testing worldwide



Regulatory cost in animal use: gross approximation*

Annual animal use in research world-wide 115 million/year 15% used for regulatory testing 17 million/year *Estimates based on:

UK numbers extrapolated to other countries Reported numbers Most countries don’t require reporting US AWA does not cover • fish, amphibians, reptiles, birds • rodents • (these are covered by OLAW and AAALAC but

not required reporting)

Likely underestimated

Primates 0.1%

Dogs, cats 0.1%

small mammals 0.8%

large mammals 0.4%

fish, amphibians, reptiles, birds 18%

rodents 81%



Animal suffering

Lifetime captivity • “purpose-bred” mammal maintain instincts • demonstrate signs of depression • clinical signs of stress

Toxicological testing

• By definition is “purposeful poisoning” • MTD required in most guideline studies • Acute studies can involve high levels of pain • Lifetime studies lifetime of suffering



from an animal welfare perspective

The “3Rs” approach: • Refinement (better cages, enrichment, lower doses) • Reduction (fewer numbers) • Replacement

Pathway-based approaches offer an opportunity to:

• move away from animal testing (reduce, replace) • increase efficiency of chemical assessment • improve hazard and risk assessment

Win, Win, Win situation


Capitalize on advances in chemistry, biology, and engineering (since ~1970)

Fully utilize all existing knowledge

Increase relevance to humans and ecological species

Increase assessment capacity (“throughput”)

Increase efficiency (benefit/cost)

Increase predictivity

Decrease uncertainty in hazard and risk assessment

The opportunity for a better approach


1. Dose-response modeling • Using pharmacokinetic and mechanistic information

2. IPCS/WHO mode of action frameworks • Human relevance of rodent cancer findings • Extrapolated to non-cancer endpoints

3. Mode of action pathways in drug development

• Drug and target-specific

4. National Research Council in 2007 Report, Toxicity testing in the 21st century: A vision and a strategy:

“envisions a new toxicity-testing system that evaluates biologically significant perturbations in key toxicity pathways by using new methods

in computational biology and a comprehensive array of in vitro tests based on human biology”

Precedents for pathway-based toxicology


1. OECD Test Guidelines Programme • Task Force on Hazard Assessment • QSAR Toolbox Management Group • Extended Advisory Group on Molecular Screening and Toxicogenomics • VMG-non-animal under the EDTA-AG

2. US EPA • Office of Research and Development

o Mid-Continent Ecology Division – Predictive Toxicology o National Center for Computational Toxicology

• Extramural Science to Achieve Results (STAR) grants

3. European Commission Joint Research Centre (JRC) • Institute for Health and Consumer Protection (IHCP) • AOP Knowledge-bases • ECVAM – assay development

4. RIKEN Center for Sustainable Resource Science (Japan)

5. Others

Current pathway development programs


1. SEURAT-I: EUR 50 million FP7 joint EC – Cosmetics Europe project to address “Safety Evaluation Ultimately Replacing Animal Testing” • Repeat-dose, liver toxicity • 6 research projects including:

o COSMOS – integrated in silico models o ToxBank - database to support SEURAT projects

2. Johns Hopkins Center for Alternative to Animal Testing • Pathways of Toxicity • Evidence Based Toxicology

3. The Hamner Institutes • PPARa and Estrogen Receptor signaling pathways as prototypes • Including dose-response extrapolation modeling

Current pathway projects

Advancing AOPs for Regulatory Applications | March 2 – 7, 2014 | Somma Lombardo, Italy

AOPs in the work OECD plan:

• Mitochondrial toxicity – OECD

• Cell proliferation/differentiation – OECD

• Fish reproductive toxicity – US EPA

• Thyroid hormone pathways – US EPA

• PPARa – OEDC, Hamner

• Cancer epigenetics – S.Korea

• Germ cell mutagenicity – Canada

• Neurotoxicity and inflammation – Switzerland

• Liver Steatosis and Fibrosis – JRC

• AhR – BIAC

• Aquatic toxicity: UK and Japan

• Mutagenic MOA: US

• PPARa/CAR: US

• Embryonic vascular development: US

OECD AOPs in development


Uses and information needs

Potentialuse Necessarypathwayelements Supportinginformation Levelofcertaintyrequired

Chemicalcategories Quantitative,mechanisticunderstandingofMIE

QualitativelinkagetoAO[SomeinformationaboutIE]

MolecularinteractionsQSARAnimaldataExistingdatabases‘omics

Readacross

Chemicalprioritization Qualitative,somemechanisticunderstandingoflinkagesbetweenMIE,IEandAOHazardcharacterization

Integratedtestingstrategydesign

Qualitative,mechanisticunderstandingoflinkagesbetweenMIE,IEandAO

[somequantitativeunderstanding:dose-responseinformation,metabolism,toxicokinetics]

NetworksSystemsbiologymodeling

Cellularandtissuebiology(signaling,histology)

Riskassessment

IncreasedquantitativeunderstandingbetweenMIE,keyeventsandAO

Relationshipofintersectingpathways[Beginningtocharacterizelikelihoodofa

particularAOvssomeotheroutcome]

ToxicokineticdataMetabolisminformationLife-stage,sex,species,genetic

backgroundconsiderationsPathwaydatabasesMoreextensivenetworkand

systemsmodeling

Predictivetoxicology Somequantitativeunderstandingofrelationshipsofintersectingpathways(increasedcertaintyoflikelihoodofaparticularAOvssomeotheroutcome)

N-dimensionalrelationalknowledgebase(withuser-friendlyinterface!)


• Build a series of prototype pathways • OECD / EPA / industry / academia

• OECD Guidance

• Improve predictive tools • NIH National Center for Advancing Translational Sciences

• EPA’s Computational Toxicology Research

• OECD QSAR tool box

• The Hamner Institutes

• Develop assessment systems for querying key events including complex

endpoints • appropriate, standardized, quantitative in vitro assays

• Reconstructed tissues and organ systems

• Integrate absorption, metabolism and distribution information • PBPK modeling, QIVIVE

• Liver cells, tissues, extracts, reconstructed tissues

• Integrated databases and “knowledge bases” • ACToR and MetaPath: EPA – chemical toxicity data on over 500,000 environmental

chemicals searchable by chemical name and structure

• Kegg pathway database: collection of manually drawn pathway maps representing current

knowledge on cellular pathways in a number of different species and disease states

• AOP Wiki/Intermediate effects DB/Effectopedia (JRC/EPA/OECD) - open source

knowledge aggregation and collaboration tools that provide a means of describing adverse

outcome pathways in an encyclopedic and cooperative manner

What’s needed for the future?


What’s needed for the future?

There are a lot of projects And a lot of information needs to be developed OECD is leading in developing guidance, consolidating AOP

projects OECD/EPA/JRC are coordinating and leading development

of joint databases Is there a need for additional global coordination? End goal of developing a predictive toxicological system within (some of) our lifetimes


Implementing the Science: Bridging exiting projects, identifying and filling information needs for use of in vitro assays and pathway approaches.

Presentations · Workshops · Papers · Sponsorship

Articulating the Vision: Confidence and acceptance of a new paradigm requires effective communication to vested stakeholders, including non-scientist special interest groups, Congressional staff, and the public.

Website · Articles · Video

Lobbying/Funding: Advocate policy changes and cultivate funding opportunities that support pathway-based approaches in the U.S. and internationally.

Bill language · Appropriations · Horizon 2020


Thank You

Catherine Willett, PhD

Director, Regulatory Testing

Risk Assessment and Alternatives

Humane Society of the United States

AltTox.org

Coordinator, Human Toxicology Project

Consortium

HumanToxicologyProject.org

[email protected]

Documents

Animal Welfare Perspective on Pathway- based Approaches to ... · in the 21st century: A vision and a strategy: “envisions a new toxicity-testing system that evaluates biologically