hartung - lush prize conference 2014
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• Better science
• Less animals
• Human relevance
• Faster and cheaper results
• Refinement
• Information, Grants
• Think tank
• New tools, quality control
• EU branch, policy program
• Stakeholder consensus
Scientific American 2005
The Bernice Barbour
Foundation
Funding from industry, philanthropy and research funding agencies
…and individuals
CAAT-Europe 2010
transatlantic cooperation
Daneshian et al. (2010) Altex, 27, 63 – 69.
US Policy program 2006
EU center of excellenceEU Policy program 2012
55 years anniversary of the
3Rs concept
A societal compromise to
continuously
Reduce
Refine
Replace
to overcome animal testing.Rex Burch &
Bill Russel
Alternative methods as the solution
Animal use for
toxicology
Work for alternatives
addressing toxicology
Need for
expansion
Lighthouse
function
About 50 cent of
every dollar spent
by consumers is
for products
developed or
safety-controlled
by animal testing
Genotoxic: sugarGenotoxic: salt
Protected against
TCDD in eggs
Same calculation
for alcohol:
One glass per
345 years
Protected
against minute
amounts of
pesticides
23 of 31
tested coffee
ingredients
carcinogenic
Natural
pesticides
10,000x more,
35 of 63
carcinogenic
Enjoy!!!
R22 harmful if swallowed
(LD50 = 150-200mg/kg in rats)
R 36 irritant to eyes
R 37 respiratory irritant
R 38 irritant to skin
Not carcinogenic,
but co-carcinogen (promotor)
Unclear mutagenicity
Embryonic malformations in
cat, dog, rat, mice, rabbit,
monkey
Unlikely to be brought to the
market today
If this gives you
headache,
take an aspirin!
43 – 60% interspecies correlation3% well tested chemicals8% somewhat tested chemicals
100,000+ chemicals in consumer products
Every time has its
technologies…
If it’s true that knowledge doubles every
seven years in the life sciences,…
…we now have more than 1000fold more
knowledge than at the time, when current
toxicity tests were designed.
My “welcome present” at ECVAM
The 7th amendment of the Cosmetics Directive 2003
• Marketing ban if testing finished products or not using ECVAM-validated methods since 2004
• Phasing out ingredient testing with test and marketing bans in 2009 and 2013
• Critical need for alternatives
The wrong “victim”, but
I am happy to have one!
3R Success storiesOECD acceptance of
validated methods:
• 1999-2001- Refine: Painless testfor skin sensitisation
- Reduce: Animal numbers for acute tox.from 45 to 8
• 2004 - 2010- Replace:- phototoxicity- skin / eye corrosion / irritation
Toxicological Endpoints Status
Skin Corrosion, acute
phototoxicity, sensitization
(LLNA)
OECD accepted before
2002
Aquatic ecotoxicity 2010 OECD
accepted
Skin Absorption /
Penetration
2004 OECD
accepted
Skin Irritation 2010 OECD accepted
Genotoxicity (MNT) 2010 OECD
accepted
Eye Irritation (BCOP, ICE) 2010 OECD accepted
Sensitization (rLLNA) 2010 OECD accepted
Carcinogenicity (CTA) Under discussion
Source: ECEAE
Pipeline: sensitization in vitro, embryotoxicity, endocrine disrupters,
photogenotox, eye irritation, acute tox dose estimate
Traditional 3Rs methods
will not be the solution to
the problem
• Little perspective for
complex endpoints
• 2/3 fail validation
• hardly solved the
cosmetics 7th amendment
challenge for 2009, no way
for 2013
http://en.wikipedia.org/wiki/Organ-on-a-chip
Human on Chip Approach
• Prompted by DoD need for
medical countermeasure
evaluation
• Could overcome many test
shortcomings, especially using
stem cells
• NAS panel
• $200 million program
• CAAT InfoDay 2012
• CAAT workshop 3D in 2012
• 10 May 2013 conference FDA / NIH
/ DARPA / CAAT
• GCCP for iPSC workshop to come
Stem cells &
Organo-typic
culture & High-
content
Limitations of in vitro models
Mycoplasma
Dedifferentiation favored by
growth conditions and cell
selection
Cells are bored to death
Lack of oxygen
Lack of metabolism and
defense
Unknown fate of test
compounds in culture
Tumor origin of many cells
Cell identity
ALTEX 2013, 30:275-291
How to improve the predictive value of cell cultures
Good Cell Culture Practice
Functional
endpoints /
biomarker
= mechanism
High-content
= wholesome
characterization
High-throughput
= replicates & many
comparisons
Organo-typic
culture
Human (stem) cells
Integrated
Testing
Strategies
Coecke et al. ‘Good Cell Culture
Practice draft Guidance Document’,
ATLA 33, 261-287, 2005
1. characterisation and maintenance
of essential characteristics
2. quality assurance
3. recording
4. reporting
5. safety
6. education and training
7. ethics
Chemical Universe
The galaxy of
Human toxicity
The galaxy of
Rat toxicity
At maximum
tolerated dose,
without mixtures and
individual differences
• ITS development sensitization &
eye irritation
• Commissioned whitepaper
Jaworska & Hoffmann
• WORKSHOP 2013
‘Omics’ Image analysis
High content High through-put
Information rich
Bioinformatics &
Data-mining
Knowledge on
pathways
Systems Toxicology
Robotised / automated
testing
Mapping the Human Toxome by Systems Toxicology
Hewitt et al., 2005. Science, 307:1572-1573
Endocrine disruption• Use “omics” to map PoT for endocrine disruption
• Develop software tools
• Identify PoT
• Develop a process for PoT annotation, validation
• Establish public database on PoT.
www.humantoxome.com
32 articles / reports published
2 commissioned articles in
preparation
5 workshop reports pending
In vitro publication standards
5+ workshops planned
Ambassadors
Thomas Hartung
Marcel Leist
Bas Blaauboer
Alan Goldberg
Scientific roadmap for the future of animal-
free systemic toxicity testing
May 2011: EC report on status of alternatives
Sep 2011: Independent review by 19 international experts
Oct 2011: Five white paper on the way forward
Consensus workshop with 35 experts
Feb 2012: Roadmap published
Mar 2012: Stakeholder Forum in Brussels (150 experts)
May 2013: Stakeholder Forum in Washington (200 experts)
New tests need a QA sparring partner:
21st Century Validation for 21st Century Tests
Limitations of current validation approaches:
• Time-consuming
• Non-systematic
• Focus on prediction of animal
data
Advantages of
an EBT
Approach:
• Faster
• Systematic
• Can focus on mechanistic
relevance
ALTEX 27 (2010) 253-263
2006-7: Publication / 1st conference
Mar 2011: US EBTC
Oct 2011: Secretariat at CAAT
www.ebtox.com
Jan 2012: First conference hosted by EPA
Jun 2012: EU EBTC
Diverse working groups
Jul 2013: IUTOX, Seoul, Korea
Sep 2013: EuroTox, Interlaken, Switzerland
Systematic reviews increasingly embraced
by EPA/IRIS, NTP and EFSA
21 Nov 2014: Forum Systematic Reviews,
Baltimore
Frontloading of toxicology / Green Toxicology
“fail early, fail cheap”
Anticipate human or
regulatory problems?
“test early, develop clean”
Green Toxicology
InfoDays
Green Toxicology
Connecticut, Dec 2012
Baltimore, Nov 2013
Zurich, Switzerland
23 Oct 2014
SoT 2015, San Diego
Next ALTEX
CAAT Read-across Initiative
International Steering Group & Whitepaper
Workshop in Baltimore 12-14 Jan 2015
“Good Read-across Practice”
Stakeholder Fora in Brussels & Washington end 2015
Read-across-21c • Negative vs.
positive read-
across
• Support by
biological data not
only structure
• Expression of
uncertainty
• Local validity
• Application to
complex mixtures
“Test-across”, 2007
Alternative approaches have become one of the most dynamic
areas of toxicology – “3Rs Plus, not 1R”
• Embracing latest technologies
• Emerging new concepts
• International harmonization and collaboration
• Spanning cross industrial sectors
• A role model for all life sciences as to quality assurance,
assessment of predictive capacity and humane science
Combine the drivers of
change from EU and US
EU: legislation, funding,
integrated testing,
organizations
US: technologies, Tox-
21c, TSCA reauthor.
Systemic Tox
Many industries
Many countries
Limited implementation
Proof-of-principle
Better cell culture
Tox-21c
Integrated Tests
Mechanistic Tox
Read-across
Evidence-based T.
Green Toxicology
Stop arguing whether the glass of
alternatives is half full or half empty…
…just take what we have and exploit the
opportunity!!!
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