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Hartung - Lush Prize Conference 2014
- 1. Is 1R the new 3Rs? Thomas Hartung & CAAT team
- 2. • 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
- 3. Henry Spira and the start of CAAT
- 4. Funding from industry, philanthropy and research funding agencies The Bernice Barbour Foundation …and individuals
- 5. CAAT-Europe 2010 US Policy program 2006 EU center of excellence transatlantic cooperation EU Policy program 2012 Daneshian et al. (2010) Altex, 27, 63 – 69.
- 6. Russell and Burch In vitro testing Validation Tox-21c Toward humane science CAAT ECVAM
- 7. Alternative methods as the solution 55 years anniversary of the 3Rs concept A societal compromise to continuously Reduce Refine Replace Rex Burch & to overcome animal testing. Bill Russel
- 8. Animal use for toxicology Work for alternatives addressing toxicology Need for expansion Lighthouse function
- 9. About 50 cent of every dollar spent by consumers is for products developed or safety-controlled by animal testing
- 10. $3 trillion $3 trillion Animal testing at $3 billion per year $200 billion $3 trillion
- 11. 1R only? Read-across Replace Refine The 4th R? Reduce* *pesticides
- 12. The most important R – Relevance ! …, which holds true first of all for the animal test
- 13. Protected against minute amounts of pesticides Natural pesticides 10,000x more, 35 of 63 carcinogenic Genotoxic: sugar Protected against TCDD in eggs Same calculation for alcohol: One glass per 345 years Genotoxic: salt 23 of 31 tested coffee ingredients carcinogenic Enjoy!!!
- 14. 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 If this gives you headache, take an aspirin! Unlikely to be brought to the market today
- 15. There is some good reason for regulating new products….
- 16. More and more innovative products with even more new chemicals….
- 17. 43 –36%0% w einllt etersspteedc icehse cmoircraellsation 8% somewhat tested chemicals 100,000+ chemicals in consumer products
- 18. 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.
- 19. All models are wrong, some are useful (G. Box) naive not less naive 60%
- 20. 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!
- 21. 3R Success stories OECD acceptance of validated methods: • 1999-2001 - Refine: Painless test for skin sensitisation - Reduce: Animal numbers for acute tox. from 45 to 8 • 2004 - 2010 - Replace: - phototoxicity - skin / eye corrosion / irritation
- 22. 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 Pipeline: sensitization in vitro, embryotoxicity, endocrine disrupters, photogenotox, eye irritation, acute tox dose estimate Source: ECEAE
- 23. 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
- 24. 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 Stem cells & Organo-typic culture & High-content • 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
- 25. 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
- 26. How to improve the predictive value of cell cultures Good Cell Culture Practice Functional endpoints / biomarker = mechanism Human (stem) cells High-content = wholesome characterization High-throughput = replicates & many comparisons Organo-typic culture Integrated Testing Strategies
- 27. 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
- 28. Workshop on GCCP for iPSC In preparation
- 29. Chemical Universe The galaxy of Human toxicity The galaxy of Rat toxicity At maximum tolerated dose
- 30. Chemical Universe The galaxy of Human toxicity The galaxy of Rat toxicity At maximum tolerated dose, without mixtures and individual differences
- 31. Chemical Universe The galaxy of Human toxicity Covering with a battery of reductionist tests
- 32. Chemical Universe The galaxy of Human toxicity Covering with a Integrated Testing Strategy
- 33. • ITS development sensitization & eye irritation • Commissioned whitepaper Jaworska & Hoffmann • WORKSHOP 2013
- 34. Mechanistic & evidence-based toxicology
- 35. ‘Omics’ Image analysis Robotised / automated testing High content High through-put Information rich Bioinformatics & Data-mining Knowledge on pathways Systems Toxicology
- 36. Mapping the Human Toxome by Systems Toxicology Endocrine disruption Hewitt et al., 2005. Science, 307:1572-1573 • 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
- 37. 32 articles / reports published 2 commissioned articles in preparation 5 workshop reports pending In vitro publication standards 5+ workshops planned Ambassadors Bas Blaauboer Alan Goldberg Thomas Hartung Marcel Leist
- 38. 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)
- 39. 30-31 May 2013
- 40. New tests need a QA sparring partner: 21st Century Validation for 21st Century Tests Limitations of current validation approaches: ALTEX 27 (2010) 253-263 • Time-consuming • Non-systematic • Focus on prediction of animal data Advantages of an EBT Approach: • Faster • Systematic • Can focus on mechanistic relevance
- 41. 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
- 42. Frontloading of toxicology / Green Toxicology InfoDays Green Toxicology “fail early, fail cheap” Connecticut, Dec 2012 Anticipate human or regulatory problems? Baltimore, Nov 2013 Zurich, Switzerland 23 Oct 2014 “test early, develop clean” SoT 2015, San Diego Green Toxicology
- 44. 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
- 45. 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
- 46. 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
- 47. Combine the drivers of change from EU and US EU: legislation, funding, integrated testing, organizations US: technologies, Tox- 21c, TSCA reauthor.
- 48. 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
- 49. Stop …just arguing take what whether we have the and glass exploit of the opportunity!!! alternatives is half full or half empty…
- 50. The difficulty lies, not in the new ideas, but in escaping from the old ones. John Maynard Keynes (1883 - 1946)