Accelerating Implementation of the NRC Vision for Toxicity Testing in the 21 st Century

1. Taking the NRC Vision SeriouslyMartin StephensThe Humane Society of the United States andThe Human Toxicology Project Consortium Accelerating Implementation of the NRC Vision for Toxicity Testing in the 21st Century Gallaudet University, November 9-10, 2010

2. I’m blending three perspectives today Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

3. Talk Outline • HSUS • NRC Vision • HTP Consortium • Implementation • Workshop • Going Forward • Housekeeping Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

4. The Humane Society of the United States • Based in DC • No formal tie to local HSs • Full array of animal issues • Emphasizes national issues • Work towards day when animals are no longer used in harmful research • Focus on 3Rs, including repl. • Parent org’n of HSI & HSLF • Supporter of NRC vision • Our views: • “An Animal Prot’n Perspective on 21st Century Tox” JTEH 2010 Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

5. Talk Outline • HSUS • NRC Vision • HTP Consortium • Implementation • Workshop • Going Forward • Housekeeping Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

6. U.S. National Research Council (2007) Likely benefits: • More relevant scientific foundation for human health RAs • Broader coverage of chemicals, health effects, life stages & mixtures, given the higher throughput • Lower costs and decreased time required to obtain results • Phased reductions in animal usage “TT21C” Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

7. Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

8. Favorable Reception • Presentations • Articles • Workshops • Elaborations • Government programs • “21st Century Toxicology” “21cTox” Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

9. Talk Outline • HSUS • NRC Vision • HTP Consortium • Implementation • Workshop • Going Forward • Housekeeping Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

10. Human Toxicology Project Consortium A multi-stakeholder coalition dedicated to accelerating the global implementation of 21st Century Toxicology in general, and the NRC vision in particular, into risk assessment, to better safeguard human health and hasten the replacement of animal use in toxicology. Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

11. Human Toxicology Project Consortium Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

12. Why Another Effort? • No existing initiative fully captures the NRC vision • Relevant govt programs are limited in funding & scope • Int’l coordination is limited • Stakeholders beyond govt can add their talents & ideas Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

13. Talk Outline • HSUS • NRC Vision • HTP Consortium • Implementation • Workshop • Going Forward • Housekeeping Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

14. A Closer Look at NRC Vision Computational, interpretive tools The assays ? Screening/Prioritization ToxCast, Tox21 Risk Assessment TT21C “Tox21” 21st Century Toxicity Testing 21cTox Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

15. Implementation Approaches I II III 21 st Century Organic NRC Vision Toxicology Direct/ Approach Lassez Faire Indirect/Evolutionary Revolutionary Organized effort No Yes Yes Resource Low Medium High investment Possible timeline 40 years 20-25 years 10 - 15 years Relation to current Under the radar Enhancing Supplanting paradigm Relative impact on Low Medium High animal use Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

16. Implementation Approaches I II III 21 st Century Organic NRC Vision Toxicology Direct/ Approach Lassez Faire Indirect/Evolutionary Revolutionary Organized effort No Yes Yes Resource Low Medium High investment Possible timeline 40 years 20-25 years 10 - 15 years Relation to current Under the radar Enhancing Supplanting paradigm Relative impact on Low Medium High animal use Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

17. Implementation Approaches I II III 21 st Century Organic NRC Vision Toxicology Direct/ Approach Lassez Faire Indirect/Evolutionary Revolutionary Organized effort No Yes Yes Resource Low Medium High investment Possible timeline 40 years 20-25 years 10 - 15 years Relation to current Under the radar Enhancing Supplanting paradigm Relative impact on Low Medium High animal use Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

18. Implementation Approaches I II III 21 st Century Organic NRC Vision Toxicology Direct/ Approach Lassez Faire Indirect/Evolutionary Revolutionary Organized effort No Yes Yes Resource Low Medium High investment Possible timeline 40 years 20-25 years 10 - 15 years Relation to current Under the radar Enhancing Supplanting paradigm Relative impact on Low Medium High animal use Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

19. Consortium Aims to Help by Promoting… • Buy-in & sense of urgency among stakeholders • Implementation via int’l research roadmap • Pilot projects that show proof-of-principle • A “big biology” project a la HGP • Funding & any appropriate policy changes • Application to RA, not simply hazard ID or priority setting Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

20. “Human Toxicology Project” • HTP = Consortium’s label for the focused R&D needed • Analogous to the Human Genome Project • HGP on our agenda: • Austin “Lessons learned from the HGP” • Rowan “The need for a Human Genome-type Project” • Analogy underscores sense of: • Mission • Urgency • Focus • Leadership Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

21. Talk Outline • HSUS • NRC Vision • HTP Consortium • Implementation • Workshop • Going Forward • Housekeeping Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

22. Workshop Aims & Goal • Introduce stakeholders to HTPC & HTP • Survey current efforts • Encourage urgency & buy-in on application to RA • Encourage trans-Atlantic partnerships • Develop recommendations for accelerating implementation of the NRC vision Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

23. Structure of Meeting • Day 1 • Stage setting • Review of current efforts • Day 2 • “Big biology” programs: HGP & HTP • Break-out groups • Summary of BGs • Discussants’ perspectives  recommendations • Wrap-up Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

24. BG1: Are all NRC vision elements being worked on? Some lagging or not fully integrated? • Vision itself under-emphasized some elements • E.g., exposure assessment • Complicating issues: metabolism, validation, solubility • Targeted testing • “Adversity” • Necessary policy changes? Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

25. BG2: Ways to refine ongoing initiatives to make better progress on NRC vision? Increased use of … • Human cells? • PBPK & computational modeling? • Systems biology? • Human effects data? • Targeted testing in vitro to supplement pathway testing? Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

26. BG3: New approaches to accelerate NRC vision implementation? Hamner approach? • Hamner pilot study/proof of principle approach? • A HTP-type effort? • Human tissue assays for targeting testing? • Incorporating human reverse dosimetry and exposure into HTS Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

27. BG4: Current efforts sufficiently well-funded and coordinated internationally? • AXLR8, JRC in EU • ToxCast, Tox21 in US • Current levels of funding • Current levels of coordination • Opportunities for synergies? Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

28. Talk Outline • HSUS • NRC Vision • HTP Consortium • Implementation • Workshop • Going Forward • Housekeeping Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

29. Where Consortium goes from here • Symposium recommendations Toxicological Sciences, SOT Conference • Other activity • Lobby US Congress and Administration for R&D funding • Develop pilot projects to jumpstart vision implementation • Through presentations and writings, champion vision and its implementation as a ‘big biology’ project a la HGP • Coordinate with EU ‘AXLR8’ program to foster synergies Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

30. Going Forward Encourage Enthusiasm Avoid Over- promising Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

31. The mix of pathway vs. targeted testing Targeted Testing Pathway Testing time time

32. Evolving Nature of Targeted Testing Itself In Vivo Schuler & Esch, 2009 http://alttox.org/ttrc/way-forward/ In Vitro time time

33. Going Forward:Role of animal-based cells, testing & legacy data? • Pathway testing: when to use animal cells? • Targeted testing: moving from in vivo to in vitro • Role of animal legacy data in evaluation? • Role for new animal testing? • Answers depend on the implementation path • “Animal testing not needed for scientific reasons but to satisfy regulators” – comment @ recent meeting Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

34. Going Forward p. 35 Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

35. Talk Outline • HSUS • NRC Vision • HTP Consortium • Implementation • Workshop • Going Forward • Housekeeping Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

36. Housekeeping • Speakers: • See Loree Talley to upload your presentations • Presentations will be put online • Soccer rules for timing: • Yellow card: 3 minutes left • Red card: you’re out of time • Chairpersons: speaker bios are in packet • Break-out sessions: • Pre-selected your choice • No AV equipment for presentations • To be recorded for note-taking purposes • Rapporteurs have morning break to prepare summaries Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

37. Many thanks to… Workshop Sponsors Others Workshop Endorsers • HSUS staff & volunteers: • Jen Ball • Carol England • Leah Gomez • Loree Talley • Dawn McPherson Workshop Partners Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century

38. Thank you! Martin Stephens mstephens@hsus.org info@htpconsortium.org Accelerating Implementation of the NRC Vision for Tox. Testing in the 21st Century