2. Overview of the NRC Vision for the Future of Toxicity Testing Daniel Krewski, PhD, MHA Professor and Director McLaughlin Centre for Population Heath Risk Assessment & Risk Sciences International March 31, 2010

3. Toxicity Testing in the 21 st Century: A Vision and A Strategy Committee on Toxicity Testing and Assessment of Environmental Agents Board on Environmental Studies and Toxicology Institute for Laboratory Animal Research Division on Earth and Life Studies National Research Council

4. Interim and Final Reports www.nas.edu

5. Components of the Vision

6. Chemical Characterization

7. Toxicity Testing

8. McLaughlin Centre for Population Health Risk Assessment Progress since 2007: Regulatory Implications

9. Reaction from the Legal Community

10. Reaction from the Animal Law Community International Symposia on Challenges and Opportunities in Implementation June 29-30, 2009 September 12, 2009 November 5, 2009 June 21-23, 2010 “There is widespread support for the NAS vision. There are also real but surmountable challenges in moving the vision into routine regulatory practice. Progress is being made in producing the necessary science and knowledge base — we need to redouble our efforts to see that these insights carry over into the worlds of law and policy.” Paul Locke, Johns Hopkins University Center for Alternatives to Animal Testing

11. McLaughlin Centre for Population Health Risk Assessment Discussion Progress since 2007: Endorsement by Scientific Community

12. Endorsement by the Scientific Community Collins, F.S., Gray, G.M. & Bucher, J.R. (2008), Science (Policy Forum). Vol. 319. pp. 906 - 907

13. “We propose a shift from primarily in vivo animal studies to in vitro assays, in vivo assays with lower organisms, and computational modeling for toxicity assessments.” *Collins, F.S., Gray, G.M. & Bucher, J.R. (2008), Science (Policy Forum). Vol. 319. pp. 906 - 907 Making it Happen*

14. Further Scientific Debate Meek & Doull (2009) Bus & Becker, 2009 MacDonald & Robertson (2009) Hartung (2009) Hubal (2009) Chapin & Stedman (2009) Walker & Bucher (2009) Boekelheide & Campion (2010) Holsapple, Afshari & Lehman-McKeeman, Editors (2009) 8 +1 Invited Commentaries 2009-2010

15. Recurring Themes in the Commentaries Definition of adversity Predicting in vivo results from in vitro toxicity pathway assay results Setting standards from results of in vitro assays How can the change from current practices to a new paradigm occur?

16. One of the most frequent questions we have been asked is how the NRC vision will be validated. Validation cannot be done against animal test results obtained at high doses that we are seeking to replace; rather, validation can only be achieved through an in-depth understanding of toxicity pathways, identification of critical pathway perturbations, and the demonstration that in vitro tests are able to identify those perturbations, with high sensitivity and specificity. Thus, validation of the NRC vision will not be done against an existing ‘gold standard’, but rather through a detailed mechanistic understanding of toxicity pathways, as envisaged by Hartung. Andersen & Krewski, Toxicological Sciences (2010) Hartung’s Ten Challenges #4. What should a new test be validated against?

17. McLaughlin Centre for Population Health Risk Assessment Progress since 2007: Regulatory Implications Progress since 2007: Implications for Risk Assessment

18. Reaction from Experts in Risk Assessment “Suresh Moolgavkar, our Area Editor for Health Risk Assessment, asked six experts with different perspectives to comment on the paper. Each praises the vision and offers suggestions for making it more useful.” Michael Greenberg & Karen Lowrie, Editors

19. Toxicity Testing and Risk Assessment (from Krewski et al., 2010, Annual Review of Public Health, in press)

20. McLaughlin Centre for Population Health Risk Assessment Progress since 2007: Federal Agency Commitment

21. http://www.epa.gov/osa/spc/toxicitytesting/docs/toxtest_strategy_032309.pdf

22. “This strategic plan describes an ambitious and substantive change in the process by which chemicals are evaluated for toxicity. The NRC (2007) suggested that such a transformation would require up to $100 million per year in funding over a 10 - 20 year period to have a reasonable chance of reaching its goals.” Resources Needed to Implement EPA’s Strategic Plan* *U.S. Environmental Protection Agency (2009). Strategic Plan for the Future of Toxicity Testing at the U.S. Environmental Protection Agency. (www.epa.gov/osa/spc/toxicitytesting/)

23. Ongoing Federal Agency Initiatives U.S. EPA’s ToxCast Program: Forecast toxicity based on bioactivity profiling National Institute for Environmental Health Sciences: Development of high throughput in vitro screening assays National Chemical Genomics Centre: Robotics assisted in vitro tests for genomic change in human cells

24. McLaughlin Centre for Population Health Risk Assessment Progress since 2007: US National Research Council

25. Human and Environmental Exposure Science in the 21 st Century “An NRC committee will develop a long-range vision for exposure science.... It will include development of a unifying conceptual framework for advancement of exposure science to study and assess human and ecological contact with chemical, biological, and physical stressors in their environments. concern. The committee's report will be a potential companion document to previous NRC reports such as Toxicity Testing in the 21st Century.” http://www8.nationalacademies.org/cp/projectview.aspx?key=49180

26. McLaughlin Centre for Population Health Risk Assessment Progress since 2007: Animal Welfare

27. Long-term goal: eliminate use of animals in harmful research Promote 3 R’s: Replacement, Reduction, Refinement Animal Rights Perspective: Humane Society of the United States

28. Dual Motivation for Change Better Science Animal Welfare

29. McLaughlin Centre for Population Health Risk Assessment Progress since 2007: Reaction from the International Community

30. “This convergence of factors, coupled with the need to evaluate the safety of an increasingly large number of chemicals and their mixtures, has prompted some of the world’s leading scientific authorities to call for a fundamental paradigm shift in toxicology....” Future Directions in the European Union http://cordis.europa.eu/documents/documentlibrary/106691831EN6.pdf

31. Expert Panel on the Integrated Testing of Pesticides http://www.scienceadvice.ca/pesticides.html “Integrated testing, using in vitro data from diverse fields of study, represents an exciting means by which we can refine and reduce in vivo toxicity testing requirements. By this approach, it may be possible to avoid the need for full batteries of animal-based toxicity tests for each pesticide under assessment, while still maintaining defensibility of the assessments.”

32. McLaughlin Centre for Population Health Risk Assessment Progress since 2007: Implementing the Vision

33. McLaughlin Centre for Population Health Risk Assessment JTEH Special Issue: Future Directions in Toxicity Testing

34. McLaughlin Centre for Population Health Risk Assessment Future Directions in Toxicity Testing Part A: 2007 U.S. NRC Report Tox21-c

35. McLaughlin Centre for Population Health Risk Assessment Future Directions in Toxicity Testing Part B: U.S. EPA Strategic Plan Federal Government Leadership

36. McLaughlin Centre for Population Health Risk Assessment Toxicity Testing Tools and Technologies Future Directions in Toxicity Testing Part C: Individual Contributions

37. Building the Scientific Toolbox

38. McLaughlin Centre for Population Health Risk Assessment Computational Toxicology Future Directions in Toxicity Testing Part C: Individual Contributions

39. McLaughlin Centre for Population Health Risk Assessment Validation of Alternative Tests Future Directions in Toxicity Testing Part C: Individual Contributions

40. McLaughlin Centre for Population Health Risk Assessment Animal Welfare Future Directions in Toxicity Testing Part C: Individual Contributions

41. McLaughlin Centre for Population Health Risk Assessment Risk Assessment Implications Future Directions in Toxicity Testing Part C: Individual Contributions

42. McLaughlin Centre for Population Health Risk Assessment Regulatory Considerations Future Directions in Toxicity Testing Part C: Individual Contributions

43. McLaughlin Centre for Population Health Risk Assessment European Union Perspective (REACH) Future Directions in Toxicity Testing Part C: Individual Contributions

44. McLaughlin Centre for Population Health Risk Assessment Conclusion: Making the Vision a Reality

45. Next Steps Complete the science base on which the NRC vision rests Consideration of the implications of the vision for application of current and future regulatory statutes Re-orientation of risk assessment practice to focus on prevention of perturbation of toxicity pathways National/international coordination, and mid- course corrections over the next 5 – 10 years