overview of the nrc vision for the future of toxicity testing
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Overview of the NRC Visionfor the
Future of Toxicity TestingDaniel Krewski, PhD, MHA
Professor and DirectorMcLaughlin Centre for
Population Heath Risk Assessment&
Risk Sciences International
March 31, 2010
Toxicity Testing in the 21st 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
Interim and Final Reports
www.nas.edu
Components of the Vision
Chemical Characterization
Toxicity Testing
McLaughlin Centre for Population Health Risk Assessment
Progress since 2007:Regulatory Implications
Reaction from the Legal Community
Reaction from the Animal Law Community
International Symposia onChallenges 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 UniversityCenter for Alternatives to Animal Testing
McLaughlin Centre for Population Health Risk Assessment
DiscussionProgress since 2007:
Endorsement by Scientific Community
Endorsement by the Scientific Community
Collins, F.S., Gray, G.M. & Bucher, J.R. (2008), Science (Policy Forum). Vol. 319. pp. 906 - 907
“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*
Further Scientific Debate
Meek & Doull (2009)Bus & Becker, 2009MacDonald & 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
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?
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?
McLaughlin Centre for Population Health Risk Assessment
Progress since 2007:Regulatory ImplicationsProgress since 2007:
Implications for Risk Assessment
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
Toxicity Testing and Risk Assessment(from Krewski et al., 2010, Annual Review of Public Health, in press)
McLaughlin Centre for Population Health Risk Assessment
Progress since 2007:Federal Agency Commitment
Federal Agency Commitment
http://www.epa.gov/osa/spc/toxicitytesting/docs/toxtest_strategy_032309.pdf
“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 toImplement 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/)
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
McLaughlin Centre for Population Health Risk Assessment
Progress since 2007:US National Research Council
Human and Environmental Exposure Sciencein the 21st 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
McLaughlin Centre for Population Health Risk Assessment
Progress since 2007:Animal Welfare
• 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
Dual Motivation for Change
Better Science
Animal Welfare
McLaughlin Centre for Population Health Risk Assessment
Progress since 2007: Reaction from the
International Community
“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
Expert Panel on theIntegrated 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.”
McLaughlin Centre for Population Health Risk Assessment
Progress since 2007: Implementing the Vision
McLaughlin Centre for Population Health Risk Assessment
JTEH Special Issue:
Future Directions in
Toxicity Testing
McLaughlin Centre for Population Health Risk Assessment
Future Directions in Toxicity TestingPart A: 2007 U.S. NRC Report
Tox21-c
McLaughlin Centre for Population Health Risk Assessment
Future Directions in Toxicity TestingPart B: U.S. EPA Strategic Plan
Federal Government Leadership
McLaughlin Centre for Population Health Risk Assessment
Toxicity Testing Tools and Technologies
Future Directions in Toxicity TestingPart C: Individual Contributions
Building the Scientific Toolbox
McLaughlin Centre for Population Health Risk Assessment
Computational Toxicology
Future Directions in Toxicity TestingPart C: Individual Contributions
McLaughlin Centre for Population Health Risk Assessment
Validation of Alternative Tests
Future Directions in Toxicity TestingPart C: Individual Contributions
McLaughlin Centre for Population Health Risk Assessment
Animal Welfare
Future Directions in Toxicity TestingPart C: Individual Contributions
McLaughlin Centre for Population Health Risk Assessment
Risk Assessment Implications
Future Directions in Toxicity TestingPart C: Individual Contributions
McLaughlin Centre for Population Health Risk Assessment
Regulatory Considerations
Future Directions in Toxicity TestingPart C: Individual Contributions
McLaughlin Centre for Population Health Risk Assessment
European Union Perspective (REACH)
Future Directions in Toxicity TestingPart C: Individual Contributions
McLaughlin Centre for Population Health Risk Assessment
Conclusion:Making the Vision a Reality
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
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