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

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

www.nas.edu
Interim and Final Reports

Components of the Vision

Chemical Characterization

Toxicity Testing

Progress since 2007:
McLaughlin Centre for Population Health Risk Assessment

Reaction from the Legal Community

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

Progress since 2007:
McLaughlin Centre for Population Health Risk Assessment

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

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

Hartung’s Ten Challenges
#4. What should a new test be validated against?
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)

McLaughlin Centre for Population Health 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)

Progress since 2007:
McLaughlin Centre for Population Health Risk Assessment

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.”
*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

Progress since 2007:
McLaughlin Centre for Population Health Risk Assessment

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

Progress since 2007:
McLaughlin Centre for Population Health Risk Assessment

•
Long-term goal: eliminate use of animals in harmful research
• Promote 3 R’s:
Replacement, Reduction,
Refinement

Better Science Animal Welfare

Progress since 2007:
McLaughlin Centre for Population Health Risk Assessment

Future Directions in the European Union
“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 . . . .” http://cordis.europa.eu/documents/documentlibrary/106691831EN6.pdf

Expert Panel on the
Integrated Testing of Pesticides
“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.” http://www.scienceadvice.ca/pesticides.html

Progress since 2007:
McLaughlin Centre for Population Health Risk Assessment

JTEH Special Issue:
McLaughlin Centre for Population Health Risk Assessment

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

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

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

Building the Scientific Toolbox

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

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

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

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

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

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

Conclusion:
McLaughlin Centre for Population Health Risk Assessment

• 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 midcourse corrections over the next 5 – 10 years