Transcript Krewski`s Presentation June 2010 - Chemical Toxicity Testing: The

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 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
Progress since 2007:
Regulatory Implications
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:
Discussion by
Endorsement
Scientific Community
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
Making it Happen*
“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)
Progress since 2007:
Implications
for Risk
Assessment
Regulatory
Implications
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:
Federal Agency Commitment
McLaughlin Centre for Population Health Risk Assessment
Federal Agency Commitment
http://www.epa.gov/osa/spc/toxicitytesting/docs/toxtest_strategy_032309.pdf
Resources Needed to
Implement EPA’s Strategic Plan*
“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:
US National Research Council
McLaughlin Centre for Population Health Risk Assessment
Human and Environmental Exposure Science
in 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
Progress since 2007:
Animal Welfare
McLaughlin Centre for Population Health Risk Assessment
Animal Rights Perspective:
Humane Society of the United States
• Long-term goal:
eliminate use of animals
in harmful research
• Promote 3 R’s:
Replacement, Reduction,
Refinement
Dual Motivation for Change
Better Science
Animal Welfare
Progress since 2007:
Reaction from the
International Community
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:
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 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:
Making the Vision a Reality
McLaughlin Centre for Population Health Risk Assessment
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 midcourse corrections over the next 5 – 10 years