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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.

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Overview of the nrc vision for the future of toxicity testing

Overview of the NRC Visionfor 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
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






Progress since 2007:

Regulatory Implications



Reaction from the Animal Law Community

International Symposia onChallenges and Opportunities in Implementation

September 12, 2009

June 21-23, 2010

June 29-30, 2009

November 5, 2009

“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:

Endorsement by

Scientific Community

Discussion


Collins, F.S., Gray, G.M. & Bucher, J.R. (2008),

Science (Policy Forum). Vol. 319. pp. 906 - 907

Endorsement by the Scientific Community


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)

Hubal (2009)

Chapin & Stedman (2009)

Walker & Bucher (2009)

Boekelheide & Campion (2010)

Meek & Doull (2009)

Bus & Becker, 2009

MacDonald & Robertson (2009)

Hartung (2009)


Recurring themes in the commentaries
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

Progress since 2007:

Regulatory Implications


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


Federal agency commitment
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
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


Human and environmental exposure science in the 21 st century
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


Progress since 2007:

Animal Welfare


Animal rights perspective humane society of the united states
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
Dual Motivation for Change

Better Science

Animal Welfare


Progress since 2007:

Reaction from the

International Community


Future directions in the european union
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


Jteh special issue future directions in toxicity testing
JTEH Special Issue:Future Directions in Toxicity Testing


Future directions in toxicity testing part a 2007 u s nrc report
Future Directions in Toxicity TestingPart A: 2007 U.S. NRC Report

Tox21-c


Future directions in toxicity testing part b u s epa strategic plan
Future Directions in Toxicity TestingPart B: U.S. EPA Strategic Plan

Federal Government Leadership


Future directions in toxicity testing part c individual contributions
Future Directions in Toxicity TestingPart C: Individual Contributions

Toxicity Testing Tools and Technologies


Building the Scientific Toolbox


Future directions in toxicity testing part c individual contributions1
Future Directions in Toxicity TestingPart C: Individual Contributions

Computational Toxicology


Future directions in toxicity testing part c individual contributions2
Future Directions in Toxicity TestingPart C: Individual Contributions

Validation of Alternative Tests


Future directions in toxicity testing part c individual contributions3
Future Directions in Toxicity TestingPart C: Individual Contributions

Animal Welfare


Future directions in toxicity testing part c individual contributions4
Future Directions in Toxicity TestingPart C: Individual Contributions

Risk Assessment Implications


Future directions in toxicity testing part c individual contributions5
Future Directions in Toxicity TestingPart C: Individual Contributions

Regulatory Considerations


Future directions in toxicity testing part c individual contributions6
Future Directions in Toxicity TestingPart C: Individual Contributions

European Union Perspective (REACH)


Conclusion:

Making the Vision a Reality


Next steps
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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