Overview of the NRC Vision for the Future of Toxicity Testing

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


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?


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)


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


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


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


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.”


Progress since 2007: Implementing the Vision


JTEH Special Issue:

Future Directions in

Toxicity Testing


Future Directions in Toxicity TestingPart A: 2007 U.S. NRC Report

Tox21-c


Future Directions in Toxicity TestingPart B: U.S. EPA Strategic Plan

Federal Government Leadership


Toxicity Testing Tools and Technologies

Future Directions in Toxicity TestingPart C: Individual Contributions

Building the Scientific Toolbox


Computational Toxicology



Validation of Alternative Tests



Animal Welfare



Risk Assessment Implications



Regulatory Considerations



European Union Perspective (REACH)



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

Documents

Overview of the NRC Vision for the Future of Toxicity Testing