Toxicity testing in the 21st century: a vision and a strategy.
With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.
Krewski
Daniel
D
R Samuel McLaughlin Centre for Population Health Risk Assessment, Institute of Population Health, University of Ottawa, Ottawa, Ontario, Canada. dkrewski@uottawa.ca
Acosta
Daniel
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Andersen
Melvin
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Anderson
Henry
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Bailar
John C
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Boekelheide
Kim
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Brent
Robert
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Charnley
Gail
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Cheung
Vivian G
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Green
Sidney
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Kelsey
Karl T
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Kerkvliet
Nancy I
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Li
Abby A
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McCray
Lawrence
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Meyer
Otto
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Patterson
Reid D
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Pennie
William
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Scala
Robert A
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Solomon
Gina M
GM
Stephens
Martin
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Yager
James
J
Zeise
Lauren
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D000818:Animals; D004785:Environmental Pollutants / Q000032:analysis / Q000633:toxicity*; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D009307:National Academy of Sciences, U.S.; D018570:Risk Assessment / Q000379:methods; D018675:Toxicity Tests / Q000266:history / Q000379:methods* / Q000639:trends*; D014481:United States; D014484:United States Environmental Protection Agency
D004785:Environmental Pollutants