## Perspectives on In Vitro to In Vivo Extrapolations

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2018
Journal article
Published
##### Published in
Applied In Vitro Toxicology ; 4 (2018), 4. - pp. 305-316. - ISSN 2332-1512. - eISSN 2332-1539
##### Abstract
Quantitative in vitro to in vivo extrapolation (QIVIVE) is broadly considered a prerequisite bridge from in vitro findings to a dose paradigm. Quality and relevance of cell systems are the first prerequisite for QIVIVE. Information-rich and mechanistic endpoints (biomarkers) improve extrapolations, but a sophisticated endpoint does not make a bad cell model a good one. The next need is reverse toxicokinetics (TK), which estimates the dose necessary to reach a tissue concentration that is active in vitro. The Johns Hopkins Center for Alternatives to Animal Testing (CAAT) has created a roadmap for animal-free systemic toxicity testing, in which the needs and opportunities for TK are elaborated, in the context of different systemic toxicities. The report was discussed at two stakeholder forums in Brussels in 2012 and in Washington in 2013; the key recommendations are summarized herein. Contrary to common belief and the Paracelsus paradigm of everything is toxic, the majority of industrial chemicals do not exhibit toxicity. Strengthening the credibility of negative results of alternative approaches for hazard identification, therefore, avoids the need for QIVIVE. Here, especially the combination of methods in integrated testing strategies is most promising. Two further but very different approaches aim to overcome the problem of modeling in vivo complexity: The human-on-a-chip movement aims to reproduce large parts of living organism's complexity via microphysiological systems, that is, organ equivalents combined by microfluidics. At the same time, the Toxicity Testing in the 21st Century (Tox-21c) movement aims for mechanistic approaches (adverse outcome pathways as promoted by Organisation for Economic Co-operation and Development (OECD) or pathways of toxicity in the Human Toxome Project) for high-throughput screening, biological phenotyping, and ultimately a systems toxicology approach through integration with computer modeling. These 21st century approaches also require 21st century validation, for example, by evidence-based toxicology. Ultimately, QIVIVE is a prerequisite for extrapolating Tox-21c such approaches to human risk assessment.
##### Subject (DDC)
570 Biosciences, Biology
##### Keywords
alternative methods, extrapolation, new approaches, validation
##### Cite This
ISO 690HARTUNG, Thomas, 2018. Perspectives on In Vitro to In Vivo Extrapolations. In: Applied In Vitro Toxicology. 4(4), pp. 305-316. ISSN 2332-1512. eISSN 2332-1539. Available under: doi: 10.1089/aivt.2016.0026
BibTex
@article{Hartung2018-12Persp-45295,
year={2018},
doi={10.1089/aivt.2016.0026},
title={Perspectives on In Vitro to In Vivo Extrapolations},
number={4},
volume={4},
issn={2332-1512},
journal={Applied In Vitro Toxicology},
pages={305--316},
author={Hartung, Thomas}
}

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<dcterms:abstract xml:lang="eng">Quantitative in vitro to in vivo extrapolation (QIVIVE) is broadly considered a prerequisite bridge from in vitro findings to a dose paradigm. Quality and relevance of cell systems are the first prerequisite for QIVIVE. Information-rich and mechanistic endpoints (biomarkers) improve extrapolations, but a sophisticated endpoint does not make a bad cell model a good one. The next need is reverse toxicokinetics (TK), which estimates the dose necessary to reach a tissue concentration that is active in vitro. The Johns Hopkins Center for Alternatives to Animal Testing (CAAT) has created a roadmap for animal-free systemic toxicity testing, in which the needs and opportunities for TK are elaborated, in the context of different systemic toxicities. The report was discussed at two stakeholder forums in Brussels in 2012 and in Washington in 2013; the key recommendations are summarized herein. Contrary to common belief and the Paracelsus paradigm of everything is toxic, the majority of industrial chemicals do not exhibit toxicity. Strengthening the credibility of negative results of alternative approaches for hazard identification, therefore, avoids the need for QIVIVE. Here, especially the combination of methods in integrated testing strategies is most promising. Two further but very different approaches aim to overcome the problem of modeling in vivo complexity: The human-on-a-chip movement aims to reproduce large parts of living organism's complexity via microphysiological systems, that is, organ equivalents combined by microfluidics. At the same time, the Toxicity Testing in the 21st Century (Tox-21c) movement aims for mechanistic approaches (adverse outcome pathways as promoted by Organisation for Economic Co-operation and Development (OECD) or pathways of toxicity in the Human Toxome Project) for high-throughput screening, biological phenotyping, and ultimately a systems toxicology approach through integration with computer modeling. These 21st century approaches also require 21st century validation, for example, by evidence-based toxicology. Ultimately, QIVIVE is a prerequisite for extrapolating Tox-21c such approaches to human risk assessment.</dcterms:abstract>
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