Food for Thought … Mechanistic Validation
Open accessAbstract
Validation of new approaches in regulatory toxicology is commonly defined as the independent assessment of the reproducibility and relevance (the scientific basis and predictive capacity) of a test for a particular purpose. In large ring trials, the emphasis to date has been mainly on reproducibility and predictive capacity (comparison to the traditional test) with less attention given to the scientific or mechanistic basis. Assessing predictive capacity is difficult for novel approaches (which are based on mechanism), such as pathways of toxicity or the complex networks within the organism (systems toxicology). This is highly relevant for implementing Toxicology for the 21st Century, either by high-throughput testing in the ToxCast/Tox21 project or omics-based testing in the Human Toxome Project. This article explores the mostly neglected assessment of a test's scientific basis, which moves mechanism and causality to the foreground when validating/qualifying tests. Such mechanistic validation faces the problem of establishing causality in complex systems. However, pragmatic adaptations of the Bradford Hill criteria, as well as bioinformatic tools, are emerging. As critical infrastructures of the organism are perturbed by a toxic mechanism we argue that by focusing on the target of toxicity and its vulnerability, in addition to the way it is perturbed, we can anchor the identification of the mechanism and its verification.
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Alternative validation approaches include mechanistic validation.
“Alternative validation approaches (using processes and principles different from GD34) include mechanistic validation (Hartung et al., 2013).”
From Recommendations on fit-for-purpose criteria to establish quality management for microphysiological systems and for monitoring their reproducibility (2024) · cites this paper as Hartung et al., 2013
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A call for a Human Exposome Project
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Utility of the adverse outcome pathway concept in drug development
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The need for strategic development of safety sciences
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- Authors
- Hartung, T.
- Venue
- ALTEX
- Publisher
- ALTEX Edition
- Published
- 2013
- Volume
- 30
- Issue
- 2
- Pages
- 119-130
- ISSN
- 0946-7785 (ISSN-L)
- 1868-596X
- PMC
- PMC4086802
- OpenAlex
- W2319709284
- Cited by
- 93
- References
- 70
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 11 · 2023: 6 · 2022: 5 · 2021: 2 · 2020: 4 · 2019: 5 · 2018: 6 · 2017: 6 · 2016: 13 · 2015: 7 · 2014: 15 · 2013: 3
- FWCI
- 17.83
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- ALTEX (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- KOPS (University of Konstanz) (submittedVersion, cc-by)
- WBI Studies Repository (submittedVersion)
- Funders
- National Institutes of Health (U18TR000547, RO1ES020750)
- U.S. Food and Drug Administration (U01 FD004230)
- National Institute of Environmental Health Sciences (R01ES020750)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Life Sciences › Agricultural and Biological Sciences › Food Science › Agricultural safety and regulations
- Keywords
- regulatory toxicology, Bradford Hill criteria, systems toxicology, ToxCast, Tox21, high-throughput testing
- MeSH terms
- Algorithms, Animals, Animal Testing Alternatives, Computer Simulation, Gene Expression Regulation, Homeostasis, Humans, Predictive Value of Tests, Risk Factors, Reproducibility of Results, Computational Biology, Animal Experimentation
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