Food for thought: Integrated testing strategies for safety assessments

Johns Hopkins University, Bloomberg School of Public Health, CAAT, Baltimore, USA.
ALTEX 01/2013; 30(1):3-18.
Source: PubMed


Despite the fact that toxicology uses many stand-alone tests, a systematic combination of several information sources very often is required: Examples include: when not all possible outcomes of interest (e.g., modes of action), classes of test substances (applicability domains), or severity classes of effect are covered in a single test; when the positive test result is rare (low prevalence leading to excessive falsepositive results); when the gold standard test is too costly or uses too many animals, creating a need for prioritization by screening. Similarly, tests are combined when the human predictivity of a single test is not satisfactory or when existing data and evidence from various tests will be integrated. Increasingly, kinetic information also will be integrated to make an in vivo extrapolation from in vitro data. Integrated Testing Strategies (ITS) offer the solution to these problems. ITS have been discussed for more than a decade, and some attempts have been made in test guidance for regulations. Despite their obvious potential for revamping regulatory toxicology, however, we still have little guidance on the composition, validation, and adaptation of ITS for different purposes. Similarly, Weight of Evidence and Evidence-based Toxicology approaches require different pieces of evidence and test data to be weighed and combined. ITS also represent the logical way of combining pathway-based tests, as suggested in Toxicology for the 21st Century. This paper describes the state of the art of ITS and makes suggestions as to the definition, systematic combination, and quality assurance of ITS.

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    • "On the basis of such new technologies, roadmaps have been defined on how to approach an evaluation of toxicological hazard and risk employing mainly animal-free methods (Basketter et al., 2012; Leist et al., 2014; Embry et al., 2014; Pastoor et al., 2014). Importantly, methods are increasingly combined in integrated testing strategies (ITS) or integrated approaches to testing and assessment (IATA) (Hartung et al., 2013; Rovida et al., 2015; Tollefsen et al., 2014). It will be important that these efforts are met with adaptations to the validation process (Hartung , 2007; Judson et al., 2013; Leist et al., 2012a). "
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    • "Indeed, it is generally believed that the safety of a compound cannot be based on a single in vitro assay. Therefore, scientists are working on the design of testing batteries and coupled strategies (Hartung et al. 2013). Over the last decade, imaging as a detection system for cell-based assays has emerged and offers a new way of evaluating a wide range of cell biological parameters. "
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    • "Simplified models, such as permeation in human skin explants (Davies et al., 2011), haptenation reaction (Mutschler et al., 2009) or cell culture based models (Corsini et al., 2009) taking into consideration only one parameter of the sensitization process, can hardly reproduce the complexity of in vivo mechanisms. Integrated testing strategies (ITS) combining multiple in vitro, in silico and even in chemico approaches (Hoffmann et al., 2008; Jaworska et al., 2011, 2013; Wanner et al., 2010) have been developed to approach the complexity of human physiology and generally provide reliable in vivo extrapolations from in vitro data (Hartung et al., 2013). However, the cost and technical requirements of highly sophisticated multicellular human skin models (Aeby et al., 2010), represents a major limitation for industrial use. "
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