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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Available from: Thomas Hartung, Oct 09, 2015
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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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    ABSTRACT: High-content screening is the application of automated microscopy and image analysis to both cell biology and drug discovery. Over the last decade, this technique has emerged as a useful technology that allows the simultaneous measurement of different parameters at a single-cell level. Hepatotoxicity is a compelling reason for drug nonapprovals and withdrawals. It is recognized that the safety of a compound cannot be based on a single in vitro assay, and existing methods are not predictive of drug-induced toxicity. However, different HCS assays have been recently demonstrated as being powerful for identifying different mechanisms implicated in drug-induced toxicity with high sensitivity and specificity. These assays integrate the data obtained from different cell function indicators and can be easily incorporated into basic screening processes for the safety evaluation and selection of drug candidates; thus, they contribute greatly to lessen the likelihood of drug failure. Exploring the use of cellular imaging technology in drug-induced liver injury by reviewing the different tests proposed provides evidence that this technology has a strong impact on drug discovery.
    Archives of Toxicology 03/2015; 89(7). DOI:10.1007/s00204-015-1503-z · 5.98 Impact Factor
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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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    ABSTRACT: Most animal experiments on cosmetics safety are prohibited and since March 2013, this obligation includes sensitization tests. However, until now there has been no validated alternative in vitro method. In this work, 400 compounds used in the cosmetic industry were selected to cover the greatest diversity of structures, biological activities and sensitizing potential. These molecules were submitted to a series of tests aimed at reproducing essential steps in sensitization and to distinguish between sensitization and irritations, i.e., transcutaneous permeation (factor A), haptenation (factor B), sensitization cytokines production (factor C) and acute toxicity (factor D). The transcutaneous diffusion was measured on human skin explants using Franz cells. Haptenation was tested in solution on human serum albumin. Sensitization cytokine production was investigated by measurement of interleukin-18 release by keratinocytes. Acute toxicity was determined using an 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(75) cell viability test. As only sufficiently stable, soluble and detectable compounds are usable, 33, 72, 68 and 68 molecules were finally tested on factors A, B, C and D, respectively, and 32 were completely screened by the four factors. The individual correlation of the four factors with the reference in vivo tests was limited but the combination of these factors led to a correlation between in vivo and in vitro assays of 81.2% and the safety of the test (risk of false negative) reached 96.8%. The techniques employed are simple and inexpensive and this model of four tests appears as a promising technique to evaluate in vitro the skin sensitization potential of unknown molecules. Copyright © 2014 John Wiley & Sons, Ltd.
    Journal of Applied Toxicology 01/2015; 35(1). DOI:10.1002/jat.2986 · 2.98 Impact Factor
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    • "The ways forward are integrated testing strategies (ITSs). A scientifically accepted definition of ITS still does not exist (Hartung et al., 2013). However, any ITS aims to optimize the testing of chemicals with regard to costs (money, time, animal welfare, etc.) in relation to the information gain to come to a robust conclusion about a particular hazard of a chemical. "
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    ABSTRACT: To satisfy REACH requirements a high number of data on chemical of interest should be supplied to the European Chemicals Agency. To organize the various kinds of information and help the registrants to choose the best strategy to obtain the needed information limiting at the minimum the use of animal testing, integrated testing strategies (ITSs) schemes can be used. The present work deals with regulatory data requirements for assessing the hazards of chemicals to the aquatic pelagic environment. We present an ITS scheme for organizing and using the complex existing data available for aquatic toxicity assessment. An ITS to optimize the choice of the correct prediction strategy for aquatic pelagic toxicity is described. All existing information (like physico-chemical information), and all the alternative methods (like in silico, in vitro or the acute-to-chronic ratio) are considered. Moreover the weight of evidence approach to combine the available data is included.
    Environmental Research 09/2014; 135C:156-164. DOI:10.1016/j.envres.2014.09.002 · 4.37 Impact Factor
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