Integrated testing strategies (ITS) for safety assessment

Abstract

SummaryIntegrated testing strategies (ITS), as opposed to a single definitive test or fixed batteries of tests, are expected to efficiently combine different information sources in a quantifiable fashion to satisfy an information need, in this case for regulatory safety assessments. With increasing awareness of the limitations of each individual tool and the development of highly targeted tests and predictions, the need for combining pieces of evidence increases. The discussions that took place during this workshop, which brought together a group of experts coming from different related areas, illustrate the current state of the art of ITS, as well as promising developments and identifiable challenges. The case of skin sensitization was taken as an example to understand how possible ITS can be constructed, optimized and validated. This will require embracing and developing new concepts such as adverse outcome pathways (AOP), advanced statistical learning algorithms and machine learning, mechanistic validation and "Good ITS Practices".Keywords: in vitro methods, testing strategy, Tox21c, skin sensitization, computational toxicology this is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/ licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is appropriately cited. *A report of t 4 -the transatlantic think tank for toxicology, a collaboration of the toxicologically oriented chairs in Baltimore, Konstanz and Utrecht sponsored by the Doerenkamp-Zbinden Foundation; participants do not represent their institutions and do not necessarily endorse all recommendations made.

An economic approach to non-animal toxicity testing for skin sensitisation

“…During the past decade, a lot of attention has been dedicated to developing non-animal testing methods and testing strategies for the toxicological endpoint skin sensitisation (Jaworska and Hoffmann, 2010;Jaworska et al, 2011;Hartung et al, 2013;Rovida et al, 2015;Jaworska, 2016). Skin sensitisation is the toxicological endpoint assessing a substance's ability to cause allergic contact dermatitis (ACD) (UNECE, 2011).…”

“…Since non-animal testing methods are not considered suitable to provide sufficient information to draw conclusions upon the skin sensitisation potential of chemicals (Mehling et al, 2012;Reisinger et al, 2015), a solution suggested is to integrate information from different sources and testing methods by using hypothesis-based approaches such as Bayesian networks (Jaworska and Hoffmann, 2010;Jaworska et al, 2011;Hartung et al, 2013;Jaworska et al, 2013;Jaworska, 2016) or deterministic ITS approaches (Bauch et al, 2012;Urbisch et al, 2015a). For the development of integrated strategies assessing skin sensitisation potential and potency (Jaworska, 2016) different sets of criteria have been proposed including transparency, coherency, ambiguity, or cost effectiveness (Hartung et al, 2013;Rovida et al, 2015) which are applicable also for other toxicological endpoints . It has also been suggested that the combination of individual non-animal testing methods into batteries or sequential strategies should be guided by the skin sensitisation AOP (Vinken, 2013;Patlewicz et al, 2014).…”

“…For skin sensitisation potential and potency assessment criteria for developing nonanimal testing strategies have been suggested in the literature (Jaworska and Hoffmann, 2010;Jaworska et al, 2011;Hartung et al, 2013;Rovida et al, 2015;Jaworska, 2016).…”

“…balancing information gains against costs (Gabbert and Weikard 2013;Norlén et al, 2014;Hartung et al, 2013;Rovida et al, 2015), has been repeatedly emphasised. Still, an approach to optimising non-animal testing strategies and a comprehensive evaluation of their efficiency in relation to animal tests have not become available so far.…”

“…Whereas early studies addressing the development of testing strategies took the form of qualitative decision flow charts, there has been a scientific discussion on suitable criteria and principles for the development of testing strategies. Specific attention has been given to developing testing strategies using non-animal testing methods (Hartung et al, 2013;Rovida et al, 2015). In June 2016, the OECD published two reports (OECD, 2016b;OECD, 2016c) in which concepts related to testing strategies and risk assessment of chemicals were presented (see Table 2.1 in Chapter 2 of this thesis).…”