Abstract
This chapter explores the concepts, processes, tools and challenges relating to the validation of alternative methods for toxicity and safety testing. In general terms, validation is the process of assessing the appropriateness and usefulness of a tool for its intended purpose. Validation is routinely used in various contexts in science, technology, the manufacturing and services sectors. It serves to assess the fitness-for-purpose of devices, systems, software up to entire methodologies. In the area of toxicity testing, validation plays an indispensable role: “alternative approaches” are increasingly replacing animal models as predictive tools and it needs to be demonstrated that these novel methods are fit for purpose. Alternative approaches include in vitro test methods, non-testing approaches such as predictive computer models up to entire testing and assessment strategies composed of method suites, data sources and decision-aiding tools. Data generated with alternative approaches are ultimately used for decision-making on public health and the protection of the environment. It is therefore essential that the underlying methods and methodologies are thoroughly characterised, assessed and transparently documented through validation studies involving impartial actors. Importantly, validation serves as a filter to ensure that only test methods able to produce data that help to address legislative requirements (e.g. EU’s REACH legislation) are accepted as official testing tools and, owing to the globalisation of markets, recognised on international level (e.g. through inclusion in OECD test guidelines). Since validation creates a credible and transparent evidence base on test methods, it provides a quality stamp, supporting companies developing and marketing alternative methods and creating considerable business opportunities. Validation of alternative methods is conducted through scientific studies assessing two key hypotheses, reliability and relevance of the test method for a given purpose. Relevance encapsulates the scientific basis of the test method, its capacity to predict adverse effects in the “target system” (i.e. human health or the environment) as well as its applicability for the intended purpose. In this chapter we focus on the validation of non-animal in vitro alternative testing methods and review the concepts, challenges, processes and tools fundamental to the validation of in vitro methods intended for hazard testing of chemicals. We explore major challenges and peculiarities of validation in this area. Based on the notion that validation per se is a scientific endeavour that needs to adhere to key scientific principles, namely objectivity and appropriate choice of methodology, we examine basic aspects of study design and management, and provide illustrations of statistical approaches to describe predictive performance of validated test methods as well as their reliability.
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- 1.
Repeatability has been defined as “the agreement of test results obtained within a single laboratory when the procedure is performed on the same substance and under identical conditions” (OECD 2005) i.e. the same operator and equipment.
Reproducibility has been defined as “the agreement of test results obtained from testing the same substance using the same protocol” (OECD 2005), but not necessarily under identical conditions (i.e. different operators and equipment).
- 2.
Such strategic combinations have been proposed in the context of “Integrated Testing Strategies” that were proposed during the implementation of the REACH legislation in the EU (2006–2007) and consisted of steps of data gathering, evaluations and empirical (strategic) testing using several data sources. Later the concept of ITS has been further promoted under the term “Integrated Approaches to Assessment and Testing (IATA) by the OECD (OECD 2008).
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Griesinger, C., Desprez, B., Coecke, S., Casey, W., Zuang, V. (2016). Validation of Alternative In Vitro Methods to Animal Testing: Concepts, Challenges, Processes and Tools. In: Eskes, C., Whelan, M. (eds) Validation of Alternative Methods for Toxicity Testing. Advances in Experimental Medicine and Biology, vol 856. Springer, Cham. https://doi.org/10.1007/978-3-319-33826-2_4
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