Chapter 4: Validation of Alternative In Vitro Methods to Animal Testing: Concepts, Challenges, Processes and Tools

摘要

This chapter explores the concepts, processes, tools and challenges relatingto the validation of alternative methods for toxicity and safety testing. In generalterms, validation is the process of assessing the appropriateness and usefulness of atool for its intended purpose. Validation is routinely used in various contexts in science,technology, the manufacturing and services sectors. It serves to assess thefitness- for-purpose of devices, systems, software up to entire methodologies. In thearea of toxicity testing, validation plays an indispensable role: “alternative approaches”are increasingly replacing animal models as predictive tools and it needs to be demonstratedthat these novel methods are fit for purpose. Alternative approaches includein vitro test methods, non-testing approaches such as predictive computer models upto entire testing and assessment strategies composed of method suites, data sourcesand decision-aiding tools. Data generated with alternative approaches are ultimatelyused for decision-making on public health and the protection of the environment. It istherefore essential that the underlying methods and methodologies are thoroughlycharacterised, assessed and transparently documented through validation studiesinvolving impartial actors. Importantly, validation serves as a filter to ensure that onlytest 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 globalisationof markets, recognised on international level (e.g. through inclusion inOECD test guidelines). Since validation creates a credible and transparent evidencebase on test methods, it provides a quality stamp, supporting companies developingand marketing alternative methods and creating considerable business opportunities.Validation of alternative methods is conducted through scientific studies assessing twokey hypotheses, reliability and relevance of the test method for a given purpose.Relevance encapsulates the scientific basis of the test method, its capacity to predictadverse effects in the “target system” (i.e. human health or the environment) as wellas its applicability for the intended purpose. In this chapter we focus on the validationof non-animal in vitro alternative testing methods and review the concepts, challenges,processes and tools fundamental to the validation of in vitro methods intended forhazard testing of chemicals. We explore major challenges and peculiarities of validationin this area. Based on the notion that validation per se is a scientific endeavour thatneeds to adhere to key scientific principles, namely objectivity and appropriate choiceof methodology, we examine basic aspects of study design and management, andprovide illustrations of statistical approaches to describe predictive performance ofvalidated test methods as well as their reliability.