Validation: A highly charged concept

In order that a proposal for an alternative to an animal test be developed as an internationally accepted guideline, there needs to be consensus on the validity of the method proposed. Over the years, considerable attempts have been made to 'validate' promising alternatives. Probably without exception, these validation programmes demanded considerable budgets whereas the high expectations as to the output, which would justify the costs involved, were hardly ever met. What went wrong? Obviously, as for each new animal test, each new alternative to an animal test should be subjected to a critical appraisal procedure involving its scientific justification, its sensitivity and its reproducibility, before it could be internationally acceptable. Although there may be differences of opinion on the extent of this exercise, there is considerable agreement that validation in one way or another is essential. None the less, validation programmes so far have not resulted in the broad acceptance of any alternative test method. There may be two reasons for this failure. First, the results of the validation studies may have been unsatisfactory, which could mean that either the method subjected to validation failed to show the desired relevance and reliability, or the validation study as such yielded inconclusive results. Secondly, despite clear-cut (supporting) results from the validation exercise, toxicologists/regulators appear reluctant actually to use the data provided for hazard and risk assessment procedures because of a lack of confidence with the (types of) endpoints of the new test. The latter in particular can be considered a major hurdle in the process of acceptance of alternative tests. Therefore, an independent and objective review of any new test, with a view to its usefulness as a contribution to the set of data essential for hazard characterization and risk assessment, should be considered the first step of any comprehensive validation project. Further, the establishment of international centres such as the Johns Hopkins Center for Alternatives to Animal Testing (CAAT) and the European Centre for the Validation of Alternative Methods (ECVAM) where scientists, including regulators, can meet and discuss strategies not only for validation but also for the use of alternative methods in risk assessment, is considered essential for a good understanding of the relevance of the new in vitro, toxicity tests.