A critical analysis of the rabbit eye irritation test variability and its impact on the validation of alternative methods.

Determining the validity of alternative methods as replacements for the rabbit eye irritation tests is a goal of the scientific, regulatory and political communities and is being evaluated in several studies. The results from the Draize rabbit eye test are used as a standard against which to compare the performance of the in vitro methods. However, the quantitative performance of the modern Draize eye test is unknown. This paper is a review of the findings of a previous study to estimate the historical variability and a comparison with more contemporary data in order to estimate the performance of the modern methods. The question of whether it is practical to obtain an accurate description of in vivo variability of the modern Draize test is considered by calculating the size of the interlaboratory study that would be required to determine whether variability had changed since 1971. The impact that in vivo variability has on the validation of alternative methods is then discussed. The authors conclude that validation studies have a greater chance of success if the alternative methods are soundly based on mechanisms of toxicity operating in vivo, the Draize data are well defined with regard to their variability, the goals of the study are realistic and the customers of the study are in broad agreement with the study design and the in vivo data used as the reference test set.