title: Comparing and evaluating alternative (in vitro) tests on their ability to predict the Draize maximum average score.
abstract: The Cosmetic, Toiletry, and Fragrance Association (CTFA) Evaluation of Alternatives Program comprised a multi-phased study of the relationship between Draize eye irritation test data and comparable data from a selection of promising alternative (in vitro) tests. The CTFA Program was designed to determine the effectiveness and limitations of several in vitro tests over a range of different cosmetic and personal-care product types. Test materials constituted experimental formulations representative of three distinct product types. Each material was tested in vivo (according to a modified Draize eye irritation test protocol) and in vitro (according to one of up to forty different protocols). A statistical ranking and selection procedure ("concordance analysis") was used to identify those in vitro tests where the relationships between in vitro and in vivo score was sufficiently well defined to warrant further statistical analysis. In vitro test performance was then evaluated by regression modelling of these relationships. Maximum average Draize score (MAS) was utilized as the primary quantitative measure of eye irritation potential in vivo. The goodness-of-fit of the observed data to the regression model and comparison of the magnitude of upper and lower prediction-bounds on the range of probable MAS values associated with the regression model fit (prediction intervals) provide a means by which the performance of each in vitro test may be measured relative to Draize test outcome. The narrower the prediction interval (i.e. the more precise the fit), the more predictive of in vivo score (MAS) is the in vitro test result. The prediction interval thus represents uncertainty associated with Draize test prediction. Such uncertainty depends heavily on the degree of irritancy. In Phases I and II, the widths of the prediction intervals were narrowest in the region corresponding to low irritation potential; increasing widths were observed as irritation potential increased. In Phase III, relatively narrow prediction interval widths were observed at both the low and high end of the observed range of irritation potential; wider intervals were observed in the middle of the observed range. In general, the selected endpoints in each phase had similar average prediction interval widths and thereby differed only slightly in their ability to predict MAS to a given level of precision; any differences between endpoints tended to occur at the low and/or high ends of the observed range of irritation potential. The primary contributor to total variability associated with prediction of MAS is the deviation between the Draize score as observed in the laboratory and what is predicted by the model for a given formulation. Consistently, this component is responsible for 70% to 95% of the total variability. The other components (i.e. variability among replicate MAS and in vitro scores) could be reduced simply by increasing the number of replicate tests performed on each test formulation. However, this would have relatively little impact on the overall precision of prediction.
authors.affiliation: Battelle, Columbus, OH, 43201, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Lordo
authors.forename: P I
authors.initials: PI
authors.lastname: Feder
authors.forename: S D
authors.initials: SD
authors.lastname: Gettings