Lordo R A, Feder P I, Gettings S D
Battelle, Columbus, OH, 43201, USA.
Toxicol In Vitro. 1999 Feb;13(1):45-72. doi: 10.1016/s0887-2333(98)00062-9.
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.
化妆品、盥洗用品和香料协会（CTFA）替代方法评估项目包括一项多阶段研究，该研究探讨了德雷兹眼刺激试验数据与一系列有前景的替代（体外）试验的可比数据之间的关系。CTFA项目旨在确定几种体外试验在一系列不同化妆品和个人护理产品类型中的有效性和局限性。试验材料由代表三种不同产品类型的实验配方组成。每种材料都进行了体内试验（根据改良的德雷兹眼刺激试验方案）和体外试验（根据多达40种不同方案中的一种）。使用一种统计排名和选择程序（“一致性分析”）来识别那些体外试验，在这些试验中，体外和体内评分之间的关系定义得足够明确，值得进行进一步的统计分析。然后通过对这些关系进行回归建模来评估体外试验性能。最大平均德雷兹评分（MAS）被用作体内眼刺激潜力的主要定量指标。观察到的数据与回归模型的拟合优度以及与回归模型拟合相关的可能MAS值范围内的上下预测界限大小的比较（预测区间）提供了一种手段，通过该手段可以相对于德雷兹试验结果来衡量每个体外试验的性能。预测区间越窄（即拟合越精确），体外试验结果对体内评分（MAS）的预测性就越强。因此，预测区间代表了与德雷兹试验预测相关的不确定性。这种不确定性在很大程度上取决于刺激程度。在第一阶段和第二阶段，预测区间的宽度在对应于低刺激潜力的区域最窄；随着刺激潜力的增加，观察到宽度增加。在第三阶段，在观察到的刺激潜力范围的低端和高端都观察到相对较窄的预测区间宽度；在观察到的范围中间观察到较宽的区间。一般来说，每个阶段选择的终点具有相似的平均预测区间宽度，因此在以给定精度预测MAS的能力上仅略有不同；终点之间的任何差异往往发生在观察到的刺激潜力范围的低端和/或高端。与MAS预测相关的总变异性的主要贡献因素是实验室观察到的德雷兹评分与给定配方模型预测值之间的偏差。一致地，该成分占总变异性的70%至95%。其他成分（即重复MAS和体外评分之间的变异性）可以通过增加对每个试验配方进行的重复试验次数来简单地降低。然而，这对预测的整体精度影响相对较小。
