Abstract
The development of non-animal skin sensitization test methods and strategies is quickly progressing. Either individually or in combination, the predictive capacity is usually described in comparison to local lymph node assay (LLNA) results. In this process the important lesson from other endpoints, such as skin or eye irritation, to account for variability reference test results - here the LLNA - has not yet been fully acknowledged. In order to provide assessors as well as method and strategy developers with appropriate estimates, we investigated the variability of EC3 values from repeated substance testing using the publicly available NICEATM (NTP Interagency Center for the Evaluation of Alternative Toxicological Methods) LLNA database. Repeat experiments for more than 60 substances were analyzed - once taking the vehicle into account and once combining data over all vehicles. In general, variability was higher when different vehicles were used. In terms of skin sensitization potential, i.e., discriminating sensitizer from non-sensitizers, the false positive rate ranged from 14-20%, while the false negative rate was 4-5%. In terms of skin sensitization potency, the rate to assign a substance to the next higher or next lower potency class was approx.10-15%. In addition, general estimates for EC3 variability are provided that can be used for modelling purposes. With our analysis we stress the importance of considering the LLNA variability in the assessment of skin sensitization test methods and strategies and provide estimates thereof.
Highlights
Along with the advances in the life sciences, new testing and non-testing methods for improved, more efficient and animalfree assessment of toxicological hazards are being developed at an increasing rate
Disregarding these aspects for the routine test methods inevitably results in an overestimation of its predictive performance, which results in unrealistically high expectations for the predictive capacity of the new test method/testing strategy
The predictive capacity of individual skin sensitization test methods and testing strategies is primarily assessed by comparison with local lymph node assay (LLNA) data
Summary
Along with the advances in the life sciences, new testing and non-testing methods for improved, more efficient and animalfree assessment of toxicological hazards are being developed at an increasing rate. The predictive capacity of individual skin sensitization test methods and testing strategies is primarily assessed by comparison with LLNA data (see e.g., Jaworska et al, 2013; TsujitaInoue et al, 2014). With the aim to support assessors as well as method and strategy developers of both non-animal methods and testing assessment strategies for skin sensitization hazard and potency of substances, estimates of LLNA EC3 variability from repeat testing data of 68 substances were derived.
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