Chemical applicability domain of the local lymph node assay (LLNA) for skin sensitisation potency. Part 4. Quantitative correlation of LLNA potency with human potency

ABSTRACT Prediction of skin sensitisation potential and potency by non‐animal methods is the target of many active research programmes. Although the aim is to predict sensitisation potential and potency in humans, data from the murine local lymph node assay (LLNA) constitute much the largest source of quantitative data on in vivo skin sensitisation. The LLNA has been the preferred in vivo method for identification of skin sensitising chemicals and as such is potentially valuable as a benchmark for assessment of non‐animal approaches. However, in common with all predictive test methods, the LLNA is subject to false positives and false negatives with an overall level of accuracy said variously to be approximately 80% or 90%. It is also necessary to consider the extent to which, for true positives, LLNA potency correlates with human potency. In this paper LLNA potency and human potency are compared so as to express quantitatively the correlation between them, and reasons for non‐agreement between LLNA and human potency are analysed. This leads to a better definition of the applicability domain of the LLNA, within which LLNA data can be used confidently to predict human potency and as a benchmark to assess the performance of non‐animal approaches. HIGHLIGHTSCorrelation between skin sensitisation potency in the LLNA and in humans is quantified, and applies to most sensitizers.There are chemistry‐based explanations for the few chemicals with disagreement between LLNA and human potency.Alerts are defined for chemicals outside the applicability domain, where the LLNA is not a good predictor of human potency.Within the applicability domain, LLNA data can be used confidently to predict human potency directly.Only within the applicability domain should LLNA data be used as a benchmark to assess non‐animal approaches.

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