Meaningful and accurate reference data are crucial for the validation of New Approach Methodologies (NAMs) in toxicology. For skin sensitization, multiple reference datasets are available including human patch test data, guinea pig data and data from the mouse local lymph node assay (LLNA). The LLNA provides the largest and most homogenous database, and has been the regulatory standard for two decades. When assessed against the LLNA, a reduced sensitivity of the h-CLAT test was reported for lipophilic chemicals with a LogP ≥3.5, resulting in reliability restrictions within the h-CLAT OECD test guideline. A similar drop in sensitivity vs LLNA data for lipophilic chemicals was also observed for other in vitro and in chemico assays. Here we address the question of whether LLNA data are an appropriate reference for chemicals in this physicochemical range. Analysis of LLNA vs human reference data indicates that the false-discovery rate of the LLNA is significantly higher for chemicals with LogP ≥3.5, which, at least partly, explains the apparent reduced sensitivity of in vitro data when evaluated against the LLNA only. The analysis indicates that for lipophilic chemicals with negative calls in in vitro and in chemico assays, resorting to the LLNA is not necessarily a better option. These results indicate that the validation of NAMs in this particular LogP range should be based on a more holistic evaluation of the reference data and not solely upon LLNA data.

NATSCH Andreas;  KLEINSTREUER Nicole;  ASTURIOL BOFILL David; 

2023-01-19

ACADEMIC PRESS INC ELSEVIER SCIENCE

JRC130668

0273-2300 (online),   

https://www.sciencedirect.com/science/article/pii/S0273230023000016,    https://publications.jrc.ec.europa.eu/repository/handle/JRC130668,   

10.1016/j.yrtph.2023.105333 (online),