Nothing is perfect, not even the local lymph node assay: a commentary and the implications for REACH

Area of Science:

• Toxicology
• Dermatology
• Regulatory Science

Background:

• The local lymph node assay (LLNA) is the preferred method for identifying skin-sensitizing chemicals by regulatory authorities.
• It is a requirement under the EU's REACH regulations, valued for animal welfare benefits and performance.
• LLNA serves as a benchmark for validating new testing approaches, including in vitro alternatives.

Purpose of the Study:

• To review the limitations of the LLNA for skin sensitization testing.
• To assess the impact of these limitations on chemical identification, classification, and potency assessment.
• To explore the relevance of LLNA limitations for developing and validating alternative testing methods.

Main Methods:

• Review of published literature on the LLNA.
• Analysis of LLNA's strengths and limitations, including false positives/negatives.
• Consideration of factors affecting LLNA results, such as vehicle effects and interspecies differences.

Main Results:

• The LLNA, while considered a 'gold standard,' exhibits limitations similar to traditional guinea-pig tests.
• Key limitations include the occurrence of false positive and false negative results.
• Susceptibility to vehicle changes and potential interspecies differences can complicate interpretation.

Conclusions:

• Despite its advantages, the LLNA has inherent limitations that require careful consideration.
• Understanding LLNA's shortcomings is vital for accurate skin sensitizer assessment.
• These limitations inform the ongoing development and validation of novel in vitro and in silico alternatives.