Evaluation of radioisotopic and non-radioisotopic versions of local lymph node assays for subcategorization of skin sensitizers compliant to UN GHS rev 4

• Published in: Regulatory toxicology and pharmacology Vol. 85; pp. 124 - 131
• Main Authors: Ha, Soojin, Ahn, Il Young, Kim, Da-eun, Lee, Jong Kwon, Sohn, Soojung, Jung, Mi-Sook, Heo, Yong, Omori, Takashi, Bae, SeungJin, Lim, Kyung-Min
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.04.2017
• Subjects: Allergens - classification; Allergens - toxicity; Alternative to animal test; Animals; Dermatitis, Allergic Contact; GHS; Haptens - classification; Haptens - toxicity; Humans; Local Lymph Node Assay; Mice; Non-radioisotopic LLNAs; Radioisotopes; Reproducibility of Results; Skin sensitization; UN Global Harmonization System; United Nations; Local lymph node assay; GHS; Skin sensitization; UN Global Harmonization System; Alternative to animal test; Non-radioisotopic LLNAs
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2017.02.003

Recently UN GHS has introduced the sub-categorization of skin sensitizers for which ECt (concentration estimated to induce stimulation index above threshold) of the murine local lymph node assay (LLNA) is used as criteria. Non-radioisotopic variants of LLNA, LLNA: DA, LLNA: BrdU-ELISA, LNCC and LLNA: BrdU-FCM were developed yet their utilities for potency sub-categorization are not established. Here we assessed the agreement of LLNA variants with LLNA or human data in potency sub-categorization for 22 reference substances of OECD TG429. Concordance of sub-categorization with LLNA was highest for LLNA: BrdU-FCM(91%, κ = 0.833, weighted kappa) followed by LLNA: BrdU-ELISA (82%, κ = 0.744) and LLNA: DA (73%, κ = 0.656) whereas LNCC only showed a modest association (64%, κ = 0.441). With human data, LLNA agreed best (77%) followed by LLNA: DA and LLNA: BrdU-FCM(73%), LLNA: BrdU-ELISA (68%) and LNCC(55%). Bland-Altman plot revealed that ECt's of LLNA variants largely agreed with LLNA where most values fell within 95% limit of agreement. Correlation between ECt's of LLNA and LLNA variants were high except for LNCC(pair-wise with LLNA, LLNA: DA, r = 0.848, LLNA: BrdU-ELISA, r = 0.744, LLNA: BrdU-FCM, r=0.786, and LNCC, r = 0.561 by Pearson). Collectively, these results demonstrated that LLNA variants exhibit performance comparable to LLNA in the potency sub-categorization although additional substances shall be analyzed in the future. •LLNA and LLNA variants were assessed for potency subcategorization of skin sensitizers.•LLNA and LLNA variants were compared with human data for 22 reference chemicals.•LLNA variants exhibit performances comparable to LLNA (55–73% vs 77%).