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

Soojin Ha, Il Young Ahn, Da-Eun Kim, Jong Kwon Lee, Soojung Sohn, Mi-Sook Jung, Yong Heo, Takashi Omori, SeungJin Bae, Kyung-Min Lim

Regulatory toxicology and pharmacology : RTP 2017 Apr

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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. Copyright © 2017 Elsevier Inc. All rights reserved.

Citation

Soojin Ha, Il Young Ahn, Da-Eun Kim, Jong Kwon Lee, Soojung Sohn, Mi-Sook Jung, Yong Heo, Takashi Omori, SeungJin Bae, Kyung-Min Lim. Evaluation of radioisotopic and non-radioisotopic versions of local lymph node assays for subcategorization of skin sensitizers compliant to UN GHS rev 4. Regulatory toxicology and pharmacology : RTP. 2017 Apr;85:124-131