title: Evaluation of radioisotopic and non-radioisotopic versions of local lymph node assays for subcategorization of skin sensitizers compliant to UN GHS rev 4.
abstract: 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.
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Soojin
authors.initials: S
authors.lastname: Ha
authors.affiliation: National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Republic of Korea.
authors.forename: Il Young
authors.initials: IY
authors.lastname: Ahn
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Da-Eun
authors.initials: DE
authors.lastname: Kim
authors.affiliation: National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Republic of Korea.
authors.forename: Jong Kwon
authors.initials: JK
authors.lastname: Lee
authors.affiliation: National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Republic of Korea.
authors.forename: Soojung
authors.initials: S
authors.lastname: Sohn
authors.affiliation: Pharmacology Efficacy Team, Biotoxtech Co., Ltd, O-Chang, Republic of Korea.
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Jung
authors.affiliation: Department of Occupational Health, College of Natural Sciences, Catholic University of Daegu, Republic of Korea.
authors.forename: Yong
authors.initials: Y
authors.lastname: Heo
authors.affiliation: Division of Biostatistics, Department of Social/Community Medicine and Health Science, Kobe University School of Medicine, Kobe, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Omori
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea. Electronic address: sjbae@ewha.ac.kr.
authors.forename: SeungJin
authors.initials: S
authors.lastname: Bae
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea. Electronic address: kmlim@ewha.ac.kr.
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Lim
mesh_terms: D000485:Allergens / Q000145:classification / Q000633:toxicity; D000818:Animals; D017449:Dermatitis, Allergic Contact; D006241:Haptens / Q000145:classification / Q000633:toxicity; D006801:Humans; D023441:Local Lymph Node Assay; D051379:Mice; D011868:Radioisotopes; D015203:Reproducibility of Results; D014480:United Nations
chemical_list: D000485:Allergens; D006241:Haptens; D011868:Radioisotopes
keywords: Alternative to animal test; GHS; Local lymph node assay; Non-radioisotopic LLNAs; Skin sensitization; UN Global Harmonization System