PMID- 36608925
OWN - NLM
STAT- MEDLINE
DCOM- 20230208
LR  - 20230501
IS  - 1096-0295 (Electronic)
IS  - 0273-2300 (Print)
IS  - 0273-2300 (Linking)
VI  - 138
DP  - 2023 Feb
TI  - Reduced specificity for the local lymph node assay for lipophilic chemicals: 
      Implications for the validation of new approach methods for skin sensitization.
PG  - 105333
LID - S0273-2300(23)00001-6 [pii]
LID - 10.1016/j.yrtph.2023.105333 [doi]
LID - 105333
AB  - 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). When assessed against the 
      LLNA, a reduced sensitivity has been reported for in vitro and in chemico assays 
      for lipophilic chemicals with a LogP >/=3.5, resulting in reliability restrictions 
      within the h-CLAT OECD test guideline. 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. We present a mechanistic hypothesis whereby irritation caused by testing 
      lipophilic chemicals at high test doses leads to unspecific cell proliferation. 
      The accompanying 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.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Natsch, Andreas
AU  - Natsch A
AD  - Fragrances S&T, Ingredients Research, Givaudan Schweiz AG, Kemptthal, 
      Switzerland.
FAU - Kleinstreuer, Nicole
AU  - Kleinstreuer N
AD  - National Toxicology Program Interagency Center for the Evaluation of Alternative 
      Toxicological Methods, RTP, NC, USA.
FAU - Asturiol, David
AU  - Asturiol D
AD  - European Commission, Joint Research Centre (JRC), Ispra, Italy. Electronic 
      address: David.ASTURIOL@ec.europa.eu.
LA  - eng
PT  - Journal Article
DEP - 20230103
PL  - Netherlands
TA  - Regul Toxicol Pharmacol
JT  - Regulatory toxicology and pharmacology : RTP
JID - 8214983
RN  - 0 (Allergens)
SB  - IM
CIN - Regul Toxicol Pharmacol. 2023 May;140:105370. PMID: 36898648
MH  - Animals
MH  - Mice
MH  - Humans
MH  - Guinea Pigs
MH  - *Local Lymph Node Assay
MH  - *Dermatitis, Allergic Contact/etiology/pathology
MH  - Reproducibility of Results
MH  - Skin
MH  - Patch Tests
MH  - Allergens/toxicity
MH  - Lymph Nodes/pathology
PMC - PMC9941753
OTO - NOTNLM
OT  - Alternative assays
OT  - Lipophilic chemicals
OT  - Local lymph node assay
OT  - Predictivity
OT  - Skin sensitization
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/01/08 06:00
MHDA- 2023/02/09 06:00
PMCR- 2023/02/01
CRDT- 2023/01/07 16:06
PHST- 2022/09/24 00:00 [received]
PHST- 2022/12/11 00:00 [revised]
PHST- 2023/01/03 00:00 [accepted]
PHST- 2023/01/08 06:00 [pubmed]
PHST- 2023/02/09 06:00 [medline]
PHST- 2023/01/07 16:06 [entrez]
PHST- 2023/02/01 00:00 [pmc-release]
AID - S0273-2300(23)00001-6 [pii]
AID - 105333 [pii]
AID - 10.1016/j.yrtph.2023.105333 [doi]
PST - ppublish
SO  - Regul Toxicol Pharmacol. 2023 Feb;138:105333. doi: 10.1016/j.yrtph.2023.105333. 
      Epub 2023 Jan 3.