PMID- 25338925
OWN - NLM
STAT- MEDLINE
DCOM- 20151001
LR  - 20150128
IS  - 1096-0929 (Electronic)
IS  - 1096-0929 (Linking)
VI  - 143
IP  - 2
DP  - 2015 Feb
TI  - Predicting skin sensitizer potency based on in vitro data from KeratinoSens and 
      kinetic peptide binding: global versus domain-based assessment.
PG  - 319-32
LID - 10.1093/toxsci/kfu229 [doi]
AB  - Three in vitro methods for the prediction of the skin sensitization hazard have 
      been validated. However, predicting sensitizer potency is a key requirement for 
      risk assessment. Here, we report a database of 312 chemicals tested in the 
      KeratinoSens assay and for kinetic peptide binding. These data were used in 
      multiple regression analysis against potency in the local lymph node assay 
      (LLNA). The dataset covers the majority of chemicals from the validation of the 
      LLNA to predict human potency and this subset was analyzed for prediction of 
      human sensitization potency by in vitro data. Global analysis yields a regression 
      of in vitro data to LLNA pEC3 with an R(2) of 60% predicting LLNA EC3 with a mean 
      error of 3.5-fold. The highest weight in the regression has the reaction rate 
      with peptides, followed by Nrf2-induction and cytotoxicity in KeratinoSens. The 
      correlation of chemicals tested positive in vitro with human data has an R(2) of 
      49%, which is similar to the correlation between LLNA and human data. Chemicals 
      were then grouped into mechanistic domains based on experimentally observed 
      peptide-adduct formation and predictions from the TIMES SS software. Predictions 
      within these domains with a leave-one-out approach were more accurate, and for 
      several mechanistic domains LLNA EC3 can be predicted with an error of 2- to 
      3-fold. However, prediction accuracy differs between domains and domain 
      assignment cannot be made for all chemicals. Thus, this comprehensive analysis 
      indicates that combining global and domain models to assess sensitizer potency 
      may be a practical way forward.
CI  - (c) The Author 2014. Published by Oxford University Press on behalf of the Society 
      of Toxicology. All rights reserved. For Permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Natsch, Andreas
AU  - Natsch A
AD  - *Bioscience and Analytical Chemistry, Givaudan Schweiz AG, CH-8600 Duebendorf, 
      Switzerland and Regulatory Affairs and Product Safety, Givaudan International SA, 
      CH-1214 Vernier, Switzerland andreas.natsch@givaudan.com.
FAU - Emter, Roger
AU  - Emter R
AD  - *Bioscience and Analytical Chemistry, Givaudan Schweiz AG, CH-8600 Duebendorf, 
      Switzerland and Regulatory Affairs and Product Safety, Givaudan International SA, 
      CH-1214 Vernier, Switzerland.
FAU - Gfeller, Hans
AU  - Gfeller H
AD  - *Bioscience and Analytical Chemistry, Givaudan Schweiz AG, CH-8600 Duebendorf, 
      Switzerland and Regulatory Affairs and Product Safety, Givaudan International SA, 
      CH-1214 Vernier, Switzerland.
FAU - Haupt, Tina
AU  - Haupt T
AD  - *Bioscience and Analytical Chemistry, Givaudan Schweiz AG, CH-8600 Duebendorf, 
      Switzerland and Regulatory Affairs and Product Safety, Givaudan International SA, 
      CH-1214 Vernier, Switzerland.
FAU - Ellis, Graham
AU  - Ellis G
AD  - *Bioscience and Analytical Chemistry, Givaudan Schweiz AG, CH-8600 Duebendorf, 
      Switzerland and Regulatory Affairs and Product Safety, Givaudan International SA, 
      CH-1214 Vernier, Switzerland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141022
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Peptide Fragments)
SB  - IM
MH  - Animal Testing Alternatives
MH  - Cell Line
MH  - *Databases, Chemical
MH  - Humans
MH  - Keratinocytes/*drug effects
MH  - Kinetics
MH  - *Local Lymph Node Assay
MH  - Models, Theoretical
MH  - Peptide Fragments/*chemistry
MH  - Predictive Value of Tests
MH  - Regression Analysis
MH  - Risk Assessment
OTO - NOTNLM
OT  - KeratinoSens
OT  - Nrf2
OT  - TIMES SS
OT  - applicability domains
OT  - cytotoxicity
OT  - in vitro testing
OT  - multiple regression
OT  - peptide binding
OT  - rate constants
OT  - skin sensitization
EDAT- 2014/10/24 06:00
MHDA- 2015/10/02 06:00
CRDT- 2014/10/24 06:00
PHST- 2014/10/24 06:00 [entrez]
PHST- 2014/10/24 06:00 [pubmed]
PHST- 2015/10/02 06:00 [medline]
AID - kfu229 [pii]
AID - 10.1093/toxsci/kfu229 [doi]
PST - ppublish
SO  - Toxicol Sci. 2015 Feb;143(2):319-32. doi: 10.1093/toxsci/kfu229. Epub 2014 Oct 
      22.