TIMES-SS--a mechanistic evaluation of an external validation study using reaction chemistry principles.
The TImes MEtabolism Simulator platform used for predicting skin sensitization (TIMES-SS) is a hybrid expert system that was developed at Bourgas University using funding and data from a consortium comprised of industry and regulators. TIMES-SS encodes structure-toxicity and structure-skin metabolism relationships through a number of transformations, some of which are underpinned by mechanistic three-dimensional quantitative structure-activity relationships. Here, we describe an external validation exercise that was recently carried out. As part of this exercise, data were generated for 40 new chemicals in the murine local lymph node assay (LLNA) and then compared with predictions made by TIMES-SS. The results were promising with an overall good concordance (83%) between experimental and predicted values. The LLNA results were evaluated with respect to reaction chemistry principles for sensitization. Additional testing on a further four chemicals was carried out to explore some of the specific reaction chemistry findings in more detail. Improvements for TIMES-SS, where appropriate, were put forward together with proposals for further research work. TIMES-SS is a promising tool to aid in the evaluation of skin sensitization potential under legislative programs such as REACH.
Roberts
David W
DW
Liverpool John Moores University, Liverpool, United Kingdom.
Patlewicz
Grace
G
Dimitrov
Sabcho D
SD
Low
Lawrence K
LK
Aptula
Aynur O
AO
Kern
Petra S
PS
Dimitrova
Gergana D
GD
Comber
Mike I H
MI
Phillips
Richard D
RD
Niemelä
Jay
J
Madsen
Charlotte
C
Wedebye
Eva B
EB
Bailey
Paul T
PT
Mekenyan
Ovanes G
OG
D000085:Acetates / Q000737:chemistry; D000498:Allyl Compounds / Q000737:chemistry; D000826:Animal Testing Alternatives / Q000379:methods*; D000818:Animals; D000077463:Carbamide Peroxide; D004338:Drug Combinations; D007509:Irritants / Q000737:chemistry*; D023441:Local Lymph Node Assay; D008956:Models, Chemical; D015394:Molecular Structure; D010545:Peroxides; D021281:Quantitative Structure-Activity Relationship; D023422:Skin Irritancy Tests / Q000379:methods*; D018675:Toxicity Tests / Q000379:methods / Q000639:trends; D014508:Urea / Q000031:analogs & derivatives
D000085:Acetates; D000498:Allyl Compounds; D004338:Drug Combinations; D007509:Irritants; D010545:Peroxides; D000077463:Carbamide Peroxide; D014508:Urea; C498551:allyl acetate