and Skin Sensitisation Screening: A case study KREATiS, 23 rue du - - PowerPoint PPT Presentation
Replacing Experimentation MechoA (M (Mechanism of f Action) ) SAR Model and Skin Sensitisation Screening: A case study KREATiS, 23 rue du Creuzat, 38080 LISLE DABEAU, FRANCE | Email: contact@kreatis.eu Presented by: Melanie DELANNOY.
KREATiS, 23 rue du Creuzat, 38080 L’ISLE D’ABEAU, FRANCE| Email: contact@kreatis.eu
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Replacing Experimentation
Presented by: Melanie DELANNOY. Co-Authors: C. CHARMEAU-GENEVOIS, F. BAUER, P. THOMAS
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INPUT: Tar arget sub substance
SMILES code
23 sub-classes of mechanisms of toxic action
MechoA scheme in-silico model Freeware available at: https://isaferat.kreatis.eu/
Bauer, F.J.; Thomas, P.C.; Fouchard, S.Y.; Neunlist, S.J.M. High-accuracy prediction of Mechanisms of Action using structural alerts. Comput. Toxicol., 2018, 7, 36-45.
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Nu
Nu = nucleophilic site of dermal protein e.g. cysteine and lysine Tar arget sub substances (hap haptens) Dir Direct-acting Ele Electrophiles
Adapted from ENV/JM/MONO(2012)10/PART1
✔ gene activation, protein production, signal alteration
specific memory T-cells)
cytokines
gene pathways
cytokines and surface molecules
Histocompatibility Complexes (MHC) by dendric cells
upon challenge with allergen
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Nu
Nu = nucleophilic site of dermal protein e.g. cysteine and lysine Tar arget sub substances (hap haptens) Dir Direct-acting Ele Electrophiles
Adapted from ENV/JM/MONO(2012)10/PART1
✔ gene activation, protein production, signal alteration
specific memory T-cells)
cytokines
gene pathways
cytokines and surface molecules
Histocompatibility Complexes (MHC) by dendric cells
upon challenge with allergen
MechoA
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Picardo (1987)
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Moridani, et al. (2003)
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✔ Predictions for 1 & 2 are considered reliable and strengthen the results obtained in vivo ✔ Common metabolite for 2 & 3 suggests substance 3 could be a skin sensitiser ✔ Toxtree protein binding alert as Michael acceptor, with no further information. ✔ The lack of alert for 3 raises awareness to run several (Q)SARs for this endpoint
*In-vivo validated study, similar to guinea pig maximization test (GPMT) **Predictions based on the reactivity of target substance and/or metabolites
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Can be used as support to strengthen: ☛ Available in-vivo studies that are K3, K4 or borderline (WoE approach) ☛ Predictions given by (Q)SARs for skin sensitisation ☛ Read-Across proposals to avoid further tests Can be used as a tool to aid in: ☛ The decision making for experimental testing ☛ Learning whether the effect caused by the substance or metabolite? Raises awareness on the necessity to run several (Q)SARs for this endpoint
The applicability domain for MechoA has been mainly based on oral exposure route and systemic toxicity. The application of MechoA for skin sensitisation and other endpoints is under validation, and can be used under expert judgement.
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PhD Paul THOMAS
President KREATiS, Senior Ecotoxicologist
PhD Faizan SAHIGARA
QSAR validation expert
Pascal BICHEREL
Ecotoxicologist and model developer
PhD Melanie DELANNOY
Chemist and model developer
PhD Carole CHARMEAU-GENEVOIS
CEO of KREATiS, Senior Toxicologist
PhD Franklin BAUER
Chemist and model developer