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 L’ISLE D’ABEAU, FRANCE | Email: contact@kreatis.eu Presented by: Melanie DELANNOY. Co-Authors: C. CHARMEAU-GENEVOIS, F. BAUER, P. THOMAS Visit us at www.kreatis.eu

Mechanism of Action scheme (MechoA) INPUT: SMILES Tar arget sub substance code 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. 23 sub-classes of mechanisms of toxic action MechoA scheme in-silico model Freeware available at: https://isaferat.kreatis.eu/ Slide / 1 10

Skin Sensitisation Adverse Outcome Pathway (AOP) - Skin epidermis inflammation upon challenge with allergen Tar arget Dir Direct-acting sub substances Ele Electrophiles (hap haptens) - Presentation of Major Histocompatibility - Induction of inflammatory Complexes (MHC) by dendric cytokines and surface cells Nu molecules -Mobilisation of DC Nu = nucleophilic site of dermal protein - Activation of inflammatory - Activation of T-cells e.g. cysteine and lysine -Proliferation of allergen cytokines specific memory T-cells) -Induction of cyto-protective gene pathways ✔ gene activation, protein production, signal alteration Adapted from ENV/JM/MONO(2012)10/PART1 Slide / 2 10

Skin Sensitisation Adverse Outcome Pathway (AOP) MechoA - Skin epidermis inflammation upon challenge with allergen Tar arget Dir Direct-acting sub substances Ele Electrophiles (hap haptens) - Presentation of Major Histocompatibility - Induction of inflammatory Complexes (MHC) by dendric cytokines and surface cells Nu molecules -Mobilisation of DC Nu = nucleophilic site of dermal protein - Activation of inflammatory - Activation of T-cells e.g. cysteine and lysine -Proliferation of allergen cytokines specific memory T-cells) -Induction of cyto-protective gene pathways ✔ gene activation, protein production, signal alteration Adapted from ENV/JM/MONO(2012)10/PART1 Slide / 2 10

MechoA and Skin Sensitisation Screening: case study Slide / 3 10

MechoA and Skin Sensitisation Screening: case study Slide / 3 10

MechoA and Skin Sensitisation Screening: case study • The rationalization of the results for substances 1 and 2 • The assessment of whether substance 3 is a skin sensitiser or not Slide / 3 10

MechoA – Online User Interface Slide / 4 10

MechoA – Online User Interface Slide / 5 10

MechoA and Skin Sensitisation Screening: case study Slide / 6 10

MechoA and Skin Sensitisation Screening: case study Slide / 6 10

MechoA and Skin Sensitisation Screening: case study Picardo (1987) Slide / 6 10

MechoA and Skin Sensitisation Screening: case study Moridani, et al. (2003) Slide / 6 10

MechoA and Skin Sensitisation Screening: case study Slide / 6 10

MechoA and Skin Sensitisation Screening: case study Slide / 6 10

MechoA and Skin Sensitisation Screening: case study Slide / 6 10

Comparison of skin sensitisation predictions by Toxtree and the MechoA *In-vivo validated study, similar to guinea pig maximization test (GPMT) **Predictions based on the reactivity of target substance and/or metabolites ✔ 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 Slide / 7 10

Conclusion - The MechoA scheme in-silico model 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: ☛ T he 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. Slide / 8 10

Thank you for your attention Slide / 9 10

Our team PhD Carole CHARMEAU-GENEVOIS PhD Paul THOMAS CEO of KREATiS, President KREATiS, Senior Toxicologist Senior Ecotoxicologist PhD Franklin BAUER PhD Faizan SAHIGARA Pascal BICHEREL PhD Melanie DELANNOY Chemist and QSAR validation expert Ecotoxicologist and Chemist and model developer model developer model developer Slide / 10 10

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