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QSAR in Cancer Assessment Purpose and Agenda G ilman Veith Duluth MN May 19-21, 2010

QSAR in Cancer Assessment Purpose and Agenda G ilman Veith Duluth MN May 19-21, 2010. Molecular Initiating Event. Biological Responses. Macro -Molecular Interactions. T oxicant. Cellular. Organism. Organ. Population. Gene Activation Protein Production Signal Alteration. Lethality

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QSAR in Cancer Assessment Purpose and Agenda G ilman Veith Duluth MN May 19-21, 2010

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  1. QSAR in Cancer AssessmentPurpose and AgendaGilman VeithDuluth MNMay 19-21, 2010

  2. Molecular Initiating Event Biological Responses Macro -Molecular Interactions Toxicant Cellular Organism Organ Population Gene Activation Protein Production Signal Alteration Lethality Sensitization Birth Defect Reproductive Impairment Cancer Chemical Reactivity Profiles Receptor, DNA, Protein Interactions Altered Function Altered Development Structure Extinction Mechanistic Profiling Cellular & In Vitro Testing In Vivo Testing ITS and Adverse Outcome Pathway

  3. Pathways in Reactive chemicals In vitro Endpoints Interaction Mechanisms Molecular Initiating Events In vivo Endpoints Membrane Alteration _ _ _ Oxidative Stress _ _ _ Genotoxicity Death Impaired Growth Impaired Development Impaired Reproduction Cancer Michael Addition Schiff base Formation SN2 Acylation Atom Centered Irreversible (Covalent) Binding Pr-S Adducts GSH Oxidation GSH Depletion NH2 Adducts RN Adducts DNA Adducts

  4. Oxidative Stress from GSH depletion Direct GSH Reactions Oxidative Stress Pr-S Adducts GSH Oxidation GSH Depletion NH2 Adducts RN Adducts DNA Adducts Altered Synthesis Cell toxicity Other Effects Oxidation How Many Ways to Deplete GSH? How Many Downstream Effects?

  5. AOP for Allergic Contact Dermatitis 1. Haptenation; 2. Epidermal inflammation & LC activation;3. LC migration; 4. DC: T cell interaction; 5. T cell proliferation; 6. Increase in hapten-specific T cells; 7. Hapten re-exposure; 8. Acute inflammation; 9. T cell-mediated inflammation Karlberg et al.Chem. Res. Toxicol. 2008, 21, 53-69.

  6. Grouping by Cancer Pathways • Genotoxic Carcinogenesis • Direct DNA damage through abiotic chemical “binding” • Most electrophiles bind to many DNA/protein sites • Metabolic differences impact cell, organ, species sensitivity • Epigenetic Carcinogenesis • Cytoxicity-induced cell proliferation • Receptor-mediated pathways • Disturbance of homeostatic control • Loss of immune surveillance • Oxidative Stress- Indirect DNA damage • Loss of intercellular communication

  7. Mode of Action GENOTOXICITY Direct DNA Damage Indirect DNA Damage NON-GENOTOXICITY Receptor-mediated pathways Disturbance of homeostaticcontrol Loss of immune surveillance Oxidative Stress- Indirect DNA damage Loss of intercellular communication Cytotoxicity-induced cell proliferation

  8. Mode of action Mechanism/Alert GENOTOXICITY DNA Mechanism #1 DNA Mechanism #2 Direct DNA Damage DNA Mechanism #3 …………………………… DNA Mechanism #n Prot Mechanism #1 Prot Mechanism #2 Indirect DNA Damage Prot Mechanism #3 …………………………… Prot Mechanism #n NON-GENOTOXICITY Receptor-mediated pathways AR Binding ER Binding Aromatase Inh. Disturbance of homeostaticcontrol Thyroid Disturbance Loss of immune surveillance Oxidative Stress- Indirect DNA damage Loss of intercellular communication Cytotoxicity-induced cell proliferation

  9. Mode of action Mechanism/Alert Mechanism/Metabolites GENOTOXICITY DNA #1 DNA Mechanism #1-Met 1…m DNA #2 DNA Mechanism #2-Met 1…m Direct DNA Damage DNA #3 DNA Mechanism #3-Met 1…m …………………………… …………. DNA #n DNA Mechanism #3-Met 1…m Prot #1 Prot Mechanism #1 - Met 1..m Prot Mechanism #2 - Met 1..m Prot #2 Indirect DNA Damage Prot Mechanism #3 - Met 1..m Prot #3 …………………………… ………….. Prot Mechanism #n - Met 1..m Prot #n NON-GENOTOXICITY Receptor-mediated pathways -Met 1…m Receptor-mediated pathways AR Binding ER Binding Aromatase Inh. Disturbance of homeostaticcontrol Disturbance of homeostatic control -Met 1…m Thyroid Disturbance Loss of immune surveillance Loss of immune surveillance-Met 1…m Oxidative Stress- Indirect DNA damage Oxidative Stress- Indirect DNA damage -Met 1…m Loss of intercellular communication Loss of intercellular comm.-Met 1…m Cytotoxicity-induced cell proliferation Cytotoxicity-induced cell proliferation-Met 1…m

  10. Mode of action Mechanism/Alert Mechanism/Metabolites In vitro data CA+S9 Ames Ames+S9 CA MLA MLA+S9 CTA GENOTOXICITY DNA #1 DNA #1-Met 1…m DNA #2 DNA #2-Met 1…m Direct DNA Damage DNA #3 DNA #3-Met 1…m …………………………… …………. DNA #n DNA #3-Met 1…m Prot #1 Prot #1 - Met 1..m Prot #2 - Met 1..m Prot #2 Indirect DNA Damage Prot #3 - Met 1..m Prot #3 …………………………… ………….. Prot #n - Met 1..m Prot #n NON-GENOTOXICITY Receptor-mediated pathways -Met 1…m Receptor-mediated pathways AR Binding ER Binding Aromatase Inh. Disturbance of homeostaticcontrol Disturbance of homeostatic control -Met 1…m Thyroid Disturbance Loss of immune surveillance Loss of immune surveillance-Met 1…m Oxidative Stress- Indirect DNA damage Oxidative Stress- Indirect DNA damage -Met 1…m Loss of intercellular communication Loss of intercellular comm.-Met 1…m Cytotoxicity-induced cell proliferation Cytotoxicity-induced cell proliferation-Met 1…m

  11. Mode of action Mechanism/Alert Mechanism/Metabolites In vitro data In vivo data COMET UDS CA MN(BN) CTA RCA Ames GENOTOXICITY Ames+S9 DNA #1 DNA #1-Met 1…m DNA #2 DNA #2-Met 1…m CA Direct DNA Damage DNA #3 DNA #3-Met 1…m CA+S9 …………………………… …………. MLA DNA #n DNA #3-Met 1…m MLA+S9 CTA Prot #1 Prot #1 - Met 1..m Prot #2 - Met 1..m Prot #2 Indirect DNA Damage Prot #3 - Met 1..m Prot #3 …………………………… ………….. Prot #n - Met 1..m Prot #n NON-GENOTOXICITY Receptor-mediated pathways -Met 1…m Receptor-mediated pathways AR Binding ER Binding Aromatase Inh. Disturbance of homeostaticcontrol Disturbance of homeostatic control -Met 1…m Thyroid Disturbance Loss of immune surveillance Loss of immune surveillance-Met 1…m Oxidative Stress- Indirect DNA damage Oxidative Stress- Indirect DNA damage -Met 1…m Loss of intercellular communication Loss of intercellular comm.-Met 1…m Cytotoxicity-induced cell proliferation Cytotoxicity-induced cell proliferation-Met 1…m

  12. Screening Level Hazard ID Parent Chemical Direct DNA Binding Individual Initiating Events/ Structural Alerts Grouping Data for Interaction Categories Indirect DNA Damage Nongenotoxic Mechanisms Activated Metabolites Structural Evidence of Cancer Potential Category with Data for Cancer Potential No Evidence Of Cancer Potential

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