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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. McKim Workshop Goals. Summarize regulatory contexts for hazard identification and risk estimation of carcinogenesis

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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. McKim Workshop Goals • Summarize regulatory contexts for hazard identification and risk estimation of carcinogenesis • Review progress on alternative methods for estimating endpoints needed in cancer assessment • Discuss the need for a mechanistic framework for improving the transparency of alternative models • Identify examples of chemical categories for which alternatives reliably predict outcomes of rodent assays

  3. Regulatory Contexts Precautionary Perspective “What additional other test results would I want to see before I am willing to conclude a chemical is safe?” Holistic Risk Perspective “How can I identify greatest carcinogenic risks among all chemicals regardless of their testing status?”

  4. Hazard Classification Carcinogenicity

  5. Hazard Classification Carcinogenicity • Carcinogenic to Humans (epi data required) • Likely to be Carcinogenic to Humans (tumors in two species) • Suggestive Evidence of Carcinogenic Potential • Inadequate Information to Assess Carcinogenic Potential • Not Likely to be Carcinogenic to Humans (no tumors in two species)

  6. Data Driven Hazard AssessmentCarciNogenic Potential

  7. Data Driven Hazard AssessmentCarciNogenic Potential Number Of Chemicals New Product Development Testing/ Assessment Requirements Safety Assessment Process

  8. Initial Hazard Assessments • Screening Information Datasets – SIDS • Globally Harmonised System of C&L – GHS • REACH –Dossier Testing Plan Reviews • TSCA –PMNs (predictive hazard identification)

  9. StreamliNing Data Requirements • QSAR in chemical engineering has always been used to focus attention/resources on specific activities • QSAR orders chemicals according to intrinsic attributes and generates initial hypotheses for more strategic use of testing and assessment resources • Structural alerts are a convenient and transparent approach to identifying hazard-specific priorities

  10. Conceptual Framework Chemical Speciation and Metabolism Molecular Initiating Events Measurable Biological Effects Adverse Outcomes Parent Chemical Schultz et al. 2006. SAR QSAR in Environ.Res. 17(4) 1-16.

  11. Conceptual Framework Speciation and Metabolism Molecular Initiating Events Measurable Biological Effects Adverse Outcomes Parent Chemical Response Pathways Chemistry/ Biochemistry QSAR

  12. Conceptual Framework Chemical Speciation and Metabolism Molecular Initiating Events Measurable Biological Effects Adverse Outcomes Parent Chemical Mortality -systemictoxicity -disease -cancer Impaired Development -terata -prenatal deficits Reproductive Fitness -fertility -viable offspring • Interaction • Mechanisms • -Nonspecific Targets • Atom Center Targets • -Receptor Targets Chemical Inventories and Categories (~200,000)

  13. At the Molecular Initiating Event Chemical Speciation and Metabolism Molecular Initiating Events Measurable Biological Effects Adverse Outcomes Parent Chemical The QSAR Question is: “How many other chemicals can interact at this target?” While the Assessment Question is: “What are the known biological effects from this altered target…. organelles, cells , organs, species ”

  14. From the Library of Initiating Events Chemical Speciation and Metabolism Library Of Molecular Initiating Events Measurable Biological Effects Adverse Outcomes Parent Chemical Chemical Profilers Available in A Variety of Commercial & Public Software Conformations Targets Interactions Metabolic Simulators Inventories Structural Requirements

  15. From the Library of Initiating Events Chemical Speciation and Metabolism Library Of Molecular Initiating Events Measurable Biological Effects Adverse Outcomes Parent Chemical Altered Genes/Proteins Acquisition of Tumorigenicity DNA Binding Premature Death Genetic Instability/ Cell Immortality

  16. 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

  17. 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

  18. Models for the Metabolism Gap Simulated 2-Acetylaminofluorene Metabolism

  19. 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

  20. 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?

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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

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