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Organization for Economic Co-operation and Development. QSAR Application Toolbox. -filling data gaps using available information-. McKim Conference, September 2007, Duluth, MN. Organization for Economic Co-operation and Development. QSAR Application Toolbox.

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Organization for Economic Co-operation and Development


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    1. Organization for Economic Co-operation and Development QSAR Application Toolbox -filling data gaps using available information- McKim Conference, September 2007, Duluth, MN

    2. Organization for Economic Co-operation and Development QSAR Application Toolbox -filling data gaps using available information- Historical Notes • First “organized” discussions – ‘Red Lobsters’, Duluth - 1992 • Organized actions of EU and OECD – coming with REACH • The role of the “revolutionary” notions – category, analogues • OECD and EU Guidance documents on ‘Category’, ‘QSAR’ • Need for translation documents into a working machinery

    3. Organization for Economic Co-operation and Development QSAR Application Toolbox -filling data gaps using available information- General Objectives • Improve accessibility of (Q)SAR methods and databases • Facilitate selection of chemical analogues and categories • Integrate metabolism/mechanisms with categories/(Q)SAR • Assist in the estimation of missing values for chemicals • -ENV/JM(2006)47

    4. Bob Diderich Gilman Veith Terry Schultz Take Fukushima Environment Directorate OECD Paris

    5. Special thanks to: DG Environment European Chemicals Bureau Danish Ministry of the Environment US EPA Environment Canada NITE Japan CEFIC MultiCase (USA) SRC (USA) A collaborative effort of all member countries and stakeholders

    6. Developers of the system: Laboratory of Mathematical Chemistry, Bourgas, Bulgaria http://oasis-lmc.org/

    7. Is the chemical included in regulatory inventories or existing chemical categories? Has the chemical already been assessed by other agencies/organisations? Would you like to search for available data on assessment endpoints for each chemical? Typical queries included in the (Q)SAR Application Toolbox

    8. Explore a chemical list for possible analogues using predefined, mechanistic, empiric and custom built categorization schemes? Group chemicals based on common chemical/toxic mechanism and/or metabolism? Design a data matrix of a chemical category? Typical Queries included in the (Q)SAR Application Toolbox

    9. Fill data gaps in a chemical category using: read-across, trend analysis or QSAR models Report the results: Work history Export the data matrix IUCLID 5 harmonized templates Typical Queries included in the (Q)SAR Application Toolbox

    10. System Workflow

    11. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report

    12. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report • User Alternatives for Chemical ID: • A. Single target chemical • Name • CAS# • SMILES/InChi • Draw Chemical Structure • Select from UserList/Inventory • B. Group of chemicals • User List • Inventory • Specialized Databases

    13. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report • User Alternatives for Chemical ID: • A. Single target chemical • Name • CAS# • SMILES/InChi • Draw Chemical Structure • Select from User List/Inventory • B. Group of chemicals • User List/Inventory • Specialized Databases • Toolbox Inventories: • US EPA TSCA • Canadian DSL • OECD HPVCs, • USEPAHPVCs • EU EINECS • Japanese MITI • DANISHEPA

    14. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report • General characterization by the following grouping schemes: • Substance information • Predefined • Mechanistic • Empirical • Custom • Metabolism

    15. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report • General characterization by the following grouping schemes: • Substance information: • CAS • Name • Structural formula • OECD Global portal

    16. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report • General characterization by the following grouping schemes: • Substance information • Predefined: • US EPA categorization • OECD categorization • Database affiliation • Inventory affiliation • Substance type: polymers, mixtures, discrete, hydrolyzing

    17. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report • General characterization by the following grouping schemes: • Substance information • Predefined: • US EPA categorization • OECD categorization • Database affiliation • Inventory affiliation • Substance type: polymers, mixtures, discrete, hydrolyzing

    18. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report • General characterization by the following grouping schemes: • Substance information • Predefined • Mechanistic: • Acute Toxicity MOA • Protein binding (OASIS) • DNA binding (OASIS) • Electron reach fragments (Superfragments) BioBite • Cramer Classification Tree (ToxTree) • Veerhar/Hermens reactivity rules (ToxTree) • Lipinski rules (MultiCase)

    19. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report • General characterization by the following grouping schemes: • Substance information • Predefined • Mechanistic: • Acute Toxicity MOA (OASIS) • Protein binding (OASIS) • DNA binding (OASIS) • Electron reach fragments (Superfragments) BioBite • Cramer Classification Tree (ToxTree) • Veerhar/Hermens reactivity rules (ToxTree) • Lipinski rules (MultiCase)

    20. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report • General characterization by the following grouping schemes: • Substance information • Predefined • Mechanistic • Empirical: • Chemical elements • Groups of elements • Natural functional groups • AIM (EPA/SRC)

    21. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report • General characterization by the following grouping schemes: • Substance information • Predefined • Mechanistic • Empirical • Custom: • Mechanistic boundaries example (aldehydes forming Shiff base but not Michael type addition)

    22. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report • General characterization by the following grouping schemes: • Substance information • Predefined • Mechanistic • Empirical • Custom • Metabolism: • Documented: microbial, liver • Simulated: microbial, liver, GI tract, skin

    23. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report • Finding Data for SIDS and Other Endpoints • Selecting Data Base(s): • Toolbox databases • Publicly available • Proprietary databases • Toolbox Links to External Databases (DSSTOX) • Selecting type of extracting data: • Measured Data • Estimated Data • Both

    24. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report • Extracting SIDS and Other Endpoints • Selecting Data Base(s): • Internal databases • Publicly available • Proprietary databases • Toolbox Links to External Databases (DSSTOX) • Selecting type of extracting data: • Measured Data • Estimated Data • Both

    25. Measured data summary of the Current Toolbox • Biodegradation DB – 745 chemicals • Genotox DB - 5584 chemicals • ISSCAN Genotox – 873 chemicals • Skin sensitization DB - 738 chemicals • Estrogen RBA - 1514 chemicals • Bioaccumulation DB – 700 chemicals • ECOTOX database – 5071chemicals • ECETOC database – 777 chemicals

    26. Estimated Data Summary of the Current Toolbox 1. Danish EPA DB - data for165438 chemicals

    27. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report • Finding Data for SIDS and Other Endpoints • Selecting Data Base(s): • Toolbox databases • Publicly available • Proprietary databases • Toolbox Links to External Databases (DSSTOX) • Selecting type of extracting data: • Measured Data • Estimated Data • Both

    28. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report

    29. Categorization and QSAR Basic Concept • Each QSAR estimate is a result of two predictions: • Qualitative prediction of predominant interaction mechanisms and hazard identification (defined by category) • Quantitative prediction of the intensity (potency) of the specific mechanisms of interaction (predicted by QSAR) • Wrong selection of the mechanism could cause greater errors than the potency estimate by the QSAR model

    30. Categorization and QSAR Basic Concept • Example: • Phenols are polar narcotics, uncouplers or electrophilic chemicals. • QSAR models for each mechanism have comparable uncertainty • The potency of the electrophilic mechanism can be orders of magnitude greater than polar narcotics • Wrong categorization of chemicals could cause significant errors in defining the potency

    31. Categorization and QSAR Basic Concept • The logic for selecting a specific model for a specific chemical (category) is the cornerstone of regulatory acceptance OECD QSAR AD-Hoc group meeting,Madrid, April 2007

    32. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report • Forming and Pruning Categories: • Predefined • Mechanistic • Empirical • Custom • Metabolism

    33. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report • Forming and Pruning Categories: • Predefined • OECD categorization • US EPA categorization • Inventory affiliation • Database affiliation • Substance type

    34. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report Current categorization status of chemical inventories HPVCs 4843 substances OECD Categories US EPA Categories

    35. Logical sequence of components usage Chemical input Profiling Endpoints Category Definition Filling data gap Report • Forming and Pruning Categories: • Predefined • Mechanistic • Acute Toxicity MOA • Protein binding • DNA binding • Electron reach fragments (Superfragments) • Cramer Classification Tree • Veerhar/Hermens reactivity rules • Lipinski rules