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The Category Approach for Predicting Mutagenicity and Carcinogenicity

The Category Approach for Predicting Mutagenicity and Carcinogenicity. Laboratory of Mathematical Chemistry, University “Prof. As. Zlatarov”, Bourgas, Bulgaria. Toolbox General Scheme. Input. IUCLID5 interface: XML, Web Services Transfer of data from IUCLID 5 to Toolbox.

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The Category Approach for Predicting Mutagenicity and Carcinogenicity

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  1. The Category Approach for Predicting Mutagenicity and Carcinogenicity Laboratory of Mathematical Chemistry, University “Prof. As. Zlatarov”, Bourgas, Bulgaria

  2. Toolbox General Scheme

  3. Input • IUCLID5 interface: • XML, Web Services • Transfer of data • from IUCLID 5 to Toolbox

  4. Comparison and visualization functionalities in Toolbox

  5. Functionalities 1: Correlation between the categories of two profiling schemes Bar diagram showing the number of chemicals meeting the boundaries of two binary profiles The fist profiler has the categories: Active; Non active The second one has the categories: Binding; Non binding

  6. Functionality 2: Correlation between two profiles by analyzing the distribution of the categories of one of the profile across the categories of the other profile The fist profile has categories: Strong, Weak, Non The second one has categories: Category1, Category2, Category3, Category4

  7. Functionality 3: Correlation between two profiles by analyzing the distributions of their categories in case of using category combinations (working with multifunctional chemicals) When more than one category is assigned simultaneously to a chemical, then unique combinations of such categories are used

  8. The proposed stages of the categorization approach Stage 1. Profiling databases according to endpoint specific profiles • The following endpoint specific profiles were implemented • Oncologic Primary Classification • Mutagenicity/carcinogenicity alerts by Benigni/Bossa • Micronucleus alerts by Benigni/Bossa • The following databases with mutagenicity and carcinogenicity data were used: • HPV Carcinogenicity containing 216 chemicals and • ISSCAN containing 1129 chemicals

  9. The proposed stages of the categorization approach Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms • Chemical distribution according to endpoint specific profiles is analyzed* • Categories were selected highly populated by chemicals: • Aromatic amines - consisting of 39 and 271 chemicals in HPV Carcinogenicity and ISSCAN, respectively • Halogenated linear aliphatic types of compounds - consisting of 27 and 44 chemicals in HPV Carcinogenicity and ISSCAN, respectively • The Toolbox profiles for DNA and protein binding mechanisms have been used for subcategorization of the endpoint specific categories of Aromatic amines and Halogenated linear aliphatic types of compounds • The profiling for DNA and protein binding mechanisms were applied without and with using liver rat S9 metabolism *See the presentation for Assessing correlation between the categories of profiling schemes

  10. The proposed stages of the categorization approach Stage 3. Validating the correlation between mechanistic subcategories based on DNA binding mechanisms and AMES • The validation is based on comparison of the correlations for selected classes - aromatic amines and halogenated linear aliphatic types of compoundsderived from: • HPV Carcinogenicity and • ISSCAN Stage 4. Validating the correlation between mechanistic subcategories based on DNA and protein binding mechanisms and carcinogenicity • The validation is based on comparison of the correlations for selected classes - aromatic amines and halogenated linear aliphatic types of compoundsderived from: • HPV Carcinogenicity and • ISSCAN

  11. The proposed stages of the categorization approach Stage 5. Identifying the boundaries of the combined endpoint specific and binding mechanism categories providing >75% correlation with genotoxic effects and carcinogenicity • Along with AMES and carcinogenicity the correlation with other genotox effects was also studied, such as CA, MNT and CTA Stage 6. Coding boundaries of the combined categories highly correlating with the genotox and/or carcinogenicity effects Stage 7. Screening of inventories for chemicals falling in the domains of highly correlating combined categories for searching data to support the boundaries of these categories

  12. Stage 1. Profiling databases according to endpoint specific profilesHPV Carcinogenicity database profiled according to Oncologic Primary Classifications

  13. Stage 1. Profiling databases according to endpoint specific profilesISSCAN database profiled according to Oncologic Primary Classifications

  14. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Analysis of the distribution of HPV carcinogenicity database (216) according to Oncologic Primary Classification

  15. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Highly populated categories are identified Aromatic amines as one of all categories with the biggest number of chemicals. Total number 39 chemicals

  16. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Distribution of 39 Aromatic amines across Ames experimental data

  17. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Sequence of steps to analyze the distribution of 39 Aromatic amines across DNA binding and Ames data

  18. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Distribution of 39 Aromatic amines across DNA binding and Ames data Sorted by descending order of correlation 18

  19. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Sequence of steps to analyze the distribution of 39 Aromatic amines across DNA binding taking into account liver metabolism and Ames data

  20. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Distribution of 39 Aromatic amines across DNA binding taking into account liver metabolism and Ames data Sorted by descending order of correlation Sorted by Positive data

  21. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Distribution of 39 Aromatic amines across DNA binding taking into account liver metabolism and Ames data Detailed information for generated metabolites. Highlight chemical to see detailed information for generated metabolites

  22. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Distribution of 39 Aromatic amines across DNA binding taking into account liver metabolism and Ames data Detailed information for metabolically generated metabolites. Right click 22

  23. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Distribution of 39 Aromatic amines across DNA binding taking into account liver metabolism and Ames data Detailed information for metabolically generated metabolites. Click Explain to see detailed info. 23

  24. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Distribution of 39 Aromatic amines across DNA binding taking into account liver metabolism and Ames data Detailed information for metabolically generated metabolites. Click Details to see the categories of generated metabolites 24

  25. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Distribution of 39 Aromatic amines across DNA binding taking into account liver metabolism and Ames data Detailed information for metabolically generated metabolites. The target chemical has 9 generated metabolites falling into 8 categories 25

  26. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Distribution of 39 Aromatic amines across DNA binding taking into account liver metabolism and Ames data Detailed information for metabolically generated metabolites. Highlight metabolite then click Details to see why the metabolite falls into this category 26

  27. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Distribution of 39 Aromatic amines across DNA binding taking into account liver metabolism and Ames data Detailed information for metabolically generated metabolites. The current metabolite has fragment highlighted in red corresponding to the category of Aromatic Amines Click on Amines to see mechanistic justification of the category 27

  28. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Distribution of 39 Aromatic amines across DNA binding taking into account liver metabolism and Ames data Click on Advance to see structural boundaries of each category 28

  29. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Distribution of 39 Aromatic amines across combined DNA and Protein binding categories and Carcinogenicity data Sorted by descending order of correlation

  30. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Distribution of 39 Aromatic amines across combined DNA and Protein binding categories taking into account liver metabolism, and Carcinogenicity data Sorted by descending order of correlation

  31. Distribution of ISSCAN Carcinogenicity database (1129)according to Oncologic Primary Classification

  32. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Highly populated categories are identified Aromatic amines is one of the categories with the highest population of chemicals. Total number 271 chemicals

  33. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Distribution of 271 Aromatic amines category across Ames experimental data

  34. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanismsAdding Aromatic amines as target list Click on Add as a target list button Highlight Aromatic amines

  35. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanismsAromatic amines as a target list

  36. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Distribution of 271 Aromatic amines according to DNA binding and Ames data Sorted by descending order of correlation Categories highly correlating with Ames data

  37. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Distributing of 271 Aromatic amines across DNA binding taking into account liver metabolism and Ames data Sorted by descending order of correlation Categories highly correlating with Ames data accounting for liver metabolism

  38. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Distribution of 271 Aromatic amines according to combined DNA and Protein binding categories and Carcinogenicity data Sorted by descending order of correlation Categories highly correlating with Carcinogenicity data

  39. Stage 2. Subcategorization of obtained endpoint specific categories by molecular interaction mechanisms Distributing of 271 Aromatic amines across DNA and Protein binding categories taking into account liver metabolism and Carcinogenicity data Sorted by descending order of correlation Categories highly correlating with Carcinogenicity data accounting liver metabolism

  40. Stage 3. Validating the correlation between mechanistic subcategories based on DNA binding mechanisms and AMES data Aromatic amines (39 chemicals) Aromatic amines (271 chemicals)

  41. Stage 3. Validating the correlation between mechanistic subcategories based on DNA binding taking into account liver metabolism and AMES data Aromatic amines (39 chemicals) Aromatic amines (271 chemicals)

  42. Stage 4. Validating the correlation between mechanistic subcategories based on DNA and Protein binding mechanisms and Carcinogenicity data Aromatic amines (39 chemicals) Aromatic amines (271 chemicals)

  43. Stage 4. Validating the correlation between mechanistic subcategories based on DNA and Protein binding taking into account liver metabolism and Carcinogenicity data Aromatic amines (39 chemicals) Aromatic amines (271 chemicals)

  44. Stage 5. Identifying category boundaries in terms of endpoint specific classes and binding mechanisms providing >75% correlation with genotoxic effects and carcinogenicity Common categories identified in both sets of chemicals Category 1 Aromatic amines (39 chemicals) Aromatic amines (271 chemicals)

  45. Stage 5. Identifying category boundaries in terms of endpoint specific classes and binding mechanisms providing >75% correlation with genotoxic effects and carcinogenicity Common categories identified in both set of chemicals Category 2 Aromatic amines (39 chemicals) Aromatic amines (271 chemicals)

  46. Stage 5. Identifying category boundaries in terms of endpoint specific classes and binding mechanisms providing >75% correlation with genotoxic effects and carcinogenicity Common categories identified in both set of chemicals Category 3 Aromatic amines (39 chemicals) Aromatic amines (271 chemicals)

  47. Stage 5. Identifying category boundaries in terms of endpoint specific classes and binding mechanisms providing >75% correlation with genotoxic effects and carcinogenicity Common categories identified in both set of chemicals Category 4 is based on partial overlapping between two sets 47 Aromatic amines (39 chemicals) Aromatic amines (271 chemicals)

  48. Stage 5. Identifying category boundaries in terms of endpoint specific classes and binding mechanisms providing >75% correlation with genotoxic effects and carcinogenicity Common categories identified in both set of chemicals Category 5 is based on partial overlapping between two sets 48 Aromatic amines (39 chemicals) Aromatic amines (271 chemicals)

  49. Stage 6. Building profiles for categories highly correlating with the genotox and carcinogenicity effects Building profilers for screening inventories based on Oncologic classification and DNA alerts without metabolism Oncologic class 1 and DNA boundaries 1 Oncologic class 1 and DNA boundaries 2 Oncologic class 1 and DNA boundaries 3 ………………………….. Oncologic class 2 and DNA boundaries 1 Oncologic class 2 and DNA boundaries 2 Oncologic class 2 and DNA boundaries 3 …………………………………………… Oncologic class n and DNA boundaries1 Oncologic class n and DNA boundaries2 Oncologic class n and DNA boundaries3

  50. Stage 6. Building profiles for categories highly correlating with the genotox and carcinogenicity effects Building profilers for screening inventories based on Oncologic classification and DNA alerts with metabolism Oncologic class 1 and DNA boundaries with metabolism 1 Oncologic class 1 and DNA boundaries with metabolism 2 Oncologic class 1 and DNA boundaries with metabolism 3 ………………………….. Oncologic class 2 and DNA boundaries with metabolism 1 Oncologic class 2 and DNA boundaries with metabolism 2 Oncologic class 2 and DNA boundaries with metabolism 3 …………………………………………… Oncologic class n and DNA boundaries with metabolism 1 Oncologic class n and DNA boundaries with metabolism 2 Oncologic class n and DNA boundaries with metabolism 3

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