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General Concepts in QSAR for Using the  QSAR Application Toolbox <br />
Part IITrend Analysis and Filling Data Gaps in Hazard Assessment<br />
Some Important Lessons<br />We saw that vapor pressure correlates with rodent LC50s, but hundreds of other molecular descr...
 QSAR and Trend Analysis<br />QSAR research asks simple questions about why chemicals behave the way they do in all kinds ...
Let’s Look at the Order in Boiling Point<br />Boiling Point (°C)<br />Chemical<br />Amyl amine<br />Amyl chloride<br />Dib...
 QSAR and Trend Analysis<br />If we reorder the chemicals to put the boiling points in ascending order, we have the next s...
Look for Order in Molecular Descriptors<br />Chemical<br />Boiling Point (°C)<br />Ethyl bromide<br />Methacrolein<br />Am...
 QSAR and Trend Analysis<br />In the next example, we might assume that we have compiled a set of toxicity values (LC50 in...
10+2<br />10 0<br />10_2<br />Acute <br />Toxicity<br />(Moles/L)<br />It is not uncommon  to  find endpoint<br />values s...
 QSAR and Trend Analysis<br />As with boiling points, the QSAR approach evaluates molecular descriptors and identifies tho...
10+2<br />10 0<br />Class #2<br />10_2<br />Acute<br />Toxicity<br />(moles/l)<br />10_4<br />10_6<br />10-8<br />0<br />2...
Nonpolar Narcotic Toxicants<br />
Oxidative Phosphorylase Uncouplers<br />LC50-96hr<br />MATC-30 day<br />
Reactive Chemicals (Electrophiles)<br />
Current Limitations in QSAR<br />The general QSAR approach is most reliable for chemicals where the parent chemical struct...
Which Metabolite should we use in modeling interactions?<br />O<br />N<br />H<br />O<br />O<br />O<br />O<br />O<br />N<br...
Current Limitations in QSAR<br />The general QSAR approach works well for short-term bioassays where steady-state exposure...
Adverse Outcome Pathway For<br />A Well-Defined Endpoint<br />Molecular<br />Initiating <br />Event<br />Speciation,<br />...
Molecular Initiating Event<br />Macro<br />-Molecular Interactions<br />Toxicant<br />Chemical Reactivity Profiles<br />Re...
Molecular Initiating Event<br />Biological Responses<br />Macro<br />-Molecular Interactions<br />Cellular<br />Toxicant<b...
Molecular Initiating Event<br />Biological Responses<br />Macro<br />-Molecular Interactions<br />Cellular<br />Organ<br /...
Molecular Initiating Event<br />Biological Responses<br />Macro<br />-Molecular Interactions<br />Cellular<br />Organ<br /...
Major Pathways for Reactive Toxicity from Moderate Electrophiles<br />Interaction<br />Mechanisms<br />Molecular<br />Init...
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General Concepts in QSAR for Using the QSAR Application Toolbox Part 2

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Part II .
Trend Analysis and Filling Data Gaps in Hazard Assessment

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General Concepts in QSAR for Using the QSAR Application Toolbox Part 2

  1. 1. General Concepts in QSAR for Using the QSAR Application Toolbox <br />
  2. 2. Part IITrend Analysis and Filling Data Gaps in Hazard Assessment<br />
  3. 3. Some Important Lessons<br />We saw that vapor pressure correlates with rodent LC50s, but hundreds of other molecular descriptors may not <br />The trend in the data will be evident only when the toxicity mechanism of all chemicals is the same <br />Chemicals with other mechanisms (i.e. acrolein, phosgene) will appear as statistical outliers to the major trend because they do not produce lethality as do the aliphatic ethers.<br />The QSAR approach uses trend analysis to evaluate mechanisms and to test chemical similarity in terms of common toxicity mechanisms or modes of action<br />
  4. 4. QSAR and Trend Analysis<br />QSAR research asks simple questions about why chemicals behave the way they do in all kinds of tests<br />If we wanted to model the boiling point of chemicals, we might start with a list of chemicals and their boiling points<br />In the following slide, chemicals were picked to give a wide range of boiling points<br />
  5. 5. Let’s Look at the Order in Boiling Point<br />Boiling Point (°C)<br />Chemical<br />Amyl amine<br />Amyl chloride<br />Dibromobenzene<br />Ethyl bromide<br />n-Heptanol<br />Methacrolein<br />Methyl-p-anisylketone<br />n-Octane<br />n-Nonane<br />103-4<br />98-9<br />219-2<br />38.4<br />192<br />68<br />267-9<br />126<br />151<br />
  6. 6. QSAR and Trend Analysis<br />If we reorder the chemicals to put the boiling points in ascending order, we have the next slide<br />The goal of QSAR would be to calculate molecular descriptors for each chemical and look for those giving the same order <br />If a molecular descriptor used in this canonical ordering produced an order different from that for measured boiling points, that descriptor would clearly not reflect the intra- and intermolecular forces controlling the boiling point <br />
  7. 7. Look for Order in Molecular Descriptors<br />Chemical<br />Boiling Point (°C)<br />Ethyl bromide<br />Methacrolein<br />Amyl chloride<br />Amyl amine<br />n-Octane<br />n-Nonane<br />n-Heptanol<br />Dibromobenzene<br />Methyl-p-anisylketone<br />38.4<br />68<br />98-9<br />103-4<br />126<br />151<br />192<br />219-2<br />267-9<br />
  8. 8. QSAR and Trend Analysis<br />In the next example, we might assume that we have compiled a set of toxicity values (LC50 in fish) for chemicals that are expected to be nonpolar narcotics<br />The actual toxicity values (chemical potency) for a single mechanism can range as much as six orders of magnitude<br />
  9. 9. 10+2<br />10 0<br />10_2<br />Acute <br />Toxicity<br />(Moles/L)<br />It is not uncommon to find endpoint<br />values spanning 6-10 orders for a <br />single toxicity mechanism <br />10_4<br />10_6<br />10-8<br />1<br />2<br />3<br />4<br />5<br />Chemical Class or Mechanism<br />Exploring Mechanisms with Simple Endpoints<br />
  10. 10. QSAR and Trend Analysis<br />As with boiling points, the QSAR approach evaluates molecular descriptors and identifies those descriptors that yield the same order as the LC50 values would provide <br />In this example, Log Kow explains most of the variance, as a correlation (or trend) emerges between LC50 and Log Kow<br />With a good trend between the structure and biological activity for one toxicity mechanism, the similarity of other chemicals can be judged from consistency with the trend<br />As we shall see, this type of trend analysis is the centerpiece of defining and defending chemical categories<br />
  11. 11. 10+2<br />10 0<br />Class #2<br />10_2<br />Acute<br />Toxicity<br />(moles/l)<br />10_4<br />10_6<br />10-8<br />0<br />2<br />4<br />6<br />8<br />LOG K o/w<br />Exploring Mechanisms with Simple Endpoints<br />
  12. 12. Nonpolar Narcotic Toxicants<br />
  13. 13. Oxidative Phosphorylase Uncouplers<br />LC50-96hr<br />MATC-30 day<br />
  14. 14. Reactive Chemicals (Electrophiles)<br />
  15. 15. Current Limitations in QSAR<br />The general QSAR approach is most reliable for chemicals where the parent chemical structure is the actual toxicant<br />One limitation has been predicting the effects of chemicals that are metabolically converted to more active (potent) metabolites<br />Predicting metabolic activation in many test species is a limitation being overcome with metabolic simulators (virtual livers, kidneys, skin, lung etc.)<br />Once the metabolites are predicted, the same library of toxicity models can be used on parent and metabolites to identify the most toxic form of the chemical<br />
  16. 16. Which Metabolite should we use in modeling interactions?<br />O<br />N<br />H<br />O<br />O<br />O<br />O<br />O<br />N<br />H<br />N<br />H<br />N<br />H<br />O<br />H<br />H<br />O<br />O<br />O<br />H<br />O<br />O<br />N<br />H<br />N<br />H<br />N<br />H<br />O<br />O<br />H<br />O<br />H<br />O<br />O<br />H<br />O<br />O<br />N<br />H<br />X<br />N<br />H<br />O<br />N<br />H<br />N<br />H<br />2<br />O<br />O<br />H<br />O<br />O<br />H<br />O<br />X<br />=<br />H<br />,<br />O<br />H<br />,<br />O<br />H<br />H<br />O<br />O<br />O<br />N<br />H<br />N<br />H<br />N<br />H<br />O<br />H<br />O<br />O<br />O<br />. . .<br />. . . <br />+<br />N<br />H<br />O<br />O<br />H<br />H<br />O<br />+<br />+<br />N<br />H<br />N<br />H<br />O<br />O<br />Simulated <br />2-Acetylaminofluorene<br /> Metabolism<br />Activated metabolites<br />
  17. 17. Current Limitations in QSAR<br />The general QSAR approach works well for short-term bioassays where steady-state exposures are achieved<br />Long-term toxic effects, particularly low-incident effects such as cancer, can result from a chemical perturbation of biological functions but are influenced by many other biological factors as well<br />QSAR models for long-term effects will be limited until modeling both chemistry and disease progression over time can be integrated<br />One promising approach to overcome this limitation is the use of adverse outcome pathways<br />
  18. 18. Adverse Outcome Pathway For<br />A Well-Defined Endpoint<br />Molecular<br />Initiating <br />Event<br />Speciation,<br />Metabolism<br />Reactivity<br />etc.<br />In Vitro <br />and <br />System <br />Effects<br />In Vivo<br />Adverse <br />Outcomes<br />Parent<br />Chemical<br />Chemical Interactions<br />Structure-Activity Relationships<br />Biological Responses<br />Effects at Different <br />Levels of Organization<br />
  19. 19. Molecular Initiating Event<br />Macro<br />-Molecular Interactions<br />Toxicant<br />Chemical Reactivity Profiles<br />Receptor, DNA,<br />Protein<br />Interactions<br />Biological Responses<br />Mechanistic Profiling<br />The Adverse Outcome Pathway<br />
  20. 20. Molecular Initiating Event<br />Biological Responses<br />Macro<br />-Molecular Interactions<br />Cellular<br />Toxicant<br />Chemical Reactivity Profiles<br />Gene Activation<br />Protein Production<br />Signal Alteration<br />Receptor, DNA,<br />Protein<br />Interactions<br />NRC Toxicological Pathway<br />The Adverse Outcome Pathway<br />
  21. 21. Molecular Initiating Event<br />Biological Responses<br />Macro<br />-Molecular Interactions<br />Cellular<br />Organ<br />Toxicant<br />Chemical Reactivity Profiles<br />Gene Activation<br />Protein Production<br />Signal Alteration<br />Altered<br />Function <br />Altered Development<br />Receptor, DNA,<br />Protein<br />Interactions<br />Mechanistic Profiling<br />In Vitro &<br />HTP Screening<br />The Adverse Outcome Pathway<br />
  22. 22. Molecular Initiating Event<br />Biological Responses<br />Macro<br />-Molecular Interactions<br />Cellular<br />Organ<br />Toxicant<br />Organism<br />Population<br />Chemical Reactivity Profiles<br />Gene Activation<br />Protein Production<br />Signal Alteration<br />Altered<br />Function <br />Altered Development<br />Lethality<br />Sensitization<br />Birth Defect<br />Reproductive Impairment<br />Cancer<br />Structure<br />Extinction<br />Receptor, DNA,<br />Protein<br />Interactions<br />Mechanistic Profiling<br />In Vitro &<br />HTP Screening<br />In Vivo<br />Testing<br />The Adverse Outcome Pathway<br />
  23. 23. Major Pathways for Reactive Toxicity from Moderate Electrophiles<br />Interaction<br />Mechanisms<br />Molecular<br />Initiating<br />Events<br />In vivo<br />Endpoints<br />Exposed<br />Surface<br />Irritation<br />Michael<br />Addition<br />Schiff base<br />Formation<br />SN2<br />Acylation<br />Atom<br />Centered<br /> Irreversible<br />(Covalent)<br />Binding <br />Necrosis:<br />Which Tissues?<br />Pr-S Adducts<br />GSH Oxidation<br />GSH Depletion<br />NH2 Adducts<br />RN Adducts<br />DNA Adducts<br />Oxidative <br />Stress<br />Systemic<br /> Responses<br />Skin<br />Liver<br />Lung<br />Systemic<br />Immune<br />Responses<br />Dose-Dependent Effects<br />

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