1. McKim Conference on Predictive Toxicology The Inn of Lake Superior Duluth, Minnesota September 25-27, 2007 Narcosis as a Reference Gilman Veith

2. Molecular Initiating Events Chemical Speciation and Metabolism Measurable System Effects Adverse Outcomes Parent Chemical Conceptual Framework Rather than developing statistical models of complex endpoints, key molecular initiating events become the “well-defined” endpoints for QSAR.

3. Molecular Initiating Events Speciation and Metabolism Measurable System Effects Adverse Outcomes Parent Chemical IQF Framework for QSAR 1. Identify Plausible Molecular Initiating Events 2. Design Database for Abiotic Binding Affinity/Rates 3. Explore Linkages in Pathways to Downstream Effects 4. Develop QSARs to Predict Initiating Event from Structure QSAR SystemsBiology Chemistry/Biochemistry

4. -6.00-5.50-5.00-4.50-4.00-3.50-3.00-2.50 Log Molar Concentration 0 25 50 75 100 125 Growth-Wet Weight (mg) 0 20 40 60 80 100 % Survival Octanol Growth-WW Acute Surv -6.00-5.50-5.00-4.50-4.00-3.50-3.00-2.50 Log Molar Concentration 0 5 10 15 20 25 30 35 Growth-Dry Weight (mg) 0 20 40 60 80 100 % Survival 2,4-Dinitrophenol Growth-DW Acute Surv -6.00-5.50-5.00-4.50-4.00-3.50-3.00-2.50 Log Molar Concentration 0 25 50 75 100 125 Growth-Wet Weight (mg) 0 20 40 60 80 100 Aniline Growth-WW Acute Surv % Survival

5. Appropriate Dose Metric Response Endpoint Subcellular Cell Tissue Chronic Whole Organism Acute Whole Organism

6. -202468 Log P -8 -6 -4 -2 0 2 Log Molar Concentration Framework for Estimating Toxicity Water Solubility

7. -202468 Log P -8 -6 -4 -2 0 2 Log Molar Concentration Framework for Estimating Toxicity LC 50 -96hr-fish Narcosis Water Solubility

8. Framework for Estimating Toxicity

9. -202468 Log P -8 -6 -4 -2 0 2 Log Molar Concentration Framework for Estimating Toxicity LC 50 -96hr Water Solubility

10. Framework for Estimating Toxicity

11. -202468 Log P -8 -6 -4 -2 0 2 Log Molar Concentration Framework for Estimating Toxicity LC 50 -96hr MATC-30 day Water Solubility

12. -202468 Log P -8 -6 -4 -2 0 2 Log Molar Concentration Framework for Estimating Toxicity LC 50 -96hr Water Solubility Baseline Toxicity “Excess” Toxicity

13. Water Solubility LC 50 -96hr MATC-30 day LC 50 -96hr MATC-30 day Ox PHos Uncouplering Mechanism

14. Water Solubility LC 50 -96hr MATC-30 day Ox PHos Uncouplering Mechanism Category/ Endpoint Constant

15. -202468 Log P -8 -6 -4 -2 0 2 Log Molar Concentration Framework for Estimating Toxicity LC 50 -96hr-fish Narcosis Water Solubility Hazard Index Sublethal Effect

16. -202468 Log P -8 -6 -4 -2 0 2 Log Molar Concentration Framework for Estimating Toxicity LC 50 -96hr-fish Narcosis Water Solubility Sublethal Effect Acute/ Chronic Ratio

17. Appropriate Dose Metric Response Endpoint Subcellular Cell Tissue Chronic Whole Organism Acute Whole Organism

18. For ACRYLATES & METHACRYLATES there is no relationship with Vapor Pressure but significant correlation with GSH reactivity LC50 vs GSH reactivity for acrylates and methacrylates

19. Solubility in air and Lethal Concentration vs Vapor Pressure for narcotics (rat/4h)

20.  Fish and mammal inhalation baseline toxicity are not directly comparable because the external media are different  However, blood thermodynamic activity for LC50(nar) should be the same in fish and mammal  At steady-state, the activity in air/water equals the activity in blood by definition : α = С x γ α – activity; C- concentration; γ-activity coefficient Baseline Toxicity

21.  The thermodynamic activity at any concentration can be estimated by dividing by the solubility in the medium  activity for narcosis in fish = LC50(fish)/water solubility activity for narcosis in rat = LC50 (rat)/air solubility  if activity for narcosis in fish and rat were equal, the plot of LC50 versus solubility in exposure medium should be the same Baseline Toxicity

22. LogLC50 for fish or rat vs Solubility in water or air