QSAR Foundation Goals Facilitate promising QSAR technologies for setting priorities (TIMES-SS, Multipath, ASTER, OECD Toolbox) Encourage the expansion.

Reactive Toxicity: Progress Report on Filling the Gap Gilman Veith Logan UT March 23-24,2010

QSAR Foundation Goals Facilitate promising QSAR technologies for setting priorities (TIMES-SS, Multipath, ASTER, OECD Toolbox) Encourage the expansion of public domain databases and software for QSAR applications (ECOTOX, ER mediated toxicity) Develop high quality databases for QSAR modeling (inhalation for fish and rodents, nucleophile reactivity profiles) Provide QSAR training for regulators, business experts and students

Logan Workshop Goals Review progress on developing a systematic database for GSH reactivity Review progress on linking GSH reactivity to important hazard assessment endpoints Explore progress and options in selecting the next model nucleophile Explores possibilities for creating next systematic reactivity database.

Purpose of this Overview
Review the context for using QSAR in regulatory safety assessments in relation to drug design Summarize hazard assessment endpoints which can be modeled by QSAR methods and those that cannot. Review our conceptual framework for modeling long-term adverse outcomes needed in risk assessment Summarize progress on integrating QSAR with toxicity pathways for predictive hazard identification.

Initial Hazard Assessments
-Screening Information Datasets – SIDS -Globally Harmonised System of C&L – GHS -Registration, Evaluation, Authorisation and Restriction of Chemicals – REACH -PMNs – OPPT (predictive hazard identification) Testing Requirements – OPP

QSAR Endpoints (SIDS) Physicochemical Properties and Fate
Melting Point Boiling Point Vapour Pressure Log K o/w Log K orgC/w Water Solubility Biodegradation Rates Hydrolysis Rates Atmospheric Oxidation Rates Bioaccumulation

QSAR Endpoints (~SIDS)
Human Health Effects Acute Oral Toxicity Acute Inhalation Toxicity Acute Dermal Toxicity Skin/Eye Irritation Skin Sensitisation Repeated Dose Toxicity Reproductive Toxicity Developmental Toxicity Genotoxicity (in vitro) Genotoxicity (in vitro, non bacterial) Genotoxicity (in vivo) Carcinogenicity

QSAR Endpoints (SIDS) Ecological Effects
Acute Lethality – Fish (many species) Chronic Toxicity - Fish Acute Lethality - Daphnid Phytotoxicity, Growth Inhibition - Algae Repeated Dose Effects - Mammals

Gaps in QSAR Models QSAR models have been developed for well-defined in vivo endpoints (steady-state exposures) “Well-defined” excludes most long-term in vivo endpoints and most mammalian tests >10,000 QSAR models for in vitro endpoints not yet reliably scaled to in vivo potency QSAR-based Chemical Categories bridge some of these gaps while toxicity pathways are developed

Estimating Aquatic Toxicity
2 LC50-96hr MATC-30 day Water Solubility -2 Log Molar Concentration -4 When MOA same between Acute and Chronic (growth) about factor of 10 difference in potency Acute to Chronic (therefore – we have QSAR for Chronic Tox for non-polar narcotics). -6 -8 -2 2 4 6 8 Log P

Estimating Aquatic Toxicity
2 LC50-96hr Water Solubility -2 Log Molar Concentration -4 When MOA same between Acute and Chronic (growth) about factor of 10 difference in potency Acute to Chronic (therefore – we have QSAR for Chronic Tox for non-polar narcotics). -6 -8 -2 2 4 6 8 Log P

LogLC50 for fish or rat vs Solubility in water or air

Framework for Estimating Toxicity
2 LC50-96hr Water Solubility -2 Baseline Toxicity Log Molar Concentration “Excess” Toxicity -4 When MOA same between Acute and Chronic (growth) about factor of 10 difference in potency Acute to Chronic (therefore – we have QSAR for Chronic Tox for non-polar narcotics). -6 -8 -2 2 4 6 8 Log P

Which Conformation should we use to model interactions?

Why “Reactive Toxicity”?
Nonspecific Narcosis QSAR in 1980 Covers 60-70% of Industrial Chemicals Hundreds of QSARs for Physical Toxicity Largest Gap is Nonspecific Reactive Chemicals Little Progress in Modeling Reactive Toxicity Many Effects Endpoints for of Reactive Chemicals

Our Conceptual Framework
Chemical Speciation and Metabolism Molecular Initiating Events Measurable Biological Effects Adverse Outcomes Parent Chemical

Our Conceptual Framework
Speciation and Metabolism Molecular Initiating Events Measurable Biological Effects Adverse Outcomes Parent Chemical Response Pathways Chemistry/ Biochemistry QSAR 1. Identify Plausible Molecular Initiating Events 2. Design Database for Abiotic Binding Affinity/Rates 3. Develop QSARs to Predict Initiating Event from Structure 4. Quantify Response Pathways to Downstream Effects

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

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 Toxicology Question is: “What are the known biological effects from this altered target… cell type, organ, species ”

From the Library of Initiating Events
Chemical Speciation and Metabolism Library Of Molecular Initiating Events Measurable Biological Effects Adverse Outcomes Parent Chemical OECD Toolbox Chemical Profiler Handles the Chemistry for QSAR Models Conformations Targets Interactions Metabolic Simulators Inventories Structural Requirements

From the Library of Initiating Events
Chemical Speciation and Metabolism Library Of Molecular Initiating Events Measurable Biological Effects Adverse Outcomes Parent Chemical Altered Gonad Development Gene Activation ER Binding Impaired Reproduction Protein Production

Mechanistic Profiling
Molecular Initiating Event Macro -Molecular Interactions Toxicant Chemical Reactivity Profiles Receptor, DNA, Protein Interactions Biological Responses Mechanistic Profiling The Adverse Outcome Pathway

NRC Toxicological Pathway
Molecular Initiating Event Biological Responses Macro -Molecular Interactions Toxicant Cellular Chemical Reactivity Profiles Receptor, DNA, Protein Interactions Gene Activation Protein Production Signal Alteration NRC Toxicological Pathway The Adverse Outcome Pathway

Molecular Initiating Event Biological Responses Macro -Molecular Interactions Toxicant Cellular Organ Chemical Reactivity Profiles Receptor, DNA, Protein Interactions Gene Activation Protein Production Signal Alteration Altered Function Altered Development Mechanistic Profiling In Vitro & HTP Screening The Adverse Outcome Pathway

Molecular Initiating Event Biological Responses Macro -Molecular Interactions Toxicant Cellular Organ Organism Population Chemical Reactivity Profiles Receptor, DNA, Protein Interactions Gene Activation Protein Production Signal Alteration Altered Function Altered Development Lethality Sensitization Birth Defect Reproductive Impairment Cancer Structure Extinction Mechanistic Profiling In Vitro & HTP Screening In Vivo Testing The Adverse Outcome Pathway

Major Pathways for Reactive Toxicity from Moderate Electrophiles
Interaction Mechanisms Molecular Initiating Events In vivo Endpoints Exposed Surface Irritation Michael Addition Schiff base Formation SN2 Acylation Atom Centered Irreversible (Covalent) Binding Necrosis: Which Tissues? Pr-S Adducts GSH Oxidation GSH Depletion NH2 Adducts RN Adducts DNA Adducts Oxidative Stress Systemic Responses Skin Liver Lung Systemic Immune Responses Dose-Dependent Effects

Representation of ER binding pocket (LBD), with 3 sites of interaction shown (A, B, C), and recepter protein amino acids involved in interactions with chemical ligands. T 347 C C E 353 H 524 A B R 394 Interior of binding pocket of ER. Amino acids surrounding cavity are shown – sites determined via crystal structure of estradiol & xenobiotics. Interaction areas within the pocket labeled as A, B, C after J. Katzenellenbogen J. Katzenellenbogen

Distance = 10.8 for 17-Estradiol
A_B Interaction T 347 C E 353 H 524 H CH3 H A B HO OH R 394 Estradiol in the pocket – binding distance between oxygens on E2 Use average from high affinity binders? H H Distance = 10.8 for 17-Estradiol J. Katzenellenbogen

Adverse Outcome Pathway ER-mediated Reproductive Impairment
Measurements across levels of biological organization In vivo INDIVIDUAL Reproductive Impairment Rod’s talk demonstrates that the effect seen depends upon the development stage exposed, varies with gender, dose, time, etc. I think we can generalize this to talk about ER-mediated Adverse Outcome of “Altered Reproduction”; Recognizing that the specific effects are dependent on dose, gender, etc, but my questions is broader. It’s ER-mediated Reproductive Impairment. This is adequate for the Risk Context I’ll be focusing on. Focus (2 slides earlier) – Adverse Outcome pathway; for Inerts; our research has focused on ER-mediated repro impairment pathway; fish has been a convenient test species but we’re also using the research approach I’m describing and getting parallel information for ability of chemicals to interact with human ER; -in vivo – chemical enters body and gets to target tissue (left side of slide), in this case the liver of fish; chemical binds ER, and induces gene activation; in females produces egg protein that goes to blood, to ovary to make eggs; male fish have ER (don’t normally use it) because don’t have estrogen, but chemical binds their ER, VTG produced, goes to their gonad and eggs start to form in testicular tissue (called Ova-testes); in some individual complete sex reversal has been seen where gonad of what was supposed to be a male is a complete ovary; behavior can be altered; reproduction impaired; at popul sex ratios messed up and decrease in yr classes, etc. ADVERSE EFFECT in vivo is the risk endpoint we’re protected agst. -tox pathway is the target to cell rsp; there has been a lot of in vivo work already that shows adverse repro effects from low potency ER binders – so using in vitro assays to measure binding and develop QSAR-based prioritiz model from this is well grounded in an ADVERSE OUTCOME pathway that goes from target to adverse effect. -in vitro focus area (animated slide) – binding, and liver slice gene activation confirms for pos. binders that it effect happens in tissue; - QSAR focus area – based on binding

Measurements across levels of biological organization In vivo POPULATION INDIVIDUAL Skewed Sex Ratios; Yr Class Sex reversal; Altered behavior; Repro. Rod’s talk demonstrates that the effect seen depends upon the development stage exposed, varies with gender, dose, time, etc. I think we can generalize this to talk about ER-mediated Adverse Outcome of “Altered Reproduction”; Recognizing that the specific effects are dependent on dose, gender, etc, but my questions is broader. It’s ER-mediated Reproductive Impairment. This is adequate for the Risk Context I’ll be focusing on.

Measurements across levels of biological organization In vivo POPULATION TISSUE/ORGAN INDIVIDUAL Skewed Sex Ratios; Yr Class Liver Altered gene products (timing, amt) Gonad Ova-testis; Sex-reversed; Fecundity Sex reversal; Altered behavior; Repro. Rod’s talk demonstrates that the effect seen depends upon the development stage exposed, varies with gender, dose, time, etc. I think we can generalize this to talk about ER-mediated Adverse Outcome of “Altered Reproduction”; Recognizing that the specific effects are dependent on dose, gender, etc, but my questions is broader. It’s ER-mediated Reproductive Impairment. This is adequate for the Risk Context I’ll be focusing on. Focus (2 slides earlier) – Adverse Outcome pathway; for Inerts; our research has focused on ER-mediated repro impairment pathway; fish has been a convenient test species but we’re also using the research approach I’m describing and getting parallel information for ability of chemicals to interact with human ER; -in vivo – chemical enters body and gets to target tissue (left side of slide), in this case the liver of fish; chemical binds ER, and induces gene activation; in females produces egg protein that goes to blood, to ovary to make eggs; male fish have ER (don’t normally use it) because don’t have estrogen, but chemical binds their ER, VTG produced, goes to their gonad and eggs start to form in testicular tissue (called Ova-testes); in some individual complete sex reversal has been seen where gonad of what was supposed to be a male is a complete ovary; behavior can be altered; reproduction impaired; at popul sex ratios messed up and decrease in yr classes, etc. ADVERSE EFFECT in vivo is the risk endpoint we’re protected agst. -tox pathway is the target to cell rsp; there has been a lot of in vivo work already that shows adverse repro effects from low potency ER binders – so using in vitro assays to measure binding and develop QSAR-based prioritiz model from this is well grounded in an ADVERSE OUTCOME pathway that goes from target to adverse effect. -in vitro focus area (animated slide) – binding, and liver slice gene activation confirms for pos. binders that it effect happens in tissue; - QSAR focus area – based on binding

Measurements across levels of biological organization In vivo CELLULAR Response POPULATION TISSUE/ORGAN INDIVIDUAL Skewed Sex Ratios; Yr Class Liver Altered gene products (timing, amt) Gonad Ova-testis; Sex-reversed; Fecundity Liver Cells Altered Protein Expression (marker) (effect) Vitellogenin Sex reversal; Altered behavior; Repro. Rod’s talk demonstrates that the effect seen depends upon the development stage exposed, varies with gender, dose, time, etc. I think we can generalize this to talk about ER-mediated Adverse Outcome of “Altered Reproduction”; Recognizing that the specific effects are dependent on dose, gender, etc, but my questions is broader. It’s ER-mediated Reproductive Impairment. This is adequate for the Risk Context I’ll be focusing on. Focus (2 slides earlier) – Adverse Outcome pathway; for Inerts; our research has focused on ER-mediated repro impairment pathway; fish has been a convenient test species but we’re also using the research approach I’m describing and getting parallel information for ability of chemicals to interact with human ER; -in vivo – chemical enters body and gets to target tissue (left side of slide), in this case the liver of fish; chemical binds ER, and induces gene activation; in females produces egg protein that goes to blood, to ovary to make eggs; male fish have ER (don’t normally use it) because don’t have estrogen, but chemical binds their ER, VTG produced, goes to their gonad and eggs start to form in testicular tissue (called Ova-testes); in some individual complete sex reversal has been seen where gonad of what was supposed to be a male is a complete ovary; behavior can be altered; reproduction impaired; at popul sex ratios messed up and decrease in yr classes, etc. ADVERSE EFFECT in vivo is the risk endpoint we’re protected agst. -tox pathway is the target to cell rsp; there has been a lot of in vivo work already that shows adverse repro effects from low potency ER binders – so using in vitro assays to measure binding and develop QSAR-based prioritiz model from this is well grounded in an ADVERSE OUTCOME pathway that goes from target to adverse effect. -in vitro focus area (animated slide) – binding, and liver slice gene activation confirms for pos. binders that it effect happens in tissue; - QSAR focus area – based on binding

Measurements across levels of biological organization In vivo CELLULAR Response POPULATION MOLECULAR Target TISSUE/ORGAN INDIVIDUAL Skewed Sex Ratios; Yr Class Liver Altered gene products (timing, amt) Gonad Ova-testis; Sex-reversed; Fecundity Liver Cells Altered Protein Expression (marker) (effect) Vitellogenin Sex reversal; Altered behavior; Repro. Receptor Binding ER-Chemical Binding Rod’s talk demonstrates that the effect seen depends upon the development stage exposed, varies with gender, dose, time, etc. I think we can generalize this to talk about ER-mediated Adverse Outcome of “Altered Reproduction”; Recognizing that the specific effects are dependent on dose, gender, etc, but my questions is broader. It’s ER-mediated Reproductive Impairment. This is adequate for the Risk Context I’ll be focusing on. Focus (2 slides earlier) – Adverse Outcome pathway; for Inerts; our research has focused on ER-mediated repro impairment pathway; fish has been a convenient test species but we’re also using the research approach I’m describing and getting parallel information for ability of chemicals to interact with human ER; -in vivo – chemical enters body and gets to target tissue (left side of slide), in this case the liver of fish; chemical binds ER, and induces gene activation; in females produces egg protein that goes to blood, to ovary to make eggs; male fish have ER (don’t normally use it) because don’t have estrogen, but chemical binds their ER, VTG produced, goes to their gonad and eggs start to form in testicular tissue (called Ova-testes); in some individual complete sex reversal has been seen where gonad of what was supposed to be a male is a complete ovary; behavior can be altered; reproduction impaired; at popul sex ratios messed up and decrease in yr classes, etc. ADVERSE EFFECT in vivo is the risk endpoint we’re protected agst. -tox pathway is the target to cell rsp; there has been a lot of in vivo work already that shows adverse repro effects from low potency ER binders – so using in vitro assays to measure binding and develop QSAR-based prioritiz model from this is well grounded in an ADVERSE OUTCOME pathway that goes from target to adverse effect. -in vitro focus area (animated slide) – binding, and liver slice gene activation confirms for pos. binders that it effect happens in tissue; - QSAR focus area – based on binding

Measurements made across levels of biological organization QSAR focus area In vitro Assay focus area In vivo CELLULAR Response POPULATION MOLECULAR Target TISSUE/ORGAN INDIVIDUAL Skewed Sex Ratios; Yr Class Liver Altered proteins Gonad Ova-testis; Sex-reversed; Fecundity Liver Cells Altered Protein Expression Vitellogenin Sex reversal; Altered behavior; Repro. Receptor Binding ER Binding Chemicals Focus (2 slides earlier) – Adverse Outcome pathway; for Inerts; our research has focused on ER-mediated repro impairment pathway; fish has been a convenient test species but we’re also using the research approach I’m describing and getting parallel information for ability of chemicals to interact with human ER; -in vivo – chemical enters body and gets to target tissue (left side of slide), in this case the liver of fish; chemical binds ER, and induces gene activation; in females produces egg protein that goes to blood, to ovary to make eggs; male fish have ER (don’t normally use it) because don’t have estrogen, but chemical binds their ER, VTG produced, goes to their gonad and eggs start to form in testicular tissue (called Ova-testes); in some individual complete sex reversal has been seen where gonad of what was supposed to be a male is a complete ovary; behavior can be altered; reproduction impaired; at popul sex ratios messed up and decrease in yr classes, etc. ADVERSE EFFECT in vivo is the risk endpoint we’re protected agst. -tox pathway is the target to cell rsp; there has been a lot of in vivo work already that shows adverse repro effects from low potency ER binders – so using in vitro assays to measure binding and develop QSAR-based prioritiz model from this is well grounded in an ADVERSE OUTCOME pathway that goes from target to adverse effect. -in vitro focus area (animated slide) – binding, and liver slice gene activation confirms for pos. binders that it effect happens in tissue; - QSAR focus area – based on binding Risk Assessment Relevance Toxicological Understanding

ER-mediated Adverse-outcome Pathway
Amylaniline (AAN) Molecular Cellular Organ Individual Population AAN binding to ER Liver slice Vtg (mRNA) Liver slice toxicity Altered reproduction Altered development Decreased numbers of animals In-vitro pathway Schmieder et.al. ER transcription factor In-vivo pathway Multigen assay Molecular Cellular Organ Individual Population ♂ Liver Vtg (mRNA) AAN binding to ER ER transcription factors dose: Sex reversal (altered gamete ratios) ? Anal fin papillae ? Altered sex-ratios dose: Mixed-sex gonad ? Gonadal morphology ? Population reduction ? dose: Reduced fecundity AAN binding to Hbg ? ? Splenic/head-kidney pathology ? dose: Reduced growth

Thyroid MOAs

Hearing Loss from Dioxins, Furans and PCBs (Planar Risk)
Binding to PXR Hepatic Parent or Metabolite Exposure Hepatic Phase II Enzymes Binding to AhR Alter TR Mediated Proteins Loss of cochlear hair cells  Serum T4 & T3  Tissue T3 Hearing Loss

“Narcosis” Pathways for Volatile Anesthetics
Primary Brain Region Ion Channel Receptor Cellular Response Tissue Response Behavioral Effects GABAA Increased channel-open time Facilitated inhibitory transmission Cortex - Thalamus Light Sedation Amnesia Anxiolysis nACh Decreased channel-open time Reduced excitatory transmission Hippocampus Heavy Sedation Slow responses Agent Increasing Depth of Anesthesia Reduced membrane current Reduced excitatory transmission Brain Stem Unconsciousness Loss of perceptual awareness NMDA Glycine Increased duration of mIPSCs Facilitated inhibitory transmission Spinal Cord Immobility Loss of pain response Kinetics Dynamics

Immobility Pathway for Isoflurane
Primary Brain Region Ion Channel Receptor Cellular Response Tissue Response Behavioral Effects GABAA Increased channel-open time Facilitated inhibitory transmission Cortex - Thalamus Light Sedation Amnesia Anxiolysis Increasing Depth of Anesthesia nACh Decreased channel-open time Reduced excitatory transmission Hippocampus Heavy Sedation Slow responses Agent Reduced membrane current Reduced excitatory transmission Brain Stem Unconsciousness Loss of perceptual awareness NMDA Glycine Increased duration of mIPSCs Facilitated inhibitory transmission Spinal Cord Immobility Loss of pain response Kinetics Dynamics

Amnesia Pathway for Isoflurane
Primary Brain Region Ion Channel Receptor Cellular Response Tissue Response Behavioral Effects GABAA Increased channel-open time Facilitated inhibitory transmission Cortex - Thalamus Light Sedation Amnesia Anxiolysis Increasing Depth of Anesthesia nACh Decreased channel-open time Reduced excitatory transmission Hippocampus Heavy Sedation Slow responses Agent NMDA Reduced membrane current Reduced excitatory transmission Brain Stem Unconsciousness Loss of perceptual awareness Glycine Increased duration of mIPSCs Facilitated inhibitory transmission Spinal Cord Immobility Loss of pain response Kinetics Dynamics

Effectopedia Cause Link Effect

Pathways for Reactive Toxicity
Molecular Initiating Events In vitro Endpoints Interaction Mechanisms In vivo Endpoints Membrane Alteration _ Oxidative Stress Genotoxicity Death Impaired Growth Impaired Development Reproduction 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 Dose-Dependent Pathways Species/Sex/Life-Stage

Two Questions for Building Pathways
Direct Reaction Effect #1 Pr-S Adducts GSH Oxidation GSH Depletion NH2 Adducts RN Adducts DNA Adducts Altered Synthesis Effect #2 Oxidation Effect #3 How Many Ways to Deplete GSH? How Many Downstream Effects?

Delineation of Toxicity Pathways
Linkages Across Levels of Biological Organization In vivo Methods In Silico Methods In vitro Methods Molecular/ Subcellular Electronic Cell Tissue Organ Individual Exposure/ Metabolism Penetration Routes Detoxification Pathways Activation Chemical Reactivity Profiles Reversible Nonspecific Binding Specific Covalent Response Pathways Regulatory Endpoints Chemical Inventories Molecular Initiating Events Membranes Energy Charge Nuclear Receptors Protein Synthesis DNA Integrity Lethality Growth Development Reproduction More Relevant Endpoints Intrinsic Chemical Attributes Better Defined Endpoints

Major Pathway for Reactive Toxicants To Fish
Vulnerable Organ Pathology Molecular Initiating Events Interaction Mechanisms In vivo Endpoints Pathogenesis Michael Addition Schiff base Formation SN2 Acylation Atom Centered Irreversible (Covalent) Protein Binding Death from Suffocation “Any Exposed Surface” Changes Necrosis of the Gill Epithelium Complexes Membranes, etc

Pathways for Reactive Toxicity from Soft Electrophiles
Mechanisms Molecular Initiating Events In vivo Endpoints Michael Addition Schiff base Formation SN2 Acylation Atom Centered Irreversible (Covalent) Protein Binding Exposed Surface Irritation Necrosis Skin Lung/Gills GI Tract No Immunogenic Systemic Immune Responses Systemic Responses Skin Liver Lung Yes

Major Pathways for Reactive Toxicity from Moderate Electrophiles
Interaction Mechanisms Molecular Initiating Events In vivo Endpoints Exposed Surface Irritation Michael Addition Schiff base Formation SN2 Acylation Atom Centered Irreversible (Covalent) Binding Necrosis Which Tissues? Pr-S Adducts GSH Oxidation GSH Depletion NH2 Adducts RN Adducts DNA Adducts Oxidative Stress Systemic Responses Skin Liver Lung Systemic Immune Responses Dose-Dependent Effects

2-Acetylaminofluorene
Which Metabolite should we use in modeling interactions? Simulated 2-Acetylaminofluorene Metabolism

α = С x γ Baseline Toxicity
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 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

? ? Deterministic Endpoints Probabilistic Endpoints Chemical
Inventories Chemical Properties Non-Specific Pathways Receptor-Based Pathways Deterministic Endpoints Structures QSAR Library (24,000) Conformational Analysis Virtual Metabolism ? Probabilistic Endpoints Nonreactive Families Reactive Families Antigenic Conjugate Immune Response Quenching Overload? ? Mutagenicity DNA Damage Detoxication Low High Carcinogenicity Critical Cellular Targets Necrosis Excretion Genome-Specific Endogenous Factors Test Method-Specific Factors

Peffect = P1 x P2 x P3 x P4 x …Pn Probabilistic Models
Forecasting distinct probabilities of low incident outcomes like idiosyncratic hepatic failure requires probability distributions for critical steps rather than effects under standard conditions Exposure of the individual Delivery rate to liver Formation of reactive metabolites Exceed detoxification rates Covalent binding with proteins Formation of neoantigens Immune system recognition Formation of cytotoxic antibodies Interaction with hepatocytes Overwhelm repair mechanisms Liver Function Impairment Liver Failure --after Li (2002)

Probabilistic Models for Prioritization
Prioritization does not require explicit estimates of toxicity but rather a reliable ordering with respect to explicit risk management scenarios Peffect = Pchem x Pexposure x Penviron x Pgenetic Chemical Reactivity Profiles Risk Management Scenarios

QSAR Foundation Goals Facilitate promising QSAR technologies for setting priorities (TIMES-SS, Multipath, ASTER, OECD Toolbox) Encourage the expansion.

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QSAR Foundation Goals Facilitate promising QSAR technologies for setting priorities (TIMES-SS, Multipath, ASTER, OECD Toolbox) Encourage the expansion.

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Presentation on theme: "QSAR Foundation Goals Facilitate promising QSAR technologies for setting priorities (TIMES-SS, Multipath, ASTER, OECD Toolbox) Encourage the expansion."— Presentation transcript:

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