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Dosimetry in Risk Assessment and a bit More

Dosimetry in Risk Assessment and a bit More. Mel Andersen McKim Conference QSAR and Aquatic Toxicology & Risk Assessment June 27-29, 2006. Outline. Key components in toxicological evaluations Where are we likely to go with PK and PD models and how might SAR methods be helpful

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Dosimetry in Risk Assessment and a bit More

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  1. Dosimetry in Risk Assessment and a bit More Mel Andersen McKim Conference QSAR and Aquatic Toxicology & Risk Assessment June 27-29, 2006

  2. Outline • Key components in toxicological evaluations • Where are we likely to go with PK and PD models and how might SAR methods be helpful • Hand-off to Greg Lien

  3. Key Ideas in ToxicologyCSU 2000 • Mode of Action - more specifically ‘Chemical Mode of Action’ • Target Tissue Dosimetry • Dose-Response/Risk Assessment

  4. What tools help us evaluate these relationships? Pharmacokinetic models – calculate the tissue dose of active forms of the toxic chemical for various doses, dose-routes, and animal species Pharmacodynamic models – calculate the degree of response for any level of tissue dose in different species for differing exposure scenarios

  5. Physiologically Based Pharmacokinetic (PBPK) Modeling Air Metabolic Constants Tissue Solubility Tissue Volumes Blood and Air Flows Experimental System Lung Body Tissue Concentration X Fat X X X X X X Liver X Model Equations Time Define Realistic Model Make Predictions Collect Needed Data Refine Model Structure

  6. Using PBPK models – The Process 1987 Identify toxic effects in animals and people Evaluate available data on mode(s) of action, metabolism, chemistry of compound, metabolites and related chemicals Describe potential mode(s) of action Propose relationship between response and tissue dose Develop a PBPK model to calculate tissue doses Estimate tissue dose during toxic exposures with PBPK model

  7. Mode of Action • As in ‘Clue’, i.e., the butler in the pantry using the pipe wrench • The reactive intermediate in the hepatocytes creating DNA-adducts • The estrogenic compound binding the ER in the uterus to enhance cell proliferation.

  8. Extrapolations supported by these models High doses to low doses Dose route – inhalation, oral, dermal Among species Across classes of chemicals Dosing scenarios in vitro to in vivo

  9. McDougal et al., 1986. Toxicol. Appl. Pharmacol.,85, 286-294.

  10. Improving Use of Dosimetry for Evaluating Health Risks-ILSI/HESI Research ElementsSupporting Health Evaluations HUMAN BIOMONITORING TOXICITY TESTING (std animal tstg) b a Quantitative PK Methods “DOSIMETRY” d c • in vitro; • MOA STUDIES • Gene tox • Animal Alternatives EPIDEMIOLOGY

  11. Coverage of between 700 and 900 papers. • Volatiles • Persistent organics • Drugs • Inhaled Irritants • Dioxin-like Compounds • Metals • Siloxanes, etc. Get your copies at Wiley web-site – hurry, don’t wait, they are going fast.

  12. Dosimetry Directions • Develop parameter data bases for human PBPK models including improvements in QSAR approaches parameter estimation • Expand suite of ‘validated’ human PBPK models for biomonitoring research – human studies issues here • Extend quantiative approaches (experience) to study basic biological processes perturbed by chemical exposures

  13. Exposure----Dose-----Response Circa 1985 UNCERTAINTY Exposure Tissue Dose Biologically Effective Dose Early Responses Late Responses Pathology

  14. Perturbation of Biological Processes Exposure Tissue Dose Biological interaction Systems Inputs ‘Normal’ Biological Function Impaired Function Adaptation (Complex dose response relationships – thresholds & Hormesis) Disease Morbidity & Mortality

  15. Normal Epithelial Cell Pathology Necrosis Atrophy Conceptual model for cellular toxicity Tissue Phase Reactions Cl2 HOCl + HCl Ventilation Dosimetry Inhaled Stressors Adaptive State Stressed State Developed for Diesel Exhaust Particle (DEP) toxicity – referred to as hierarchical oxidative stress (Andre Nel)

  16. Normal Epithelial Cell Pathology Necrosis Atrophy Mechanistic Dose Response Models and Genomic Data Dosimetry Inhaled Irritant (3) (1) (2) Adaptive State Stressed State • Use specific in vivo studies to develop a dose response model for activation of oxidative stress pathway following irritant exposures and differentiate dose regions that activate adaptive processes from those associated with inflammation and apoptosis (high concentrations)

  17. A model for oxidative stress in Pathway Assist-automated model building and dose response HOCl and Nrf2 and Keap-1 Dose-Responses

  18. Response Models Directions • Focus on initial cellular responses and evaluate dose-response characteristics for these initial events mechanistically….for me these models focus on the chemical mode of action and accessible ‘quantitative biology’ • Develop data bases on cell response systems including dose response in a manner to enhance value for QSAR

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