Biomarkers of Susceptibility.ppt

Environmental Disease Stochastic Modeling and Risk Assessment Group - LCBRA In each focused research area mathematical and statistical methods novel modeling structures strong biological linkage analysis tools for DIR scientists translation from the laboratory to health policy qualitative quantitative PBPK Model for Dioxin Other PBPK Models 1,3-butadiene Methyleugenol Anthraquinone Sodium Nitrite Dichloromethane PCB’s Primidone AZT Melatonin Estrogen, progesterone, etc. Uses of PBPK Models Test hypotheses Shape of exposure/internal dose Equivalence of metabolism, etc. across species, sexes Prediction Equivalent exposures for a given risk Design experiments Tissue concentrations TCDD Liver Biochemistry TCDD Transcriptional Activation Message includes poly(A) tail Poly(A) nuclease degrades tail 24 nt/hr Message removed after tail 1.2 hours T1/2 Ribosome binding protects message Mathematically….. CYP mRNA Induction Other Biochemical Models Privileged Access Model Localized metabolism Cell-Cycle Kinetics G0-G1 in hepatocytes Receptor binding/gene expression Sodium channel kinetics Uses of Biochemical Models Hypothesis testing Proposed mechanisms Alpha-2U TCDD activates Epoxide is the penultimate carcinogen Thresholds Equivalence across species, sex Prediction Mechanism-based extrapolation Use of in-vitro data Impact of genetic polymorphisms Impact of competition for binding sites Identify data gaps Simple Two-Stage Cancer Model Combining Two-Stage and PBPK Mathematically…… Colonic Crypts Two-Stage Model with Controlled Replication Five Stage Colon Cancer Model Concerning model Uses of Stochastic Models Cancer New methods Observable tumors Physiologically realistic models Better statistical approaches MCMC Hypothesis testing Prediction of risk Other Endpoints Development Spermatogenesis Controlled differentiation Pharmacology Stochastic processes Other Stuff Data analysis Graph theory * National Institute of Environmental Health Sciences NIEHS * Biomarkers of Suscepti