Introduction Why Molecular Mechanisms? Toxicokinetics and Toxicodynamics Types of Toxic Responses Adaptation to Cellular Stress Toxic Responses Disruption of Cytoprotective Mechanisms Organ-Selective Toxicity Biological Basis of Organ-Selective Toxicity Selective Hepatotoxicity and Nephrotoxicity Cellular Transport and Selective Accumulation of Potentially Toxic Xenobiotics Transmembrane Transport of Xenobiotics Cell-Specific Delivery of Xenobiotics to Intracellular Targets by Physiological Uptake Systems Xenobiotic Export Pumps Bioactivation of Xenobiotics to Reactive Metabolites Biotransformation and Bioactivation/-Inactivation Phase I (Functionalization) and Phase II (Conjugation) Reactions Net Balance of Bioactivation/Bioinactivation for Risk Assessment Mechanisms of Phototoxicity Protective Mechanisms Against Reactive Metabolites: The Stress Response Xenobiotic-Induced Oxidative Stress: Cell Injury, Signaling, and Gene Regulation Reactive Oxygen Species (ROS) and Oxidoreductive Stress Toxicological Consequences of Oxidative Stress Interference with Antioxidant Defense Mechanisms Intracellular Signaling and Gene Regulation by Oxidative Stress Disruption of Cellular Calcium Homeostasis Xenobiotic-Induced Alterations in Intracellular Ca2+Distribution Toxicological Consequences of Increased Cytosolic Ca2+Concentrations Mechanisms of Necrotic and Apoptotic Cell Death Necrosis Apoptosis Impairment of Cell Proliferation and Tissue Repair The Cell Cycle Stimulation of DNA Synthesis and Cell Proliferation: Xenobiotics as Mitogens Inhibition of Cell Proliferation by Xenobiotics Inhibition of Tissue Repair Covalent Binding of Reactive Metabolites to Cellular Macromolecules Electrophiles and Nucleophilic Targets Covalent Protein Binding Covalent DNA Binding Immune Mechanisms Xenobiotic-Induced Activation of the Innate Immune System Immunosuppression by Xenobiotics Immune-Mediated Toxicity Cytokine-Mediated Toxicity Tumor Necrosis Factor-a and Other Proinflammatory Cytokines Chemokines and Inflammatory Cell Recruitment Specific Inactivation of Enzymes and Other Proteins Inactivation of Thiol-Containing Enzymes Disruption of Acetylcholinesterase Activity Transthyretin Binding and Inactivation: Disruption of Thyroid Function Inactivation of DNA-mismatch-repair Proteins Interactions of Xenobiotics with Ion Transporters Interactions with Neuronal Na+Channels Interactions with the Na+/K+Pump Selective Inhibition of Cardiac Myocyte K+Channels and QT Prolongation Nuclear Receptor-Mediated Toxicity The Aryl Hydrocarbon Receptor (AHR) Xenoestrogens and Antiandrogens Peroxisome Proliferator-Activated Receptors (PPARs) Retinoic Acid Receptor (RAR) Activation or Disruption of Cellular Signal Transduction by Xenobiotics Signaling: Sensing and Responding Interference with Signal Transduction by Xenobiotics Disruption of Mitochondrial Function and Mitochondria-Mediated Toxicity Mitochondrial Targets and Xenobiotic-Induced Bioenergy Crisis Protonophoretic and Uncoupling Activity of Xenobiotics Inhibition of NADH Production Inhibition of the Electron Transport Chain and Increased Generation of ROS Mitochondrial Membrane Permeabilization Selective Depletion of Mitochondrial DNA Novel Mechanisms Derived from Systems Toxicology Indexoactivation/Bioinactivation for Risk Assessment Mechanisms of Phototoxicity Protective Mechanisms Against Reactive Metabolites: The Stress Response Xenobiotic-Induced Oxidative Stress: Cell Injury, Signaling, and Gene Regulation Reactive Oxygen Species (ROS) and Oxidoreductive Stress Toxicological Consequences of Oxidative Stress Interference with Antioxidant Defense Mechanisms Intracellular Signaling and Gene Regulation by Oxidative Stress Disruption of Cellular Calcium Homeostasis Xenobiotic-Induced Alterations in Intracellular Ca2+Distribution Toxicological Consequences of Increased Cytosolic Ca2+Concentrations Mechanisms of Necrotic and Apoptotic Cell Death Necrosis Apoptosis Impairment of Cell Proliferation and Tissue Repair The Cell Cycle Stimulation of DNA Synthesis and Cell Proliferation: Xenobiotics as Mitogens Inhibition of Cell Proliferation by Xenobiotics Inhibition of Tissue Repair Covalent Binding of Reactive Metabolites to Cellular Macromolecules Electrophiles and Nucleophilic Targets Covalent Protein Binding Covalent DNA Binding Immune Mechanisms Xenobiotic-Induced Activation of the Innate Immune System Immunosuppression by Xenobiotics Immune-Mediated Toxicity Cytokine-Mediated Toxicity Tumor Necrosis Factor-a and Other Proinflammatory Cytokines Chemokines and Inflammatory Cell Recruitment Specific Inactivation of Enzymes and Other Proteins Inactivation of Thiol-Containing Enzymes Disruption of Acetylcholinesterase Activity Transthyretin Binding and Inactivation: Disruption of Thyroid Function Inactivation of DNA-mismatch-repair Proteins Interactions of Xenobiotics with Ion Transporters Interactions with Neuronal Na+Channels Interactions with the Na+/K+Pump Selective Inhibition of Cardiac Myocyte K+Channels and QT Prolongation Nuclear Receptor-Mediated Toxicity The Aryl Hydrocarbon Receptor (AHR) Xenoestrogens and Antiandrogens Peroxisome Proliferator-Activated Receptors (PPARs) Retinoic Acid Receptor (RAR) Activation or Disruption of Cellular Signal Transduction by Xenobiotics Signaling: Sensing and Responding Interference with Signal Transduction by Xenobiotics Disruption of Mitochondrial Function and Mitochondria-Mediated Toxicity Mitochondrial Targets and Xenobiotic-Induced Bioenergy Crisis Protonophoretic and Uncoupling Activity of Xenobiotics Inhibition of NADH Production Inhibition of the Electron Transport Chain and Increased Generation of ROS Mitochondrial Membrane Permeabilization Selective Depletion of Mitochondrial DNA Novel Mechanisms Derived from Systems Toxicology Indexr The Cell Cycle Stimulation of DNA Synthesis and Cell Proliferation: Xenobiotics as Mitogens Inhibition of Cell Proliferation by Xenobiotics Inhibition of Tissue Repair Covalent Binding of Reactive Metabolites to Cellular Macromolecules Electrophiles and Nucleophilic Targets Covalent Protein Binding Covalent DNA Binding Immune Mechanisms Xenobiotic-Induced Activation of the Innate Immune System Immunosuppression by Xenobiotics Immune-Mediated Toxicity Cytokine-Mediated Toxicity Tumor Necrosis Factor-a and Other Proinflammatory Cytokines Chemokines and Inflammatory Cell Recruitment Specific Inactivation of Enzymes and Other Proteins Inactivation of Thiol-Containing Enzymes Disruption of Acetylcholinesterase Activity Transthyretin Binding and Inactivation: Disruption of Thyroid Function Inactivation of DNA-mismatch-repair Proteins Interactions of Xenobiotics with Ion Transporters Interactions with Neuronal Na+Channels Interactions with the Na+/K+Pump Selective Inhibition of Cardiac Myocyte K+Channels and QT Prolongation Nuclear Receptor-Mediated Toxicity The Aryl Hydrocarbon Receptor (AHR) Xenoestrogens and Antiandrogens Peroxisome Proliferator-Activated Receptors (PPARs) Retinoic Acid Receptor (RAR) Activation or Disruption of Cellular Signal Transduction by Xenobiotics Signaling: Sensing and Responding Interference with Signal Transduction by Xenobiotics Disruption of Mitochondrial Function and Mitochondria-Mediated Toxicity Mitochondrial Targets and Xenobiotic-Induced Bioenergy Crisis Protonophoretic and Uncoupling Activity of Xenobiotics Inhibition of NADH Production Inhibition of the Electron Transport Chain and Increased Generation of ROS Mitochondrial Membrane Permeabilization Selective Depletion of Mitochondrial DNA Novel Mechanisms Derived from Systems Toxicology Index Activity Transthyretin Binding and Inactivation: Disruption of Thyroid Function Inactivation of DNA-mismatch-repair Proteins Interactions of Xenobiotics with Ion Transporters Interactions with Neuronal Na+Channels Interactions with the Na+/K+Pump Selective Inhibition of Cardiac Myocyte K+Channels and QT Prolongation Nuclear Receptor-Mediated Toxicity The Aryl Hydrocarbon Receptor (AHR) Xenoestrogens and Antiandrogens Peroxisome Proliferator-Activated Receptors (PPARs) Retinoic Acid Receptor (RAR) Activation or Disruption of Cellular Signal Transduction by Xenobiotics Signaling: Sensing and Responding Interference with Signal Transduction by Xenobiotics Disruption of Mitochondrial Function and Mitochondria-Mediated Toxicity Mitochondrial Targets and Xenobiotic-Induced Bioenergy Crisis Protonophoretic and Uncoupling Activity of Xenobiotics Inhibition of NADH Production Inhibition of the Electron Transport Chain and Increased Generation of.