The Toxicology of Methanol -- Contents -- Preface -- Contributors -- 1 Methanol Production and Markets: Past, Present, and Future -- 2 Methanol: Fate and Transport in the Environment -- 2.1 Introduction -- 2.1.1 Release Scenarios -- 2.1.2 Fate in the Environment -- 2.2 Partitioning of Methanol in the Environment -- 2.2.1 Methanol Partitioning Among Environmental Media -- 2.2.2 Air/Water Partitioning -- 2.2.3 Soil/Water Partitioning -- 2.2.4 Methanol Dissolution -- 2.2.5 Commingling/Cosolvency Effects -- 2.3 Fate and Transport of Methanol in the Environment -- 2.3.1 Soil and/or Groundwater Release -- 2.3.1.1 Sources of Methanol in Soil and Groundwater -- 2.3.1.2 Losses of Methanol from Soil and Groundwater -- 2.3.1.3 Methanol/BTEX Commingled Plumes -- 2.3.2 Surface Water Release -- 2.3.2.1 Sources of Methanol in Surface Water -- 2.3.2.2 Losses of Methanol in Surface Water -- 2.4 Methanol Additives -- 2.4.1 Luminosity -- 2.4.2 Taste -- 2.5 Conclusions -- References -- 3 Human Toxicity -- 3.1 Introduction -- 3.2 Exposure -- 3.2.1 Dietary -- 3.2.2 Environmental -- 3.3 Metabolism in Humans -- 3.3.1 Normal -- 3.3.2 High Exposure -- 3.3.3 Over Exposure -- 3.3.3.1 Symptoms -- 3.3.3.2 Blood and Urine Methanol -- 3.3.3.3 Urinary Formic Acid -- 3.3.3.4 Breath-Methanol Levels -- 3.4 History of Human Toxicity -- 3.4.1 Occupational -- 3.4.2 Ingestion -- 3.4.3 Dermal -- 3.5 Controlled Human Studies -- 3.6 In Utero Exposure -- 3.7 Repeat Inhalation Exposure -- 3.8 Management of Methanol Poisoning -- 3.9 Conclusions -- References -- 4 General Animal and Aquatic Toxicity -- 4.1 Introduction -- 4.2 Acute Toxicity -- 4.2.1 Oral -- 4.2.2 Dermal -- 4.2.3 Inhalation -- 4.2.4 Intraperitoneal -- 4.2.5 Subcutaneous -- 4.2.6 Intravenous -- 4.2.7 Other Acute Studies -- 4.3 Irritation -- 4.3.1 Dermal -- 4.3.2 Eye -- 4.4 Sensitization -- 4.5 Repeat Exposure-Inhalation.

4.5.1 Non-Human Primates -- 4.5.2 Rats -- 4.5.3 Mice -- 4.5.4 Dogs -- 4.6 Repeat Exposure-Oral -- 4.6.1 Rats -- 4.6.2 Non-Human Primates -- 4.6.3 Mice -- 4.7 Repeat Exposure-Dermal -- 4.7.1 Mice -- 4.8 Aquatic Toxicity -- 4.9 Conclusion -- References -- 5 Developmental and Reproductive Toxicology of Methanol -- 5.1 Introduction -- 5.2 Reproductive Toxicity -- 5.3 Developmental Toxicity -- 5.3.1 Rats -- 5.3.2 Mice -- 5.3.3 Non-Human Primates -- 5.3.4 Summary of Developmental Toxicity Findings in Experimental Animals Exposed to Methanol by Inhalation -- 5.3.5 Pathogenesis of Methanol-Induced Birth Defects -- 5.3.5.1 Whole Animal Studies -- 5.3.5.2 In Vitro Studies -- 5.3.6 Folate Deficiency-A Susceptibility Factor for Methanol Developmental Toxicity? -- 5.3.7 Role of Methanol and Metabolites in the Developmental Toxicity of Methanol -- 5.4 Conclusions -- Disclaimer -- References -- 6 Exploring Differences Between PBPK Models of Methanol Disposition in Mice and Humans: Important Lessons Learned -- 6.1 Background -- 6.2 Are Humans More or Less Sensitive than Mice to the Toxic Effects of Methanol? -- 6.3 Are the Two Models' Predictions of Human Blood Methanol Concentrations at Steady State Consistent with Each Other? -- 6.4 Are the Values of Key Human Metabolism Parameters Consistent with Those in the Published Scientific Literature? -- 6.5 Shouldn't the Possibility of Systematic Bias be Considered Carefully During the Model Fitting and Parameter Estimation Process? -- 6.6 Is "Visual Optimization" an Adequate Technique for Estimating PBPK Model Parameters? -- 6.7 When Human Data are Available, Shouldn't they be Utilized in Making an Objective Comparison of Model-Specific Predictions? -- 6.8 Summary of Lessons Learned -- References.

7 Oxidative Stress and Species Differences in the Metabolism, Developmental Toxicity, and Carcinogenic Potential of Methanol and Ethanol -- 7.1 Introduction -- 7.1.1 Preamble -- 7.1.1.1 The Regulatory Problem -- 7.1.1.2 Fundamental Question -- 7.1.1.3 Research Objectives -- 7.1.1.4 Approach -- 7.1.2 Methanol Developmental Toxicity -- 7.1.3 Carcinogenic Potential -- 7.1.4 Oxidative Stress and Other Potential Mechanisms of Toxicity -- 7.1.5 Factors Affecting the Human Relevance of Animal Models -- 7.1.5.1 Species Differences in Metabolism -- 7.1.5.2 Dose of Methanol and Route of Exposure -- 7.2 Species Differences in Methanol Metabolism -- 7.2.1 Enzymes and Pathways -- 7.2.1.1 Alcohol Dehydrogenase (ADH1) -- 7.2.1.2 Catalase -- 7.2.1.3 Cytochrome P450 (CYP) 2E1 -- 7.2.1.4 Formaldehyde Dehydrogenase (ADH3) -- 7.2.1.5 Folate-dependent dehydrogenase -- 7.2.2 Pharmacokinetics of Methanol and Formic Acid -- 7.3 Species and Strain Differences in Methanol Toxicity -- 7.3.1 Acute Metabolic Acidosis, Ocular Toxicity, and Death -- 7.3.2 Teratogenesis -- 7.3.3 Neurodevelopmental Effects -- 7.3.4 Carcinogenic Potential -- 7.4 Oxidative Stress -- 7.4.1 Oxidative Stress Mechanisms -- 7.4.1.1 Embryonic Drug Exposure and Reactive Oxygen Species (ROS) Formation -- 7.4.1.2 Signal Transduction -- 7.4.1.3 Macromolecular Damage -- 7.4.2 Oxidative Stress from Methanol Exposure -- 7.4.2.1 Evidence for MeOH-Initiated ROS Formation -- 7.4.2.2 Mechanism of MeOH-Initiated ROS Formation -- 7.4.3 Teratogenicity of Methanol and Comparisons to Ethanol -- 7.4.3.1 Genetic Modulation of Catalase -- 7.4.3.2 Free Radical Spin Trapping Agent -- 7.4.4 Carcinogenic Potential -- 7.4.4.1 Oxidatively Damaged DNA -- 7.4.4.2 Hydroxynonenal-Histidine Protein Adducts -- 7.5 Conclusions -- Acknowledgment -- References -- 8 Methanol and Cancer -- 8.1 Introduction -- 8.2 Rodent Bioassay -- 8.2.1 Oral.

8.2.1.1 Rats -- 8.2.1.2 Mice -- 8.2.2 Inhalation -- 8.2.2.1 Rats -- 8.2.2.2 Mice -- 8.2.3 Dermal -- 8.2.3.1 Mice -- 8.3 Possible Mechanisms -- 8.3.1 Genotoxicity -- 8.3.1.1 In Vitro -- 8.3.1.2 In Vivo -- 8.3.2 Oxidative Damage -- 8.4 Human Cancer Data -- 8.5 Conclusion -- References -- Index.