The Toxicology of Methanol

Preface xiii Contributors xv 1 Methanol Production and Markets: Past, Present, and Future 1 Gregory A. Dolan References 9 2 Methanol: Fate and Transport in the Environment 11 Rula A. Deeb, Todd L. Anderson, Michael C. Kavanaugh, and Lauren A. Kell 2.1 Introduction 11 2.1.1 Release Scenarios 11 2.1.2 Fate in the Environment 14 2.2 Partitioning of Methanol in the Environment 16 2.2.1 Methanol Partitioning Among Environmental Media 16 2.2.2 Air/Water Partitioning 16 2.2.3 Soil/Water Partitioning 18 2.2.4 Methanol Dissolution 19 2.2.5 Commingling/Cosolvency Effects 21 2.3 Fate and Transport of Methanol in the Environment 22 2.3.1 Soil and/or Groundwater Release 23 2.3.1.1 Sources of Methanol in Soil and Groundwater 23 2.3.1.2 Losses of Methanol from Soil and Groundwater 23 2.3.1.3 Methanol/BTEX Commingled Plumes 32 2.3.2 Surface Water Release 33 2.3.2.1 Sources of Methanol in Surface Water 33 2.3.2.2 Losses of Methanol in Surface Water 33 2.4 Methanol Additives 37 2.4.1 Luminosity 38 2.4.2 Taste 38 2.5 Conclusions 40 References 40 3 Human Toxicity 47 John J. Clary 3.1 Introduction 47 3.2 Exposure 48 3.2.1 Dietary 48 3.2.2 Environmental 49 3.3 Metabolism in Humans 50 3.3.1 Normal 50 3.3.2 High Exposure 51 3.3.3 Over Exposure 51 3.3.3.1 Symptoms 51 3.3.3.2 Blood and Urine Methanol 52 3.3.3.3 Urinary Formic Acid 53 3.3.3.4 Breath--Methanol Levels 53 3.4 History of Human Toxicity 54 3.4.1 Occupational 54 3.4.2 Ingestion 54 3.4.3 Dermal 59 3.5 Controlled Human Studies 60 3.6 In Utero Exposure 62 3.7 Repeat Inhalation Exposure 63 3.8 Management of Methanol Poisoning 64 3.9 Conclusions 66 References 67 4 General Animal and Aquatic Toxicity 73 John J. Clary 4.1 Introduction 73 4.2 Acute Toxicity 74 4.2.1 Oral 74 4.2.2 Dermal 78 4.2.3 Inhalation 79 4.2.4 Intraperitoneal 82 4.2.5 Subcutaneous 82 4.2.6 Intravenous 82 4.2.7 Other Acute Studies 82 4.3 Irritation 86 4.3.1 Dermal 86 4.3.2 Eye 87 4.4 Sensitization 87 4.5 Repeat Exposure--Inhalation 87 4.5.1 Non-Human Primates 87 4.5.2 Rats 91 4.5.3 Mice 93 4.5.4 Dogs 94 4.6 Repeat Exposure--Oral 94 4.6.1 Rats 94 4.6.2 Non-Human Primates 95 4.6.3 Mice 95 4.7 Repeat Exposure--Dermal 96 4.7.1 Mice 96 4.8 Aquatic Toxicity 96 4.9 Conclusion 99 References 100 5 Developmental and Reproductive Toxicology of Methanol 107 John M. Rogers, Jeffrey S. Gift, and Stanley Barone, Jr. 5.1 Introduction 107 5.2 Reproductive Toxicity 108 5.3 Developmental Toxicity 110 5.3.1 Rats 111 5.3.2 Mice 115 5.3.3 Non-Human Primates 120 5.3.4 Summary of Developmental Toxicity Findings inExperimental Animals Exposed to Methanol by Inhalation 124 5.3.5 Pathogenesis of Methanol-Induced Birth Defects 127 5.3.5.1 Whole Animal Studies 127 5.3.5.2 In Vitro Studies 128 5.3.6 Folate Deficiency--A Susceptibility Factor for Methanol Developmental Toxicity? 129 5.3.7 Role of Methanol and Metabolites in the Developmental Toxicity of Methanol 133 5.4 Conclusions 136 Disclaimer 139 References 139 6 Exploring Differences Between PBPK Models of Methanol Disposition in Mice and Humans: Important Lessons Learned 145 Thomas B. Starr 6.1 Background 145 6.2 Are Humans More or Less Sensitive than Mice to the Toxic Effects of Methanol? 148 6.3 Are the Two Models' Predictions of Human Blood Methanol Concentrations at Steady State Consistent with Each Other? 153 6.4 Are the Values of Key Human Metabolism Parameters Consistent with Those in the Published Scientific Literature? 155 6.5 Shouldn't the Possibility of Systematic Bias be Considered Carefully During the Model Fitting and Parameter Estimation Process? 160 6.6 Is "Visual Optimization" an Adequate Technique for Estimating PBPK Model Parameters? 161 6.7 When Human Data are Available, Shouldn't they be Utilized in Making an Objective Comparison of Model-Specific Predictions? 163 6.8 Summary of Lessons Learned 164 References 165 7 Oxidative Stress and Species Differences in the Metabolism, Developmental Toxicity, and Carcinogenic Potential of Methanol and Ethanol 169 Peter G. Wells, Gordon P. McCallum, Lutfiya Miller, Michelle Siu, and J. Nicole Sweeting 7.1 Introduction 169 7.1.1 Preamble 169 7.1.1.1 The Regulatory Problem 169 7.1.1.2 Fundamental Question 169 7.1.1.3 Research Objectives 170 7.1.1.4 Approach 170 7.1.2 Methanol Developmental Toxicity 172 7.1.3 Carcinogenic Potential 176 7.1.4 Oxidative Stress and Other Potential Mechanisms of Toxicity 177 7.1.5 Factors Affecting the Human Relevance of Animal Models 178 7.1.5.1 Species Differences in Metabolism 178 7.1.5.2 Dose of Methanol and Route of Exposure 179 7.2 Species Differences in Methanol Metabolism 179 7.2.1 Enzymes and Pathways 179 7.2.1.1 Alcohol Dehydrogenase (ADH1) 179 7.2.1.2 Catalase 182 7.2.1.3 Cytochrome P450 (CYP) 2E1 184 7.2.1.4 Formaldehyde Dehydrogenase (ADH3) 186 7.2.1.5 Folate-dependent dehydrogenase 187 7.2.2 Pharmacokinetics of Methanol and Formic Acid 188 7.3 Species and Strain Differences in Methanol Toxicity 191 7.3.1 Acute Metabolic Acidosis, Ocular Toxicity, and Death 191 7.3.2 Teratogenesis 194 7.3.3 Neurodevelopmental Effects 204 7.3.4 Carcinogenic Potential 207 7.4 Oxidative Stress 213 7.4.1 Oxidative Stress Mechanisms 213 7.4.1.1 Embryonic Drug Exposure and Reactive Oxygen Species (ROS) Formation 213 7.4.1.2 Signal Transduction 214 7.4.1.3 Macromolecular Damage 217 7.4.2 Oxidative Stress from Methanol Exposure 223 7.4.2.1 Evidence for MeOH-Initiated ROS Formation 223 7.4.2.2 Mechanism of MeOH-Initiated ROS Formation 227 7.4.3 Teratogenicity of Methanol and Comparisons to Ethanol 228 7.4.3.1 Genetic Modulation of Catalase 228 7.4.3.2 Free Radical Spin Trapping Agent 232 7.4.4 Carcinogenic Potential 233 7.4.4.1 Oxidatively Damaged DNA 233 7.4.4.2 Hydroxynonenal-Histidine Protein Adducts 234 7.5 Conclusions 237 Acknowledgment 238 References 238 8 Methanol and Cancer 255 John J. Clary 8.1 Introduction 255 8.2 Rodent Bioassay 256 8.2.1 Oral 256 8.2.1.1 Rats 256 8.2.1.2 Mice 263 8.2.2 Inhalation 266 8.2.2.1 Rats 266 8.2.2.2 Mice 268 8.2.3 Dermal 268 8.2.3.1 Mice 268 8.3 Possible Mechanisms 270 8.3.1 Genotoxicity 270 8.3.1.1 In Vitro 270 8.3.1.2 In Vivo 270 8.3.2 Oxidative Damage 272 8.4 Human Cancer Data 276 8.5 Conclusion 276 References 277 Index 283