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Abstract
Formaldehyde is virtually ubiquitous in the modern environment due to its cost-effective nature, its use in resin formation, and its preservative properties. Though formaldehyde is necessary for many products and processes important to the world’s economy, this economic dependence on formaldehyde comes at a cost to public health.
Growth and consequent industrialization rely heavily on formaldehyde use. New buildings—residences, public places, and offices—are not only built with timber preserved by formaldehyde, but they are also furnished with wood, wool, and textile products that contain formaldehyde. The general population faces environmental exposure from indoor and outdoor air pollution, food, and even medicine. Scientific inquiry into formaldehyde exposure has grown in response.
This book consolidates the new and established body of formaldehyde research in the scholarly community, focusing on exposure, genotoxicity, and adverse health outcomes. Through this resource, we hope to increase awareness of the broad range of health effects posed by formaldehyde exposure, and to encourage interdisciplinary interest, as well as research, into this pervasive compound—especially in the United States and China, where formaldehyde production and usage is high. This book will be useful to researchers of environmental and occupational exposure, students, and government regulators and anyone exposed to formaldehyde in the workplace and/or at home.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Front Cover | Cover | ||
| Formaldehyde: Exposure, Toxicity and Health Effects | i | ||
| Preface | vii | ||
| Acknowledgements | ix | ||
| Dedication | xiii | ||
| Contents | xv | ||
| Chapter 1 - Introduction to Formaldehyde | 1 | ||
| 1.1 Formaldehyde—The Origins of Life on Earth | 1 | ||
| 1.2 Endogenous and Exogenous Formaldehyde | 2 | ||
| 1.2.1 Endogenous Production of Formaldehyde | 2 | ||
| 1.2.2 Exogenous Synthesis of Formaldehyde | 3 | ||
| 1.3 Industrial Uses of Formaldehyde | 4 | ||
| 1.4 Medical Uses of Formaldehyde | 5 | ||
| 1.5 Global Economic Significance of Formaldehyde | 5 | ||
| 1.5.1 Production Capacity and Output | 6 | ||
| 1.5.2 Consumption and Distribution | 8 | ||
| 1.6 Public Health Risks from Formaldehyde Exposure | 11 | ||
| 1.6.1 Lumber Liquidators | 11 | ||
| 1.6.2 Brazilian Blowout | 11 | ||
| 1.6.3 Hurricanes Katrina and Rita | 11 | ||
| 1.6.4 Alaska Spill Accident | 12 | ||
| 1.7 Controversial and Neglected Issues in Formaldehyde Studies | 12 | ||
| 1.7.1 Controversy: Formaldehyde–Leukemia Association | 13 | ||
| 1.7.2 US and China Focus | 13 | ||
| 1.7.3 Controversy: Formaldehyde Systemic Effects | 14 | ||
| 1.7.4 Neglected Study Areas | 14 | ||
| 1.8 Conclusion | 14 | ||
| Acknowledgements | 15 | ||
| References | 15 | ||
| Chapter 2 - Formaldehyde Exposure, Regulation, and Metabolism | 20 | ||
| 2.1 Occupational Exposure and Regulation | 20 | ||
| 2.2 Indoor Air Exposure | 24 | ||
| 2.3 Outdoor Air Exposure | 28 | ||
| 2.4 Other Types of Exposure and Drinking Water Regulation | 29 | ||
| 2.5 Metabolism and Fate of Formaldehyde | 29 | ||
| 2.6 Conclusion | 31 | ||
| Acknowledgements | 31 | ||
| References | 32 | ||
| Chapter 3 - Formaldehyde Exposure in China | 39 | ||
| 3.1 Formaldehyde Regulation | 39 | ||
| 3.2 Formaldehyde Exposure | 42 | ||
| 3.2.1 Occupational Exposure | 42 | ||
| 3.2.2 Indoor Exposure | 42 | ||
| 3.2.2.1 Residential Exposure | 42 | ||
| 3.2.2.2 Office Exposure | 47 | ||
| 3.2.2.3 Public Places | 47 | ||
| 3.2.3 Outdoor Exposure | 47 | ||
| 3.2.4 Food Exposure | 53 | ||
| 3.3 Estimated Personal Exposure | 53 | ||
| 3.4 Conclusion | 55 | ||
| Acknowledgements | 56 | ||
| References | 56 | ||
| Chapter 4 - General Toxicity of Formaldehyde | 63 | ||
| 4.1 Acute Toxicity | 63 | ||
| 4.1.1 Acute Poisoning | 63 | ||
| 4.1.2 Irritation | 64 | ||
| 4.1.3 Dermal Allergies | 64 | ||
| 4.1.4 Worldwide Case Reports | 64 | ||
| 4.2 Chronic Toxicity | 65 | ||
| 4.2.1 Neurotoxicity | 65 | ||
| 4.2.2 Pulmonary Function Damage | 66 | ||
| 4.2.3 Allergic Asthma and Immune System Effects | 66 | ||
| 4.3 Hematotoxicity | 67 | ||
| 4.3.1 Blood Formation via Hematopoiesis | 67 | ||
| 4.3.2 Reduced Blood Cell Counts | 68 | ||
| 4.3.3 A Featured Hematotoxicity Report | 70 | ||
| 4.3.4 Altered Lymphocyte Subsets | 70 | ||
| 4.3.5 Hematotoxicity Studies in Animals | 71 | ||
| 4.4 Genotoxicity | 73 | ||
| 4.4.1 DNA–Protein Crosslinks (DPCs) | 73 | ||
| 4.4.2 DNA–Protein Crosslink Repair in Yeast | 75 | ||
| 4.4.3 DNA Damage and Repair via the FANC–BRCA Pathway | 76 | ||
| 4.4.4 DNA Adducts | 79 | ||
| 4.4.5 Cytogenetic Alterations | 80 | ||
| 4.5 Functional Toxicogenomic Profiling and Epigenomic Alterations | 81 | ||
| 4.6 Summary of Formaldehyde Induced Toxicities | 82 | ||
| Acknowledgements | 83 | ||
| References | 84 | ||
| Chapter 5 - Formaldehyde Carcinogenesis | 96 | ||
| 5.1 Carcinogenesis | 96 | ||
| 5.1.1 Nasopharyngeal Cancer | 96 | ||
| 5.1.2 Sinonasal Cancer | 98 | ||
| 5.1.3 Leukemia and Blood Cancers | 98 | ||
| 5.2 Cancer Studies in China | 99 | ||
| 5.3 History of Formaldehyde’s Carcinogenicity Classification | 100 | ||
| 5.3.1 Importance of Carcinogen Classification | 100 | ||
| 5.3.2 Cancer Classification Agencies and Categories | 101 | ||
| 5.3.2.1 IARC | 101 | ||
| 5.3.2.2 NTP | 101 | ||
| 5.3.2.3 OEHHA | 101 | ||
| 5.3.3 Classification History | 102 | ||
| 5.3.3.1 NTP Primary Classification | 102 | ||
| 5.3.3.2 OEHHA (Proposition 65) | 103 | ||
| 5.3.3.3 IARC Initial Classification | 103 | ||
| 5.3.3.4 Updated IARC Classification | 103 | ||
| 5.3.3.5 Updated NTP Classification | 103 | ||
| 5.4 Controversy Regarding Formaldehyde–Leukemia Association | 104 | ||
| 5.4.1 Can Formaldehyde Reach the Target Bone Marrow | 104 | ||
| 5.4.1.1 Formaldehyde–DNA Adducts | 105 | ||
| 5.4.1.2 Formaldehyde–Protein Adducts | 105 | ||
| 5.4.1.3 Potential Systemic Effects of Formaldehyde | 105 | ||
| 5.4.1.4 Proposed Mechanisms of Formaldehyde – Leukemogenesis | 106 | ||
| 5.4.2 Formaldehyde-induced Hematotoxicity and Stem Cell Toxicity | 106 | ||
| 5.4.2.1 Human Studies | 107 | ||
| 5.4.2.2 Animal Studies | 107 | ||
| 5.4.3 No Formaldehyde-induced Leukemia in Animal Models | 108 | ||
| 5.5 Formaldehyde Carcinogenicity Summary | 108 | ||
| Acknowledgements | 109 | ||
| References | 109 | ||
| Chapter 6 - Formaldehyde Exposure and Leukemia Risk | 116 | ||
| 6.1 Epidemiological Findings of Formaldehyde and Leukemia | 116 | ||
| 6.1.1 Classic Epidemiological Studies of Formaldehyde | 117 | ||
| 6.1.2 Updated NCI Study | 118 | ||
| 6.1.3 Updated British Follow-up Study | 118 | ||
| 6.2 Meta-analysis Approach | 118 | ||
| 6.2.1 Novel Study Design to Better Address Key Questions | 119 | ||
| 6.2.2 Collection and Selection of Epidemiological Studies | 120 | ||
| 6.3 Findings from Primary Meta-analysis | 122 | ||
| 6.3.1 Meta-analysis Results | 122 | ||
| 6.3.2 Increased Meta-relative Risks | 124 | ||
| 6.4 Results from Updated Meta-analysis | 124 | ||
| 6.5 Comparing All Meta-analyses | 126 | ||
| 6.5.1 Overview of the Results from Six Meta-analyses | 126 | ||
| 6.5.2 Comparison of Novel Approach with Traditional Meta-analyses | 128 | ||
| 6.5.3 Risk Varies in Industrial Workers vs. Professionals | 129 | ||
| 6.5.4 Comparison of Recent Meta-analyses: Exposure Metrics | 131 | ||
| 6.6 Summary and Conclusions | 131 | ||
| Acknowledgements | 136 | ||
| References | 136 | ||
| Chapter 7 - Potential Mechanisms of Formaldehyde-induced Leukemia | 141 | ||
| 7.1 Overview of Leukemogenesis | 141 | ||
| 7.1.1 Leukemic Stem Cell Theory | 142 | ||
| 7.1.2 Chemically Induced Leukemias | 143 | ||
| 7.2 Targeting Hematopoietic Stem/Progenitor Cells | 144 | ||
| 7.2.1 Culturing of Myeloid Progenitor Cells | 145 | ||
| 7.2.2 Findings in Circulating Myeloid Progenitor Colony Cells of Exposed Workers | 146 | ||
| 7.2.3 Formaldehyde Inhibited Human Myeloid Progenitor Cells in vitro | 147 | ||
| 7.2.4 Formaldehyde Suppressed Myeloid Progenitor Cells in Murine Bone Marrow | 147 | ||
| 7.3 Models of Formaldehyde-induced Leukemia | 149 | ||
| 7.3.1 Traditional Model: Targeting Bone Marrow Hematopoietic Stem Cells | 151 | ||
| 7.3.2 Alternative Model 1: Targeting Blood Stem Cells and Progenitors | 152 | ||
| 7.3.3 Alternative Model 2: Targeting Pluripotent Nasal/Oral Stem Cells | 153 | ||
| 7.3.4 Alternative Model 3: Targeting Hematopoietic Stem and Progenitor Cells in the Lungs | 154 | ||
| 7.4 Biological Plausibility of the Proposed Mechanisms | 155 | ||
| 7.4.1 Does Formaldehyde Induce Bone Marrow Toxicity and by Which Mechanisms | 155 | ||
| 7.4.2 Does Formaldehyde Induce Hematotoxicity and Stem Cell Toxicity | 157 | ||
| 7.4.3 Can Formaldehyde Damage Pluripotent Hematopoietic Stem Cells in the Nose and Lungs | 158 | ||
| 7.5 Summary of Potential Mechanisms | 159 | ||
| Acknowledgements | 159 | ||
| References | 160 | ||
| Chapter 8 - Formaldehyde Induced Leukemia-specific Chromosomal Aneuploidy | 168 | ||
| 8.1 Overview of Featured Study | 169 | ||
| 8.2 Study Design | 169 | ||
| 8.2.1 Identification of Study Factories and Subjects | 169 | ||
| 8.2.2 Demographic Characteristics of Study Subjects | 170 | ||
| 8.2.3Exposure Assessment | 170 | ||
| 8.2.4 Biological Sampling and Physical Examination | 172 | ||
| 8.2.5 Preparing Metaphase from Cultured CFU–GM Cells | 173 | ||
| 8.3 The Initial Study by Fluorescence in situ Hybridization (FISH) | 174 | ||
| 8.3.1 Modern Cytogenetics—Fluorescence in situ Hybridization (FISH) | 174 | ||
| 8.3.2 A Priori Hypothesis Tested in Benzene-exposed Workers | 174 | ||
| 8.3.3 FISH Application in CFU–GM Progenitor Cells | 175 | ||
| 8.3.4 Implication of the Initial Findings | 177 | ||
| 8.4 Chromosome-wide Aneuploidy Study (CWAS) | 178 | ||
| 8.4.1 OctoChrome-FISH | 178 | ||
| 8.4.2 Study Subjects Selected in CWAS | 178 | ||
| 8.5 Findings from the CWAS by Applying OctoChrome FISH | 180 | ||
| 8.5.1 Loss of Chromosomes (Monosomy) | 180 | ||
| 8.5.2 Gain of Chromosomes (Trisomy & Tetrasomy) | 182 | ||
| 8.5.2.1 Trisomy | 182 | ||
| 8.5.2.2 Tetrasomy | 182 | ||
| 8.5.2.3 Implications of Findings in Chromosome Gains | 182 | ||
| 8.5.3 Structural Chromosome Abnormality Rates | 183 | ||
| 8.5.4 Comparison with Other Chemically-induced AML/MDS | 183 | ||
| 8.6 Mechanistic Relevance of FISH Findings | 184 | ||
| 8.6.1 Formaldehyde-induced Chromosomal Aneuploidy in Myeloid Progenitor Cells | 184 | ||
| 8.6.2 Potential Mechanisms of Formaldehyde-induced Aneuploidy | 185 | ||
| 8.7 Conclusions | 186 | ||
| Acknowledgements | 186 | ||
| References | 187 | ||
| Chapter 9 - Formaldehyde-associated Brain Tumors | 192 | ||
| 9.1 The Basics on Brain Tumors | 192 | ||
| 9.2 Epidemiologic Studies | 193 | ||
| 9.2.1 Questionnaire-based Traditional Epidemiology | 193 | ||
| 9.2.2 Biomarker-based Molecular Epidemiology | 195 | ||
| 9.3 Epidemiologic Studies of Formaldehyde and Brain Tumors | 195 | ||
| 9.3.1 Mortality Among Professionals | 196 | ||
| 9.3.1.1 Pathologists & Anatomists | 196 | ||
| 9.3.1.2 Embalmers and Funeral Directors | 201 | ||
| 9.3.2 Brain Cancer Risk Among Industrial Workers | 201 | ||
| 9.4 Meta-analysis Approach | 202 | ||
| 9.4.1 Study Design and Exposure Information | 202 | ||
| 9.4.2 Summary of Major Findings | 205 | ||
| 9.4.3 Comparison and Discussion of Both Meta-analyses | 205 | ||
| 9.5 Summary and Discussion | 206 | ||
| Acknowledgements | 208 | ||
| References | 208 | ||
| Chapter 10 - Formaldehyde-associated Neurodegenerative Diseases | 211 | ||
| 10.1 Introduction and Importance | 211 | ||
| 10.2 Assessment of Neurodegenerative Effects | 212 | ||
| 10.3 Association Between Formaldehyde Exposure and ALS | 212 | ||
| 10.3.1 Harvard American Cancer Society Study | 213 | ||
| 10.3.2 NIEHS Case–Control Study | 213 | ||
| 10.3.3 NIOSH/NIEHS Garment Worker Study | 216 | ||
| 10.3.4 Harvard National Longitudinal Mortality Study | 216 | ||
| 10.3.5 NIEHS— Sweden Study | 216 | ||
| 10.3.6 Harvard—Danish Study | 217 | ||
| 10.4 Formaldehyde and Parkinson’s Disease, Alzheimer’s Disease, and Dementia | 217 | ||
| 10.4.1 Parkinson’s Disease | 217 | ||
| 10.4.2 Alzheimer’s Disease | 219 | ||
| 10.4.3 Dementia | 220 | ||
| 10.4.3.1 Connection with Alzheimer’s Disease | 220 | ||
| 10.4.3.2 Formaldehyde Levels in Dementia Patients | 221 | ||
| 10.5 Memory, Learning, and Behavioral Effects of Formaldehyde | 221 | ||
| 10.5.1 Memory | 222 | ||
| 10.5.2 Learning | 222 | ||
| 10.5.3 Formaldehyde-laced Drug Abuse | 222 | ||
| 10.6 Formaldehyde-induced Neurodegeneration in vivo and in vitro | 223 | ||
| 10.6.1 Analysis of Neurodegenerative Effects in Animals | 223 | ||
| 10.6.2Formaldehyde-induced Alterations in Neural Metabolism | 226 | ||
| 10.6.2.1 Endogenous Formaldehyde Production | 226 | ||
| 10.6.2.2 Formaldehyde Metabolism | 226 | ||
| 10.6.2.3 Adverse Neural Alterations Induced by Formaldehyde | 227 | ||
| 10.6.3 Potential Mechanisms and Contributors to Neurodegeneration | 227 | ||
| 10.7 Conclusions and Future Perspectives | 231 | ||
| Acknowledgements | 231 | ||
| References | 232 | ||
| Chapter 11 - Formaldehyde Toxicity in Children | 240 | ||
| 11.1 Formaldehyde Exposure in Children | 240 | ||
| 11.1.1 Routes of Exposure | 241 | ||
| 11.1.2 Exposure Assessment in Children | 243 | ||
| 11.1.3 Formaldehyde Exposure from Early-life to Young Adulthood | 243 | ||
| 11.1.3.1 In utero Exposure (Conception to Birth) | 243 | ||
| 11.1.3.2 Early-life Exposure (0–5 Years Old) | 244 | ||
| 11.1.3.3 Exposure in Children and Pre-teenagers (6–12 Years Old) | 245 | ||
| 11.1.3.4 Exposure in Teenagers (13–19 Years Old) | 245 | ||
| 11.1.3.5 Young Adults (20–26 Years Old) | 246 | ||
| 11.1.4 Major Day Care Studies | 247 | ||
| 11.2 Formaldehyde-associated Biomarkers and Health Outcomes | 247 | ||
| 11.2.1 Asthma-specific Markers | 251 | ||
| 11.2.2 Immuno-markers and Adverse Health Outcomes | 252 | ||
| 11.2.3 Cytogenetic Biomarkers and Associated Health Outcomes | 253 | ||
| 11.2.4 Childhood Leukemia and Cancer Risk | 254 | ||
| 11.2.5 Other Adverse Outcomes | 256 | ||
| 11.2.6 Challenges of Studies in Children | 256 | ||
| 11.3 Formaldehyde Regulation and Policy for Children | 257 | ||
| 11.3.1 Formaldehyde Regulation in Children | 257 | ||
| 11.3.2 Johnson & Johnson's Reformulation | 258 | ||
| 11.4 Burden of Formaldehyde Exposure Related Disease | 259 | ||
| 11.5 Conclusion | 259 | ||
| Acknowledgements | 259 | ||
| References | 260 | ||
| Chapter 12 - Reproductive and Developmental Toxicity of Formaldehyde Exposure in Humans | 265 | ||
| 12.1 Background | 265 | ||
| 12.2 Evaluation of Human Studies | 266 | ||
| 12.2.1 Literature Search for Population Studies | 266 | ||
| 12.2.1.1 Literature Search | 266 | ||
| 12.2.1.2 Population Studies | 266 | ||
| 12.2.2 Reproductive Toxicity Studies in Multiple International Cohorts | 267 | ||
| 12.2.2.1 Menstrual Disorders | 267 | ||
| 12.2.2.2 Female Fertility | 267 | ||
| 12.2.2.3 Male Reproductivity | 273 | ||
| 12.2.3 Spontaneous Abortion Studies | 274 | ||
| 12.2.4 Developmental Toxicity Studies | 276 | ||
| 12.2.4.1 Congenital Anomalies | 276 | ||
| 12.2.4.2 Low Birth Weight | 278 | ||
| 12.2.4.3 Premature Birth | 279 | ||
| 12.2.5 NIOSH Study | 279 | ||
| 12.3 Human Study Challenges | 280 | ||
| 12.4 Meta-analyses of Reproductive/Developmental Toxicity | 281 | ||
| 12.4.1 Meta-analysis by Collins et al | 281 | ||
| 12.4.2 Novel Approach in Updated Meta-analysis | 281 | ||
| 12.4.3 Major Findings of the Updated Meta-analysis | 282 | ||
| 12.4.4 Comparison of Results Between Both Meta-analyses | 287 | ||
| 12.5 Summary | 289 | ||
| Acknowledgements | 289 | ||
| References | 290 | ||
| Chapter 13 - Reproductive and Developmental Toxicity of Formaldehyde Exposure in Animals | 293 | ||
| 13.1 Overview of Experimental Animal Studies | 293 | ||
| 13.2 Reproductive Toxicity in Experimental Animals | 301 | ||
| 13.2.1 Reproductive Toxicity in Rats | 301 | ||
| 13.2.2 Reproductive Toxicity in Mice | 302 | ||
| 13.2.3 Reproductive Toxicity in Other Animal Models | 302 | ||
| 13.3 Developmental Toxicity in Animals | 303 | ||
| 13.3.1 Developmental Toxicity in Rats | 303 | ||
| 13.3.2 Developmental Toxicity in Mice | 304 | ||
| 13.3.3 Developmental Toxicity in Other Animal Models | 304 | ||
| 13.4 Toxicity Studies from Postnatal Exposure | 305 | ||
| 13.5 Animal Studies in ex vivo and in vitro | 305 | ||
| 13.6 Summary | 306 | ||
| Acknowledgements | 307 | ||
| References | 307 | ||
| Chapter 14 - Mechanisms of Action for Formaldehyde-induced Reproductive and Developmental Toxicity | 311 | ||
| 14.1 Overview of Mechanisms of Toxicity in the Reproductive System | 311 | ||
| 14.2 Formaldehyde-induced Genotoxicity | 312 | ||
| 14.3 Formaldehyde-induced Oxidative Stress | 312 | ||
| 14.4 Alternative Mechanisms of Action | 313 | ||
| 14.4.1 Roles of Dehydrogenases | 314 | ||
| 14.4.2 Involvement of Heat Shock Proteins | 314 | ||
| 14.4.3 Formaldehyde-induced Apoptosis | 314 | ||
| 14.4.4 Epigenetic Effect of Formaldehyde | 315 | ||
| 14.4.5 Sex Hormones | 315 | ||
| 14.4.6 Stress Related Outcomes | 315 | ||
| 14.5 Reproductive Toxicity Induced by Other Chemicals Compared to Formaldehyde | 316 | ||
| 14.6 Summary | 317 | ||
| Acknowledgements | 318 | ||
| References | 318 | ||
| Chapter 15 - Conclusions and Future Directions | 324 | ||
| 15.1 Formaldehyde Exposure and Regulation | 324 | ||
| 15.1.1 Exposure Types and Sources | 324 | ||
| 15.1.2 Exposure Routes in Adults and Children | 326 | ||
| 15.1.3 Regulation of Formaldehyde Exposure | 327 | ||
| 15.2 Formaldehyde Toxicities and Potential Mechanisms | 328 | ||
| 15.2.1 Acute and Chronic Toxicity | 328 | ||
| 15.2.2 Genotoxicity | 329 | ||
| 15.2.3 Hematotoxicity | 329 | ||
| 15.2.4 Neurotoxicity | 330 | ||
| 15.2.5 Reproductive Toxicity | 330 | ||
| 15.3 Adverse Health Effects of Formaldehyde | 331 | ||
| 15.3.1 Nasopharyngeal and Sinonasal Cancer | 331 | ||
| 15.3.2 Formaldehyde Associated Leukemias | 331 | ||
| 15.3.3 Brain Tumors | 332 | ||
| 15.3.4 Amyotrophic Lateral Sclerosis | 332 | ||
| 15.3.5 Health Effects in Children | 332 | ||
| 15.4 Future Directions of Formaldehyde Research | 333 | ||
| 15.4.1 Importance and Implication of Formaldehyde Research | 333 | ||
| 15.4.2 Controversy and Challenges of Formaldehyde Research | 333 | ||
| 15.4.3 Recommendations Suggested for Future Formaldehyde Research | 334 | ||
| 15.5 Summary | 336 | ||
| Acknowledgements | 336 | ||
| References | 336 | ||
| Appendix 1 - Abbreviations | 342 | ||
| Appendix 2 - Glossary | 347 | ||
| Appendix 3 - Meta-analysis Methods | 357 | ||
| Appendix 4 - Statistical Methods Appliedand Supplementary Data (Chapter 8) | 369 | ||
| Appendix 5 - Figure Index | 375 | ||
| Appendix 6 - Table Index | 379 | ||
| Subject Index | 382 |