Formaldehyde: Exposure, Toxicity and Health Effects (Issues in Toxicology, Volume 37)

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. Front Cover......Page 1 Formaldehyde: Exposure, Toxicity and Health Effects......Page 2 Preface......Page 8 Acknowledgements......Page 10 Dedication......Page 14 Contents......Page 16 1.1 Formaldehyde—The Origins of Life on Earth......Page 26 1.2.1 Endogenous Production of Formaldehyde......Page 27 1.2.2 Exogenous Synthesis of Formaldehyde......Page 28 1.3 Industrial Uses of Formaldehyde......Page 29 1.5 Global Economic Significance of Formaldehyde......Page 30 1.5.1 Production Capacity and Output......Page 31 1.5.2 Consumption and Distribution......Page 33 1.6.3 Hurricanes Katrina and Rita......Page 36 1.7 Controversial and Neglected Issues in Formaldehyde Studies......Page 37 1.7.2 US and China Focus......Page 38 1.8 Conclusion......Page 39 References......Page 40 2.1 Occupational Exposure and Regulation......Page 45 2.2 Indoor Air Exposure......Page 49 2.3 Outdoor Air Exposure......Page 53 2.5 Metabolism and Fate of Formaldehyde......Page 54 Acknowledgements......Page 56 References......Page 57 3.1 Formaldehyde Regulation......Page 64 3.2.2.1 Residential Exposure......Page 67 3.2.3 Outdoor Exposure......Page 72 3.3 Estimated Personal Exposure......Page 78 3.4 Conclusion......Page 80 References......Page 81 4.1.1 Acute Poisoning......Page 88 4.1.4 Worldwide Case Reports......Page 89 4.2.1 Neurotoxicity......Page 90 4.2.3 Allergic Asthma and Immune System Effects......Page 91 4.3.1 Blood Formation via Hematopoiesis......Page 92 4.3.2 Reduced Blood Cell Counts......Page 93 4.3.4 Altered Lymphocyte Subsets......Page 95 4.3.5 Hematotoxicity Studies in Animals......Page 96 4.4.1 DNA–Protein Crosslinks (DPCs)......Page 98 4.4.2 DNA–Protein Crosslink Repair in Yeast......Page 100 4.4.3 DNA Damage and Repair via the FANC–BRCA Pathway......Page 101 4.4.4 DNA Adducts......Page 104 4.4.5 Cytogenetic Alterations......Page 105 4.5 Functional Toxicogenomic Profiling and Epigenomic Alterations......Page 106 4.6 Summary of Formaldehyde Induced Toxicities......Page 107 Acknowledgements......Page 108 References......Page 109 5.1.1 Nasopharyngeal Cancer......Page 121 5.1.3 Leukemia and Blood Cancers......Page 123 5.2 Cancer Studies in China......Page 124 5.3.1 Importance of Carcinogen Classification......Page 125 5.3.2.3 OEHHA......Page 126 5.3.3.1 NTP Primary Classification......Page 127 5.3.3.5 Updated NTP Classification......Page 128 5.4.1 Can Formaldehyde Reach the Target Bone Marrow......Page 129 5.4.1.3 Potential Systemic Effects of Formaldehyde......Page 130 5.4.2 Formaldehyde-induced Hematotoxicity and Stem Cell Toxicity......Page 131 5.4.2.2 Animal Studies......Page 132 5.5 Formaldehyde Carcinogenicity Summary......Page 133 References......Page 134 6.1 Epidemiological Findings of Formaldehyde and Leukemia......Page 141 6.1.1 Classic Epidemiological Studies of Formaldehyde......Page 142 6.2 Meta-analysis Approach......Page 143 6.2.1 Novel Study Design to Better Address Key Questions......Page 144 6.2.2 Collection and Selection of Epidemiological Studies......Page 145 6.3.1 Meta-analysis Results......Page 147 6.4 Results from Updated Meta-analysis......Page 149 6.5.1 Overview of the Results from Six Meta-analyses......Page 151 6.5.2 Comparison of Novel Approach with Traditional Meta-analyses......Page 153 6.5.3 Risk Varies in Industrial Workers vs. Professionals......Page 154 6.6 Summary and Conclusions......Page 156 References......Page 161 7.1 Overview of Leukemogenesis......Page 166 7.1.1 Leukemic Stem Cell Theory......Page 167 7.1.2 Chemically Induced Leukemias......Page 168 7.2 Targeting Hematopoietic Stem/Progenitor Cells......Page 169 7.2.1 Culturing of Myeloid Progenitor Cells......Page 170 7.2.2 Findings in Circulating Myeloid Progenitor Colony Cells of Exposed Workers......Page 171 7.2.4 Formaldehyde Suppressed Myeloid Progenitor Cells in Murine Bone Marrow......Page 172 7.3 Models of Formaldehyde-induced Leukemia......Page 174 7.3.1 Traditional Model: Targeting Bone Marrow Hematopoietic Stem Cells......Page 176 7.3.2 Alternative Model 1: Targeting Blood Stem Cells and Progenitors......Page 177 7.3.3 Alternative Model 2: Targeting Pluripotent Nasal/Oral Stem Cells......Page 178 7.3.4 Alternative Model 3: Targeting Hematopoietic Stem and Progenitor Cells in the Lungs......Page 179 7.4.1 Does Formaldehyde Induce Bone Marrow Toxicity and by Which Mechanisms......Page 180 7.4.2 Does Formaldehyde Induce Hematotoxicity and Stem Cell Toxicity......Page 182 7.4.3 Can Formaldehyde Damage Pluripotent Hematopoietic Stem Cells in the Nose and Lungs......Page 183 Acknowledgements......Page 184 References......Page 185 Chapter 8 - Formaldehyde Induced Leukemia-specific Chromosomal Aneuploidy......Page 193 8.2.1 Identification of Study Factories and Subjects......Page 194 8.2.3Exposure Assessment......Page 195 8.2.4 Biological Sampling and Physical Examination......Page 197 8.2.5 Preparing Metaphase from Cultured CFU–GM Cells......Page 198 8.3.2 A Priori Hypothesis Tested in Benzene-exposed Workers......Page 199 8.3.3 FISH Application in CFU–GM Progenitor Cells......Page 200 8.3.4 Implication of the Initial Findings......Page 202 8.4.2 Study Subjects Selected in CWAS......Page 203 8.5.1 Loss of Chromosomes (Monosomy)......Page 205 8.5.2.3 Implications of Findings in Chromosome Gains......Page 207 8.5.4 Comparison with Other Chemically-induced AML/MDS......Page 208 8.6.1 Formaldehyde-induced Chromosomal Aneuploidy in Myeloid Progenitor Cells......Page 209 8.6.2 Potential Mechanisms of Formaldehyde-induced Aneuploidy......Page 210 Acknowledgements......Page 211 References......Page 212 9.1 The Basics on Brain Tumors......Page 217 9.2.1 Questionnaire-based Traditional Epidemiology......Page 218 9.3 Epidemiologic Studies of Formaldehyde and Brain Tumors......Page 220 9.3.1.1 Pathologists & Anatomists......Page 221 9.3.2 Brain Cancer Risk Among Industrial Workers......Page 226 9.4.1 Study Design and Exposure Information......Page 227 9.4.3 Comparison and Discussion of Both Meta-analyses......Page 230 9.5 Summary and Discussion......Page 231 References......Page 233 10.1 Introduction and Importance......Page 236 10.3 Association Between Formaldehyde Exposure and ALS......Page 237 10.3.2 NIEHS Case–Control Study......Page 238 10.3.5 NIEHS— Sweden Study......Page 241 10.4.1 Parkinson’s Disease......Page 242 10.4.2 Alzheimer’s Disease......Page 244 10.4.3.1 Connection with Alzheimer’s Disease......Page 245 10.5 Memory, Learning, and Behavioral Effects of Formaldehyde......Page 246 10.5.3 Formaldehyde-laced Drug Abuse......Page 247 10.6.1 Analysis of Neurodegenerative Effects in Animals......Page 248 10.6.2.2 Formaldehyde Metabolism......Page 251 10.6.3 Potential Mechanisms and Contributors to Neurodegeneration......Page 252 Acknowledgements......Page 256 References......Page 257 11.1 Formaldehyde Exposure in Children......Page 265 11.1.1 Routes of Exposure......Page 266 11.1.3.1 In utero Exposure (Conception to Birth)......Page 268 11.1.3.2 Early-life Exposure (0–5 Years Old)......Page 269 11.1.3.4 Exposure in Teenagers (13–19 Years Old)......Page 270 11.1.3.5 Young Adults (20–26 Years Old)......Page 271 11.2 Formaldehyde-associated Biomarkers and Health Outcomes......Page 272 11.2.1 Asthma-specific Markers......Page 276 11.2.2 Immuno-markers and Adverse Health Outcomes......Page 277 11.2.3 Cytogenetic Biomarkers and Associated Health Outcomes......Page 278 11.2.4 Childhood Leukemia and Cancer Risk......Page 279 11.2.6 Challenges of Studies in Children......Page 281 11.3.1 Formaldehyde Regulation in Children......Page 282 11.3.2 Johnson & Johnson's Reformulation......Page 283 Acknowledgements......Page 284 References......Page 285 12.1 Background......Page 290 12.2.1.2 Population Studies......Page 291 12.2.2.2 Female Fertility......Page 292 12.2.2.3 Male Reproductivity......Page 298 12.2.3 Spontaneous Abortion Studies......Page 299 12.2.4.1 Congenital Anomalies......Page 301 12.2.4.2 Low Birth Weight......Page 303 12.2.5 NIOSH Study......Page 304 12.3 Human Study Challenges......Page 305 12.4.2 Novel Approach in Updated Meta-analysis......Page 306 12.4.3 Major Findings of the Updated Meta-analysis......Page 307 12.4.4 Comparison of Results Between Both Meta-analyses......Page 312 Acknowledgements......Page 314 References......Page 315 13.1 Overview of Experimental Animal Studies......Page 318 13.2.1 Reproductive Toxicity in Rats......Page 326 13.2.3 Reproductive Toxicity in Other Animal Models......Page 327 13.3.1 Developmental Toxicity in Rats......Page 328 13.3.3 Developmental Toxicity in Other Animal Models......Page 329 13.5 Animal Studies in ex vivo and in vitro......Page 330 13.6 Summary......Page 331 References......Page 332 14.1 Overview of Mechanisms of Toxicity in the Reproductive System......Page 336 14.3 Formaldehyde-induced Oxidative Stress......Page 337 14.4 Alternative Mechanisms of Action......Page 338 14.4.3 Formaldehyde-induced Apoptosis......Page 339 14.4.6 Stress Related Outcomes......Page 340 14.5 Reproductive Toxicity Induced by Other Chemicals Compared to Formaldehyde......Page 341 14.6 Summary......Page 342 References......Page 343 15.1.1 Exposure Types and Sources......Page 349 15.1.2 Exposure Routes in Adults and Children......Page 351 15.1.3 Regulation of Formaldehyde Exposure......Page 352 15.2.1 Acute and Chronic Toxicity......Page 353 15.2.3 Hematotoxicity......Page 354 15.2.5 Reproductive Toxicity......Page 355 15.3.2 Formaldehyde Associated Leukemias......Page 356 15.3.5 Health Effects in Children......Page 357 15.4.2 Controversy and Challenges of Formaldehyde Research......Page 358 15.4.3 Recommendations Suggested for Future Formaldehyde Research......Page 359 References......Page 361 Appendix 1 - Abbreviations......Page 367 Appendix 2 - Glossary......Page 372 Appendix 3 - Meta-analysis Methods......Page 382 Appendix 4 - Statistical Methods Appliedand Supplementary Data (Chapter 8)......Page 394 Appendix 5 - Figure Index......Page 400 Appendix 6 - Table Index......Page 404 Subject Index......Page 407