The Dose Makes the Poison – A Plain–Language Guide to Toxicology 3e

Patricia Frank is President of Patricia Frank & Associates, Inc., a consulting firm founded in 1993 that assists companies in the development and registration of human and veterinary pharmaceutical agents. She is a past president of both the American College of Toxicology and the Roundtable of Toxicology Consultants. M. Alice Ottoboni lectures, writes, and consults in the field of toxicology. As Staff Toxicologist with the California State Department of Public Health for over twenty years, she originated, designed, and performed numerous toxicological studies of environmental factors of importance to public health. She is the author of the previous editions of The Dose Makes the Poison .

Introduction to the Third Edition xi Preface to the Second Edition xv 1 WHAT ARE CHEMICALS? 1 Atoms and Molecules 1 Natural Chemicals 2 Synthetic Chemicals 3 Chemical Categories 6 Chemicals: "Good" and "Bad" 8 Why the "Good-Bad" Dichotomy? 10 Man-made Chemicals Are Made by Humans 11 Man-made Chemicals May Not Be Biodegradable 12 Man-made Chemicals May Be Very Complex 16 2 WHAT HARM DO CHEMICALS CAUSE? 19 Harmful Properties of Chemicals 19 Explosiveness and Reactivity 19 Flammability and Combustibility 20 Radioactivity 21 Corrosiveness 23 Irritation 23 Sensitization and Photosensitization 24 Toxicity 26 Multiple Harmful Properties 27 Definition of Poison 28 Defi nition of Hazard 28 3 WHAT IS TOXICOLOGY? 31 Empirical Toxicology 31 Paracelsus and Ramazzini 32 A Brief History of Toxicology 34 Toxicology Today 40 What Do Toxicologists Do? 44 4 WHAT FACTORS INFLUENCE THE TOXIC EFFECTS OF CHEMICALS? 47 Acute versus Chronic Toxicity 47 Significance of Divided Doses 53 Routes of Exposure 54 Dermal Exposure 54 Inhalation Exposure 55 Oral Exposure 58 Other Routes of Exposure 59 Combinations 60 Influence of Route on Toxicity 60 Metabolism 64 Routes of Elimination (Excretion) 65 Other Factors that Infl uence Toxicity 66 Species 66 Sex 70 Age 71 Nutrition 73 State of Health 73 Biochemical Individuality (Genetic Diversity) 74 Presence of Other Chemicals 75 Adaptation 77 Light 79 5 HOW IS TOXICOLOGY STUDIED? 81 Experimental Methods 82 Acute Toxicity 83 Irritant and Corrosive Effects 85 Sensitization and Photosensitization 86 Chronic Toxicity 87 Mutagenesis 90 Carcinogenesis 91 Developmental and Reproductive Toxicity 94 Units of Trace Quantities 95 Analytical Methods 96 Animal Rights 99 6 GENERAL TOXICOLOGY 103 Acute Toxicity 103 LD50 and LC50 Values 103 Signifi cance of LDs for Humans 104 Poison Prevention 109 Antidotes 112 Chronic Toxicity 114 No-Effect Levels and Thresholds 116 Margins of Safety 117 Sufficient Challenge 119 Bioaccumulation 121 7 MUTAGENESIS AND CARCINOGENESIS 129 Mutagenesis 129 Genetic Code 129 Mutations 130 Significance of Mutations 132 Mutation and Cancer 135 Carcinogenesis 138 What Is Cancer? 138 Causes of Cancer 140 Role of Mutation 141 Incidence of Cancer 142 Categories and Characteristics of Carcinogens 143 Induction Periods 146 Thresholds 147 Practical Thresholds 149 The Real World 150 Benzo[a]pyrene 150 Cancerophobia 151 8 DEVELOPMENTAL AND REPRODUCTIVE TOXICITY 153 Male and Female Reproductive Systems 154 Prepuberty Systems 154 Adult Systems 155 The Developing Individual 156 9 CASE STUDIES IN TOXICOLOGY 163 Environmental Contaminations 164 Dioxins: Seveso, Italy 164 PCBs and Dibenzofurans: Yusho Disease 169 Bophal, India 173 Minamata Disease 174 DDT 174 Consumer Products 177 Metals 177 Lead and Cadmium 178 Zinc 178 Plastics 179 Bisphenyl A 180 Indoor Air Pollution 181 Water Pollution 185 Pharmaceuticals 186 Fen-Phen 187 Vioxx 188 Thalidomide 189 10 EPIDEMIOLOGY 191 Origins of Modern Epidemiology 191 Epidemiology of Noninfectious Diseases 193 Koch's Postulates 195 Study Design: Precepts and Pitfalls 197 Unreasonable Expectations 201 Proximate Event Approach in Assigning Cause 202 Distrust of Science and Scientists 204 11 THE STUDY OF RISK 211 Public Health Statistics 211 Inherent Risk 213 Risk Assessment 215 Perceived Risk 218 Acceptable Risk 220 Risk Benefit and Cost Benefit 222 Risk Communication 225 Risk Management 227 Bibliography 229 Abbreviations 233 Glossary 235 Appendix A 245 Index 247