Table of Contents

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

INTRODUCTION TO THE THIRD EDITION. PREFACE TO THE SECOND EDITION. CHAPTER 1: WHAT ARE CHEMICALS? ATOMS AND MOLECULES. NATURAL CHEMICALS. SYNTHETIC CHEMICALS. CHEMICAL CATEGORIES. CHEMICALS: "GOOD" AND "BAD". WHY THE "GOOD-BAD" DICHOTOMY? Man-Made Chemicals Are Man-Made. Man-Made Chemicals May Not Be Biodegradable. Man-Made Chemicals May Be Very Complex. CHAPTER 2: WHAT HARM DO CHEMICALS CAUSE? HARMFUL PROPERTIES OF CHEMICALS. Explosiveness and Reactivity. Flammability and Combustibility. Radioactivity. Corrosiveness. Irritation. Sensitization and Photosensitization. Toxicity. Multiple Harmful Properties. DEFINITION OF POISON. DEFINITION OF HAZARD. CHAPTER 3: WHAT IS TOXICOLOGY? EMPIRICAL TOXICOLOGY. PARACELSUS AND RAMAZZINI. A BRIEF HISTORY OF TOXICOLOGY. TOXICOLOGY TODAY. WHAT DO TOXICOLOGISTS DO? CHAPTER 4: WHAT FACTORS INFLUENCE THE TOXIC EFFECTS OF CHEMICALS? ACUTE VERSUS CHRONIC TOXICITY. SIGNIFICANCE OF DIVIDED DOSES. ROUTES OF EXPOSURE. Dermal. Inhalation. Oral. Other Routes of Exposure. Combinations. INFLUENCE OF ROUTE ON TOXICITY. METABOLISM. ROUTES OF ELIMINATION (EXCRETION). OTHER FACTORS THAT INFLUENCE TOXICITY. Species. Sex. Age. Nutrition. State of Health. Biochemical Individuality (Genetic Diversity). Presence of Other Chemicals. Adaptation. Light. CHAPTER 5: HOW IS TOXICOLOGY STUDIED? EXPERIMENTAL METHODS. Acute Toxicity. Irritant and Corrosive Effects. Sensitization and Photosensitization. Chronic Toxicity. Mutagenesis. Carcinogenesis. Developmental and Reproductive Toxicity (DART). UNITS OF TRACE QUANTITIES. ANALYTICAL METHODS. ANIMAL RIGHTS. CHAPTER 6: GENERAL TOXICOLOGY. ACUTE TOXICITY. LD50s and LC50s. Significance of LDs For Humans. Poison Prevention. Antidotes. CHRONIC TOXICITY. No-Effect Levels and Thresholds. Margins of Safety. Sufficient Challenge. Bioaccumulation. CHAPTER 7: MUTAGENESIS AND CARCINOGENESIS. MUTAGENESIS. The Genetic Code. Mutations. Significance of Mutations. Mutation and Cancer. CARCINOGENESIS. What Is Cancer? Causes of Cancer. The Role of Mutation. Incidence of Cancer. Categories and Characteristics of Carcinogens. Induction Periods. Thresholds. Practical Thresholds. THE REAL WORLD. Benzo[a]pyrene. Cancerophobia. CHAPTER 8: DEVELOPMENTAL AND REPRODUCTIVE TOXICITY. THE MALE AND FEMALE REPRODUCTIVE SYSTEMS. Prepuberty Systems. Adult Systems. THE DEVELOPING INDIVIDUAL. CHAPTER 9: CASE STUDIES IN TOXICOLOGY. ENVIRONMENTAL CONTAMINATIONS. Dioxins: Seveso, Italy. PCBs and Dibenzofurans: Yusho Disease. Bophal, India. Minomata Disease. DDT. CONSUMER PRODUCTS. Metals. Lead and Cadmium. Zinc. Plastics. Phthalates. Bisphenyl A (BPA). INDOOR AIR POLLUTION. WATER POLLUTION. PHARMACEUTICALS. Fen-Phen. Vioxx(r). Thalidomide. CHAPTER 10: EPIDEMIOLOGY. ORIGINS OF MODERN EPIDEMIOLOGY. EPIDEMIOLOGY OF NONINFECTIOUS DISEASES. STUDY DESIGN: PRECEPTS AND PITFALLS. UNREASONABLE EXPECTATIONS. THE PROXIMATE EVENT APPROACH IN ASSIGNING CAUSE. DISTRUST OF SCIENCE AND SCIENTISTS. CHAPTER 11: THE STUDY OF RISK. PUBLIC HEALTH STATISTICS. INHERENT RISK. RISK ASSESSMENT. PERCEIVED RISK. ACCEPTABLE RISK. RISK-BENEFIT AND COST-BENEFIT. RISK COMMUNICATION. RISK MANAGEMENT. BIBLIOGRAPHY. ABBREVIATIONS. GLOSSARY. APPENDIX A. Index.

About the Author

Patricia Frank is President of Patricia Frank &Associates, Inc., a consulting firm founded in 1993 that assistscompanies in the development and registration of human andveterinary pharmaceutical agents. She is a past president of boththe American College of Toxicology and the Roundtable of ToxicologyConsultants. M. Alice Ottoboni lectures, writes, and consults in thefield of toxicology. As Staff Toxicologist with the CaliforniaState Department of Public Health for over twenty years, sheoriginated, designed, and performed numerous toxicological studiesof environmental factors of importance to public health. She is theauthor of the previous editions of The Dose Makes thePoison.

Reviews

"This is a refreshing, invigorating as well as eye-opening text,which is reading like an exciting novel - even to a seasonedtoxicologist ... An appendix to clarify quantities of pollutantsplus an index concludes this most valuable introduction into thescience of toxicology for a broad readership." (Toxicology,2011) "I recommend this book to anyone who has ever listened to theevening news and wondered how much of the "chemical scare du jour"is hype and how much of it is fact - and to those who might want tounderstand basic concepts in toxicology and the related areas ofstudy without having to trudge through a gaggle of 1000-pagetextbooks." (International Journal of Toxicology, 2011) "Overall, this is a well-written work with wisely chosen andrelevant topics. It will be a perfect addition to any scienceenthusiast's library. Summing Up: Highly recommended. Lower-levelundergraduates through professionals/practitioners; generalreaders." (Choice, 1 September 2011) "The Dose Makes the Poison is more than just an introduction totoxicology. It is an enjoyable read with lots of interestingstories and one I can thoroughly recommend." (Chemistry &Industry, 25 July 2011) "There is much to be applauded in this book from itsstraightforward layout and honesty to its accessibility ... Manygood, and contemporary, examples are provided to deliver greatercontext for the reader." (The British Toxicology Society Journal, 1May 2011)