3rd Edition

Barile’s Clinical Toxicology Principles and Mechanisms

By Frank A. Barile Copyright 2019
    622 Pages 92 B/W Illustrations
    by CRC Press

    As with the two previous editions, Barile’s Clinical Toxicology: Principles and Mechanisms, Third edition, examines the complex interactions associated with clinical toxicological events as a result of therapeutic drug administration or chemical exposure. With special emphasis placed on signs and symptoms of diseases and pathology caused by toxins and clinical drugs, the new edition, examines the complex interactions associated with clinical toxicological events as a result of therapeutic drug administration or chemical exposure. The new edition presents the latest, up-to-date protocols for managing various toxic ingestions, and the antidotes and treatments associated with their pathology. In addition, the effect of toxins on a limited number of body systems and drug-induced adverse drug reactions are also covered.

    KEY FEATURES

    • Discusses source of the drug or chemical, pharmacological and toxicological mechanisms of action, detection, identification, and treatment

    • Examines the complex interactions associated with clinical toxicological events

    • Emphasizes the signs and symptoms of diseases and pathology caused by toxins and clinical drugs

    • Covers effect of toxins on body systems and drug-induced adverse reactions

    • Offers a unique perspective for toxicology, pharmacology, pharmacy and health professions students

    The target audience for this book is undergraduate and graduate toxicology students, clinical pharmacy (Pharm.D.) students, emergency medical personnel, regulatory agencies, and other related health science professionals. It satisfies an essential need for a concise yet detailed authoritative, fundamental text addressing the current principles of clinical toxicology.

    Contents

    Preface...................................................................................................................xxxi

    Acknowledgments............................................................................................... xxxiii

    Author...................................................................................................................xxxv

    Contributors........................................................................................................xxxvii

    Section I □Introduction to Basic

    Toxicological Principles

    Chapter 1 Introduction...........................................................................................3

    1.1 Introduction................................................................................3

    1.2 Basic Definitions.........................................................................4

    1.2.1 Toxicology.....................................................................4

    1.2.2 Clinical Toxicology.......................................................4

    1.3 Types of Toxicology...................................................................5

    1.3.1 General Toxicology.......................................................5

    1.3.2 Mechanistic Toxicology................................................5

    1.3.3 Regulatory Toxicology..................................................5

    1.3.4 Descriptive Toxicology..................................................6

    1.4 Types of Toxicologist..................................................................7

    1.4.1 Forensic Toxicologist.....................................................7

    1.4.2 Clinical Toxicologist.....................................................8

    1.4.3 Research Toxicologist....................................................8

    1.4.4 Regulatory Toxicologist................................................8

    References.............................................................................................8

    Suggested Readings...............................................................................8

    Review Articles.....................................................................................9

    Chapter 2 Risk Assessment and Regulatory Toxicology..................................... 11

    2.1 Risk Assessment....................................................................... 11

    2.1.1 Introduction................................................................. 11

    2.1.2 Hazard Identification/Risk Assessment (HIRA)......... 11

    2.1.3 Dose–Response Evaluation......................................... 11

    2.1.4 Exposure Assessment and Assessment Modeling....... 12

    2.1.5 Risk Characterization.................................................. 14

    2.2 Regulatory Toxicology............................................................. 16

    2.2.1 Nuclear Regulatory Commission (NRC).................... 16

    2.2.2 Environmental Protection Agency (EPA)................... 17

    2.2.3 The Food and Drug Administration (FDA)................ 18

    2.2.4 Drug Enforcement Administration (DEA).................. 19

    2.2.5 Consumer Products Safety Commission (CPSC)........20

    2.2.6 Occupational Safety and Health Administrations

    (OSHA)........................................................................22

    References...........................................................................................23

    Suggested Readings.............................................................................23

    Review Articles...................................................................................23

    Chapter 3 Therapeutic Monitoring of Adverse Drug Reactions (ADRs).............27

    3.1 Adverse Drug Reactions (ADRs) in Clinical Practice.............27

    3.1.1 The Joint Commission (TJC)......................................27

    3.1.2 Growing Medication Safety Concerns........................28

    3.1.3 National Patient Safety Goals (NPSG).......................28

    3.2 Factors that Contribute to Adverse Drug Reactions (ADRs)...29

    3.2.1 Inadequate Monitoring of Prescribed Drugs..............29

    3.2.2 Improper Adherence to Prescribed Directions........... 32

    3.2.3 Over-Prescribing and Overuse of Medications........... 32

    3.2.4 Drug–Drug and Drug–Disease Interactions............... 32

    3.2.5 Allergic Reactions....................................................... 32

    3.2.6 Medication Warnings.................................................. 33

    3.2.7 Medication Errors....................................................... 33

    3.2.8 Adverse Drug Reactions (ADRS)............................... 33

    3.3 Treatment of ADRs and Poisoning in Patients......................... 35

    3.3.1 History......................................................................... 35

    3.3.2 Poison Control Centers (PCCs)................................... 35

    3.3.3 Clinical Management of ADRs...................................36

    3.3.4 Clinical Management of Toxicologic Emergencies.....36

    3.4 Drug Identification and Methods of Detection......................... 41

    References...........................................................................................44

    Suggested Readings.............................................................................44

    Review Articles................................................................................... 45

    Chapter 4 Classification of Toxins in Humans.................................................... 47

    4.1 Introduction.............................................................................. 47

    4.2 Target Organ Classification...................................................... 47

    4.2.1 Agents Affecting the Hematopoietic System.............. 47

    4.2.2 Immunotoxic Agents...................................................48

    4.2.3 Hepatotoxic Agents.....................................................48

    4.2.4 Nephrotoxic Agents.....................................................49

    4.2.5 Pulmonary Toxic Agents............................................. 52

    4.2.6 Agents Affecting the Nervous System........................54

    4.2.7 Agents Affecting the Cardiovascular (CV) System.... 55

    4.2.8 Dermatotoxic Agents................................................... 55

    4.2.9 Agents Affecting the Reproductive System................ 59

    4.2.10 Agents Affecting the Endocrine System..................... 59

    4.3 Classification According to use in the Public Domain.............60

    4.3.1 Insecticides, Herbicides, Fungicides, and

    Rodenticides (Pesticides).............................................60

    4.3.2 Food and Color Additives........................................... 61

    4.3.3 Therapeutic Drugs.......................................................63

    4.3.4 By-Products of Combustion........................................63

    4.4 Classification According to Source..........................................63

    4.4.1 Botanical.....................................................................63

    4.4.2 Environmental.............................................................63

    4.5 Classification According to Effects..........................................64

    4.5.1 Pathologic....................................................................64

    4.5.2 Teratogenic, Mutagenic, and Carcinogenic.................64

    4.6 Classification According to Physical State...............................64

    4.6.1 Solids...........................................................................64

    4.6.2 Liquids.........................................................................64

    4.6.3 Gases...........................................................................65

    4.7 Classification According to Biochemical Properties................65

    4.7.1 Chemical Structure.....................................................65

    4.7.2 Mechanism of Action or Toxicity................................65

    References...........................................................................................65

    Suggested Readings.............................................................................65

    Review Articles...................................................................................65

    Chapter 5 Exposure..............................................................................................69

    5.1 Introduction..............................................................................69

    5.2 Route of Exposure....................................................................69

    5.2.1 Oral..............................................................................69

    5.2.2 Intranasal..................................................................... 70

    5.2.3 Inhalation.................................................................... 71

    5.2.4 Parenteral.................................................................... 71

    5.3 Duration and Frequency........................................................... 72

    5.3.1 Acute Exposure........................................................... 72

    5.3.2 Chronic Exposure........................................................ 73

    5.3.3 Single- or Repeated-Dose Exposure........................... 73

    5.4 Accumulation........................................................................... 73

    5.4.1 According to Physiological Compartment.................. 74

    5.4.2 According to Chemical Properties.............................. 74

    5.4.3 According to Other Biological Factors........................ 74

    References........................................................................................... 76

    Suggested Readings............................................................................. 76

    Review Articles................................................................................... 76

    Chapter 6 Effects.................................................................................................. 79

    6.1 General Classification............................................................... 79

    6.1.1 Introduction to Principles of Immunology.................. 79

    6.1.2 Chemical Allergies...................................................... 79

    6.1.3 Idiosyncratic Reactions...............................................86

    6.1.4 Immediate versus Delayed Effects..............................86

    6.1.5 Reversible versus Irreversible Reactions.....................86

    6.1.6 Local versus Systemic Effects.....................................86

    6.1.7 Target Therapeutic Effects..........................................87

    6.2 Chemical Interactions...............................................................87

    6.2.1 Potentiation..................................................................87

    6.2.2 Additive.......................................................................87

    6.2.3 Synergistic...................................................................88

    6.2.4 Antagonistic................................................................88

    References...........................................................................................88

    Suggested Readings.............................................................................88

    Review Aricles.....................................................................................89

    Chapter 7 Dose–Response................................................................................... 91

    7.1 General Assumptions............................................................... 91

    7.1.1 Types of Dose–Response Relationships...................... 91

    7.1.2 Concentration–Effect and Presence at the

    Receptor Site...............................................................93

    7.1.3 Criteria for Measurement............................................93

    7.2 LD50 (Lethal Dose 50%)...........................................................93

    7.2.1 Definition.....................................................................93

    7.2.2 Experimental Protocol................................................93

    7.2.3 Factors That Influence the LD50..................................94

    7.3 ED50 (Effective Dose 50%), TD50 (Toxic Dose 50%), and

    TI (Therapeutic Index).............................................................95

    7.3.1 Relationship to LD50....................................................95

    7.3.2 Assumptions Using the TI...........................................95

    7.4 IC50 (Inhibitory Concentration 50%)........................................96

    7.4.1 Definition.....................................................................96

    7.4.2 Experimental Determination.......................................97

    7.4.3 For In Vitro Systems....................................................97

    References...........................................................................................97

    Suggested Readings.............................................................................97

    Review Articles...................................................................................98

    Chapter 8 Descriptive Animal Toxicity Tests......................................................99

    8.1 Correlation with Human Exposure...........................................99

    8.1.1 Human Risk Assessment.............................................99

    8.1.2 Predictive Toxicology and Extrapolation to

    Human Toxicity...........................................................99

    8.2 Species Differentiation.............................................................99

    8.2.1 Selection of a Suitable Animal Species......................99

    8.2.2 Cost-Effectiveness..................................................... 100

    8.2.3 Institutional Animal Care and Use Committee

    (IACUC).................................................................... 100

    8.3 Descriptive Tests..................................................................... 101

    8.3.1 Required LD50 and Two Routes............................... 101

    8.3.2 Chronic and Subchronic Exposure............................ 101

    8.3.3 Types of Tests............................................................ 101

    References......................................................................................... 102

    Suggested Readings........................................................................... 102

    Review Aricles................................................................................... 103

    Chapter 9 In Vitro Alternatives to Animal Toxicity.......................................... 105

    9.1 In Vitro Methods.................................................................... 105

    9.1.1 Cell Culture Methods................................................ 105

    9.1.2 Organ System Cytotoxicity....................................... 105

    9.1.3 Applications to Clinical Toxicology.......................... 106

    9.1.4 Relationship to Animal Experiments........................ 107

    9.2 Correlation with Human Exposure......................................... 107

    9.2.1 Risk Assessment........................................................ 107

    9.2.2 Extrapolation to Human Toxicity.............................. 107

    9.2.3 Predictive Toxicology................................................ 108

    References......................................................................................... 108

    Suggested Readings........................................................................... 108

    Review Articles................................................................................. 108

    Chapter 10 Toxicokinetics................................................................................... 111

    10.1 Toxicokinetics......................................................................... 111

    10.1.1 Relationship to Pharmacokinetics............................. 111

    10.1.2 One-Compartment Model......................................... 111

    10.1.3 Two-Compartment Model......................................... 112

    10.1.4 Application to Clinical Toxicology........................... 112

    10.2 Absorption.............................................................................. 112

    10.2.1 Ionic and Nonionic Principles................................... 112

    10.2.2 Henderson–Hasselbalch Equation and Degree of

    Ionization................................................................... 114

    10.2.3 Route of Administration and Solubility.................... 118

    10.2.4 Absorption in Nasal and Respiratory Mucosa.......... 119

    10.2.5 Transport of Molecules............................................. 120

    10.3 Distribution............................................................................. 121

    10.3.1 Fluid Compartments.................................................. 121

    10.3.2 Ionic and Nonionic Principles................................... 122

    10.3.3 Plasma Protein Binding............................................. 123

    10.3.4 Lipids......................................................................... 125

    10.3.5 Liver and Kidney....................................................... 125

    10.3.6 Blood–Brain Barrier.................................................. 125

    10.3.7 Placenta..................................................................... 125

    10.3.8 Other Factors Affecting Distribution........................ 126

    10.4 Biotransformation (Metabolism)............................................ 126

    10.4.1 Principles of Detoxification....................................... 126

    10.4.2 Phase I Reactions...................................................... 127

    10.4.3 Phase II Reactions..................................................... 128

    10.5 Elimination............................................................................. 131

    10.5.1 Urinary...................................................................... 131

    10.5.1.1 First-Order Elimination............................. 132

    10.5.1.2 Zero-Order Elimination............................. 134

    10.5.2 Fecal.......................................................................... 135

    10.5.3 Pulmonary................................................................. 135

    10.5.4 Mammary Glands..................................................... 136

    10.5.5 Secretions.................................................................. 136

    References......................................................................................... 136

    Suggested Readings........................................................................... 136

    Review Articles................................................................................. 137

    Chapter 11 Chemical– and Drug–Receptor Interactions..................................... 139

    Zacharoula Konsoula

    11.1 Types of Chemical and Drug Receptors................................. 139

    11.1.1 Ion Channels.............................................................. 139

    11.1.2 G-Protein-Coupled Receptors................................... 142

    11.1.3 Kinases and Enzyme-Coupled Receptors................. 143

    11.1.4 Intracellular Receptors.............................................. 145

    11.2 Signal Transduction................................................................ 148

    References......................................................................................... 150

    Suggested Readings........................................................................... 150

    Review Articles................................................................................. 150

    Chapter 12 Toxicogenomics................................................................................. 151

    Anirudh J. Chintalapati, Zacharoula Konsoula, and Frank A. Barile

    12.1 Introduction............................................................................ 151

    12.2 Human Genomic Variation..................................................... 151

    12.2.1 Genomic Variation in Target Molecules................... 152

    12.2.2 Genomic Variation in Drug Metabolism................... 154

    12.3 Gene Structure and Function.................................................. 154

    12.3.1 DNA Alterations and Genotoxic Effects................... 155

    12.3.2 DNA Repair Mechanisms......................................... 157

    12.3.3 Experimental Monitoring for Genetic Toxicity......... 159

    12.3.4 Clinical Monitoring for Genetic Toxicity.................. 159

    12.4 Epigenetic Toxicology............................................................ 160

    12.4.1 Mechanisms of Epigenetic Toxicity.......................... 161

    12.4.1.1 DNA Methylation...................................... 161

    12.4.1.2 Posttranslational Modifications of

    Histone Proteins......................................... 162

    12.4.1.3 Noncoding RNA........................................ 162

    12.4.2 Epigenetics and Disease............................................ 163

    Referenes........................................................................................... 163

    Suggested Readings........................................................................... 163

    Review Articles................................................................................. 164

    Section II Toxicity of Therapeutic Agents

    Chapter 13 Sedative/Hypnotics............................................................................ 167

    Frank A. Barile and Anirudh J. Chintalapati

    13.1 Barbiturates............................................................................ 167

    13.1.1 History and Classification......................................... 167

    13.1.2 Epidemiology............................................................ 167

    13.1.3 Medicinal Chemistry................................................. 167

    13.1.4 Pharmacology and Clinical Use................................ 168

    13.1.5 Toxicokinetics and Metabolism................................ 168

    13.1.6 Mechanism of Toxicity.............................................. 169

    13.1.7 Signs and Symptoms of Acute Toxicity.................... 169

    13.1.8 Emergency Guidelines.............................................. 171

    13.1.9 Clinical Management of Acute Overdose................. 171

    13.1.10 Tolerance and Withdrawal......................................... 172

    13.1.11 Methods of Detection................................................ 172

    13.2 Benzodiazepines (BZ)............................................................ 172

    13.2.1 Epidemiology............................................................ 172

    13.2.2 Medicinal Chemistry................................................. 173

    13.2.3 Pharmacology and Mechanism of Toxicity............... 173

    13.2.4 Toxicokinetics........................................................... 173

    13.2.5 Signs and Symptoms of Acute Toxicity.................... 174

    13.2.6 Emergency Guidelines.............................................. 174

    13.2.7 Clinical Management of Acute Overdose................. 174

    13.2.8 Tolerance and Withdrawal......................................... 174

    13.2.9 Methods of Detection................................................ 174

    13.3 Miscellaneous Sedative/Hypnotics........................................ 176

    13.3.1 Chloral Hydrate......................................................... 176

    13.3.2 Meprobamate (Miltown®, Equanil®)......................... 176

    13.3.3 Zolpidem tartrate (Ambien®)..................................... 177

    13.3.4 Buspirone (Buspar®).................................................. 177

    13.3.5 Flunitrazepam (Rohypnol®)...................................... 177

    13.3.6 Gamma-hydroxybutyrate (GHB)............................... 178

    13.3.7 Ethchlorvynol (Placidyl®), Methaqualone

    (Quaalude®), Glutethimide (Doriden®),

    Methyprylon (Noludar®)............................................ 178

    13.4 Methods of Detection and Laboratory Tests for S/H............. 179

    References......................................................................................... 179

    Suggested Readings........................................................................... 180

    Review Articles................................................................................. 181

    Chapter 14 Opioids and Related Agents.............................................................. 183

    14.1 Opioids.................................................................................... 183

    14.1.1 U.S. Public Health and Historical Use...................... 183

    14.1.2 Neonatal Abstinence Syndrome (NAS).................... 185

    14.1.3 Classification............................................................. 186

    14.1.4 Medicinal Chemistry................................................. 189

    14.1.5 Mechanism of Toxicity.............................................. 189

    14.1.6 Brain Chemistry........................................................ 191

    14.1.7 Toxicokinetics........................................................... 191

    14.1.8 Mechanism of Toxicity.............................................. 191

    14.1.9 Signs and Symptoms of Clinical Toxicity................. 192

    14.1.10 Clinical Management of Acute Overdose................. 192

    14.1.11 Tolerance and Withdrawal......................................... 193

    14.1.12 Clinical Management of Addiction........................... 195

    14.2 Specific Opioid Derivatives.................................................... 195

    14.2.1 Codeine..................................................................... 195

    14.2.2 Diphenoxylate............................................................ 196

    14.2.3 Fentanyl..................................................................... 196

    14.2.4 Meperidine................................................................ 196

    14.2.5 Pentazocine............................................................... 197

    14.2.6 Propoxyphene............................................................ 197

    14.2.7 Hydrocodone/Oxycodone.......................................... 197

    14.2.8 Tramadol................................................................... 198

    14.2.9 Clonidine................................................................... 199

    14.3 Methods of Detection............................................................. 199

    References.........................................................................................200

    Suggested Readings...........................................................................200

    Review Articles................................................................................. 201

    Chapter 15 Sympathomimetics............................................................................203

    15.1 Amphetamines and Amphetamine-like Agents.....................203

    15.1.1 Incidence...................................................................203

    15.1.2 Classification.............................................................203

    15.1.3 Medicinal Chemistry.................................................204

    15.1.4 Pharmacology and Clinical Use................................204

    15.1.5 Toxicokinetics...........................................................206

    15.1.6 Effects and Mechanism of Toxicity...........................206

    15.1.7 Chronic Methamphetamine Use...............................208

    15.1.8 Tolerance and Withdrawal.........................................208

    15.1.9 Clinical Management of Amphetamine Addiction...208

    15.1.10 Methods of Detection................................................209

    15.2 Cocaine...................................................................................209

    15.2.1 Incidence and Occurrence.........................................209

    15.2.2 Medicinal Chemistry................................................. 210

    15.2.3 Pharmacology and Clinical Use................................ 210

    15.2.4 Toxicokinetics........................................................... 211

    15.2.5 Signs and Symptoms of Acute Toxicity.................... 212

    15.2.6 Clinical Management of Acute Overdose................. 212

    15.2.7 Tolerance and Withdrawal......................................... 213

    15.2.8 Clinical Management of Cocaine Addiction............. 213

    15.2.9 Methods of Detection................................................ 213

    15.3 Xanthine Derivatives.............................................................. 213

    15.3.1 Source and Medicinal Chemistry.............................. 213

    15.3.2 Occurrence................................................................ 214

    15.3.3 Pharmacology and Clinical Use................................ 214

    15.3.4 Toxicokinetics........................................................... 216

    15.3.5 Signs and Symptoms and Clinical Management

    of Caffeine Toxicity................................................... 216

    15.3.6 Signs and Symptoms and Clinical Management

    of Theophylline Toxicity........................................... 217

    15.3.7 Tolerance and Withdrawal......................................... 217

    15.4 Other Specific Sympathomimetic Agents.............................. 217

    15.4.1 Strychnine................................................................. 217

    15.4.2 Nicotine..................................................................... 218

    15.4.3 Ephedrine.................................................................. 219

    15.4.4 Phenylpropranolamine..............................................220

    15.4.5 Pseudoephedrine.......................................................220

    References.........................................................................................220

    Suggested Readings...........................................................................220

    Review Articles................................................................................. 221

    Chapter 16 Hallucinogenic Agents......................................................................225

    16.1 History and Description.........................................................225

    16.2 Ergot Alkaloids.......................................................................225

    16.2.1 Incidence and Occurrence.........................................225

    16.2.2 Medicinal Chemistry.................................................226

    16.2.3 Pharmacology and Clinical Use................................226

    16.2.4 Signs and Symptoms of Acute Toxicity....................227

    16.2.5 Clinical Management of Acute Overdose.................227

    16.3 Lysergic Acid Diethylamide (LSD)........................................228

    16.3.1 Incidence and Occurrence.........................................228

    16.3.2 Mechanism of Toxicity..............................................228

    16.3.3 Hallucinogenic Effects..............................................228

    16.3.4 Toxicokinetics...........................................................229

    16.3.5 Signs and Symptoms of Acute Toxicity....................229

    16.3.6 Clinical Management of Acute Overdose.................229

    16.3.7 Tolerance and Withdrawal.........................................230

    16.3.8 Methods of Detection................................................230

    16.4 Tryptamine Derivatives..........................................................230

    16.4.1 Incidence and Occurrence.........................................230

    16.4.2 Mechanism of Toxicity..............................................230

    16.4.3 Signs and Symptoms of Acute Toxicity.................... 231

    16.4.4 Clinical Management of Acute Overdose................. 231

    16.4.5 Tolerance and Withdrawal......................................... 231

    16.4.6 Methods of Detection................................................ 231

    16.5 Phenethylamine Derivatives................................................... 232

    16.5.1 Incidence and Occurrence......................................... 232

    16.5.2 Medicinal Chemistry................................................. 232

    16.5.3 Mescaline.................................................................. 232

    16.5.4 DOM (2,5-dimethoxy-4-methylamphetamine,

    STP) and MDA (3,4-methylenedioxyamphetamine)...............................234

    16.5.5 MDMA (3,4-methylenedioxymethamphetamine,

    ecstasy)......................................................................234

    16.5.6 Methods of Detection................................................ 235

    16.6 Phencyclidine (1-Phenylcyclohexyl Piperidine; PCP)............ 235

    16.6.1 Incidence and Occurrence......................................... 235

    16.6.2 Toxicokinetics........................................................... 235

    16.6.3 Signs and Symptoms of Acute Toxicity....................236

    16.6.4 Clinical Management of Acute Overdose.................236

    16.6.5 Tolerance and Withdrawal......................................... 237

    16.6.6 Methods of Detection................................................ 237

    16.7 Marijuana............................................................................... 237

    16.7.1 Incidence and Occurrence......................................... 237

    16.7.2 Medicinal Chemistry.................................................240

    16.7.3 Receptor Pharmacology and Toxicology..................240

    16.7.4 Clinical Use and Effects............................................ 241

    16.7.5 Toxicokinetics...........................................................242

    16.7.6 Acute Toxicity and Clinical Management.................242

    16.7.7 Tolerance, Withdrawal, and Chronic Effects............242

    16.7.8 Clinical Management of Chronic Addiction............. 243

    16.7.9 Methods of Detection................................................ 243

    16.8 Miscellaneous Hallucinogenic Agents................................... 243

    16.8.1 Ketamine (Special K, Vitamin K)............................. 243

    16.8.2 Gamma-hydroxybutyrate (GHB; Xyrem®)................245

    16.8.3 NBOMe.....................................................................246

    References.........................................................................................246

    Suggested Readings...........................................................................246

    Review Articles................................................................................. 247

    Chapter 17 Anticholinergic and Neuroleptic Drugs............................................ 251

    17.1 Introduction to Drugs Possessing Anticholinergic Effects........251

    17.2 Antihistamine, Gastrointestinal, and Antiparkinson Drugs.......251

    17.2.1 Incidence................................................................... 251

    17.2.2 Medicinal Chemistry, Pharmacology, and

    Clinical Use............................................................... 253

    17.2.3 Signs and Symptoms of Acute Toxicity.................... 253

    17.2.4 Clinical Management of Acute Overdose.................254

    17.2.5 Methods of Detection................................................254

    17.3 Tricyclic Antidepressants (TCA)............................................ 255

    17.3.1 Incidence................................................................... 255

    17.3.2 Medicinal Chemistry................................................. 255

    17.3.3 Pharmacology and Clinical Use................................ 255

    17.3.4 Toxicokinetics........................................................... 255

    17.3.5 Mechanism of Toxicity..............................................256

    17.3.6 Signs and Symptoms of Acute Toxicity....................256

    17.3.7 Clinical Management of Acute Overdose.................256

    17.3.8 Tolerance and Withdrawal......................................... 259

    17.3.9 Methods of Detection................................................ 259

    17.4 Phenothiazine, Phenylbutylpiperidine, and Thioxanthine

    Antipsychotics........................................................................ 259

    17.4.1 Classification and Indications................................... 259

    17.4.2 Pharmacology and Clinical Use................................260

    17.4.3 Toxicokinetics...........................................................260

    17.4.4 Mechanism and Signs and Symptoms of Acute

    Toxicity......................................................................260

    17.4.5 Clinical Management of Acute Overdose................. 262

    17.4.6 Tolerance and Withdrawal......................................... 262

    17.4.7 Methods of Detection................................................ 262

    17.5 Selective Serotonin Reuptake Inhibitors (SSRIS).................. 262

    17.5.1 Classification and Clinical Use................................. 262

    17.5.2 Pharmacology and Receptor Activity.......................263

    17.5.3 Toxicokinetics...........................................................264

    17.5.4 Side Effects and Adverse Reactions..........................265

    17.5.5 Signs and Symptoms of Acute Toxicity....................266

    17.5.6 Clinical Management of Acute Overdose (O.D.)......266

    17.5.7 Tolerance and Withdrawal......................................... 267

    17.5.8 Methods of Detection................................................ 267

    References......................................................................................... 267

    Suggested Readings........................................................................... 267

    Review Articles.................................................................................268

    Chapter 18 Acetaminophen, Salicylates, and Nonsteroidal Anti-

    Inflammatory Drugs (NSAIDs)........................................................ 271

    18.1 History and Description......................................................... 271

    18.2 Acetaminophen (N-Acetyl-Para-Aminophenol,

    APAP, Paracetamol)............................................................... 271

    18.2.1 Incidence................................................................... 271

    18.2.2 Medicinal Chemistry and Pharmacology................. 272

    18.2.3 Clinical Use............................................................... 272

    18.2.4 Metabolism and Mechanism of Toxicity................... 272

    18.2.5 Signs and Symptoms of Acute Toxicity.................... 274

    18.2.6 Clinical Management of Acute Overdose................. 274

    18.3 Salicylates and Acetylsalicylic Acid (ASPIRIN, ASA).......... 276

    18.3.1 Incidence and Clinical Use....................................... 276

    18.3.2 Toxicokinetics...........................................................277

    18.3.3 Mechanism of Toxicity..............................................277

    18.3.4 Signs and Symptoms of Acute Toxicity.................... 278

    18.3.5 Clinical Management of Toxicity.............................. 279

    18.4 Nonsteroidal Anti-Inflammatory Agents (NSAIDS)............. 281

    18.4.1 History and Description............................................ 281

    18.4.2 Classification, Pharmacology, and Clinical Use.......282

    18.4.3 Signs and Symptoms of Acute Toxicity....................282

    18.4.4 Clinical Management of Acute Overdose.................282

    18.5 Methods of Detection.............................................................284

    References.........................................................................................284

    Suggested Readings...........................................................................284

    Review Articles.................................................................................285

    Chapter 19 Anabolic–Androgenic Steroids.........................................................287

    19.1 The Endocrine System...........................................................287

    19.2 Neuroendocrine Physiology...................................................287

    19.2.1 Description................................................................287

    19.3 Anabolic–Androgenic Steroids (AAS)...................................288

    19.3.1 Definition and Incidence...........................................288

    19.3.2 Pharmacology and Clinical Use................................289

    19.3.3 Adverse reactions......................................................289

    19.3.4 Addiction and Withdrawal Syndrome.......................293

    19.3.5 Treatment of the Consequences of Chronic

    Steroid Use................................................................293

    19.4 Estrogen and Progestins.........................................................293

    19.4.1 Physiology.................................................................293

    19.4.2 Pharmacology and Clinical Use................................294

    19.4.3 Clinical Toxicity of Prolonged Estrogen and/or

    Progestin Administration..........................................294

    References.........................................................................................297

    Suggested Readings...........................................................................297

    Review Articles.................................................................................297

    Chapter 20 Cardiovascular Toxicology................................................................299

    20.1 Epidemiology..........................................................................299

    20.2 Cardiovascular (CV) Physiology............................................299

    20.2.1 CV Functions.............................................................299

    20.2.2 Cardiac Circulation...................................................300

    20.2.3 Electrophysiology......................................................300

    20.2.4 The Conducting System............................................ 301

    20.2.5 Electrocardiography..................................................302

    20.3 Digitalis Glycosides................................................................303

    20.3.1 Medicinal Chemistry.................................................303

    20.3.2 Pharmacology and Clinical Use................................304

    20.3.3 Toxicokinetics...........................................................304

    20.3.4 Clinical Manifestations of Toxicity...........................305

    20.3.5 Mechanisms of Toxicity............................................305

    20.3.6 Clinical Management of Intoxication........................306

    20.3.7 Methods of Detection................................................307

    20.4 Beta-Adrenergic Receptor Antagonists..................................307

    20.4.1 β-Adrenergic Receptor System..................................307

    20.4.2 Pharmacology and Clinical Use................................307

    20.4.3 Clinical Manifestations of Toxicity...........................308

    20.4.4 Clinical Management of Intoxication........................308

    20.5 Calcium Channel Antagonists (Ca2+ Channel Blockers)........309

    20.5.1 Pharmacology and Clinical Use................................309

    20.5.2 Clinical Manifestations of Toxicity........................... 310

    20.5.3 Clinical Management of Intoxication........................ 310

    20.6 Other CV Drugs..................................................................... 310

    20.6.1 Angiotensin-Converting Enzyme (ACE)

    Inhibitors................................................................... 311

    20.6.2 Direct Vasodilators.................................................... 312

    20.6.3 Antiarrhythmic Drugs............................................... 313

    References......................................................................................... 314

    Suggested Readings........................................................................... 314

    Review Articles................................................................................. 315

    Chapter 21 Antineoplastic Agents....................................................................... 317

    21.1 Description............................................................................. 317

    21.2 Review of the Cell Cycle........................................................ 317

    21.3 Antimetabolites...................................................................... 318

    21.3.1 Pharmacology and Clinical Use................................ 318

    21.3.2 Acute Toxicity........................................................... 319

    21.3.3 Clinical Management of Acute Overdose................. 319

    21.4 Alkylating Agents................................................................... 320

    21.4.1 Pharmacology and Clinical Use................................ 320

    21.4.2 Acute Toxicity........................................................... 320

    21.4.3 Clinical Management of ADRs................................. 321

    21.5 Miscellaneous Chemotherapeutic Drugs............................... 321

    21.5.1 Natural Products........................................................ 321

    21.5.2 Hormones and Antagonists....................................... 323

    21.5.3 Platinum Coordination Complexes...........................324

    21.5.4 Substituted Urea........................................................324

    References......................................................................................... 325

    Suggested Readings........................................................................... 325

    Review Articles................................................................................. 325

    Chapter 22 Vitamins............................................................................................ 329

    22.1 Introduction............................................................................ 329

    22.2 Fat-Soluble Vitamins.............................................................. 331

    22.2.1 Vitamin A and Retinoic Acid Derivatives................ 331

    22.2.2 Vitamin D.................................................................. 332

    22.2.3 Vitamin E.................................................................. 335

    22.2.4 Vitamin K.................................................................. 335

    22.3 Water-Soluble Vitamins.......................................................... 336

    22.3.1 Thiamine................................................................... 336

    22.3.2 Riboflavin.................................................................. 336

    22.3.3 Niacin........................................................................ 336

    22.3.4 Folic Acid.................................................................. 338

    22.3.5 Cyanocobalamin (Vitamin B12)................................. 338

    22.3.6 Ascorbic Acid (Vitamin C)....................................... 338

    22.3.7 Pyridoxine (Vitamin B6)........................................... 339

    22.3.8 Pantothenic Acid (Vitamin B5)................................. 339

    References.........................................................................................340

    Suggested Readings...........................................................................340

    Review Articles.................................................................................340

    Chapter 23 Herbal Remedies............................................................................... 343

    23.1 Introduction............................................................................ 343

    23.2 Nomenclature and Classification............................................344

    23.2.1 Nomenclature............................................................344

    23.2.2 Therapeutic Category................................................ 345

    23.3 Indications.............................................................................. 345

    23.4 Other Therapeutic and Toxicologic Information on

    Herbal Products...................................................................... 345

    References......................................................................................... 356

    Suggested Readings........................................................................... 356

    Review Articles................................................................................. 357

    Section III Toxicity of Nontherapeutic Agents

    Chapter 24 Alcohols and Aldehydes.................................................................... 361

    24.1 Ethanol.................................................................................... 361

    24.1.1 Incidence and Occurrence......................................... 361

    24.1.2 Chemical Characteristics.......................................... 361

    24.1.3 Toxicokinetics........................................................... 362

    24.1.4 Calculation of Blood Alcohol Concentrations

    (BAC)........................................................................ 363

    24.1.5 Mechanisms of Toxicity............................................364

    24.1.6 Clinical Manifestations of Acute Toxicity................366

    24.1.7 Management of Acute Intoxication...........................368

    24.1.8 Clinical Manifestations of Chronic Toxicity.............368

    24.1.9 Management of Chronic Intoxication....................... 370

    24.1.10 Fetal Alcohol Syndrome (FAS)................................. 371

    24.1.11 Tolerance, Dependence, and Withdrawal.................. 371

    24.1.12 Methods of Detection................................................ 372

    24.2 Methanol................................................................................. 373

    24.2.1 Incidence and Occurrence......................................... 373

    24.2.2 Toxicokinetics........................................................... 373

    24.2.3 Mechanism of Toxicity.............................................. 373

    24.2.4 Clinical Manifestations of Acute Intoxication.......... 374

    24.2.5 Management of Acute Intoxication........................... 374

    24.3 Isopropanol............................................................................. 374

    24.3.1 Toxicokinetics........................................................... 375

    24.3.2 Mechanisms of Toxicity............................................ 375

    24.3.3 Clinical Manifestations of Acute Toxicity................ 375

    24.3.4 Management of Acute Intoxication........................... 375

    24.4 Formaldehyde......................................................................... 375

    24.4.1 Incidence and Occurrence......................................... 376

    24.4.2 Toxicokinetics........................................................... 376

    24.4.3 Mechanisms of Toxicity............................................ 377

    24.4.4 Clinical Manifestations of Acute Intoxication.......... 377

    24.4.5 Management of Acute Intoxication........................... 377

    References......................................................................................... 377

    Suggested Readings........................................................................... 377

    Review Articles................................................................................. 378

    Chapter 25 Gases................................................................................................. 381

    25.1 Introduction............................................................................ 381

    25.2 Pulmonary Irritants................................................................ 381

    25.3 Simple Asphyxiants................................................................ 382

    25.3.1 Introduction............................................................... 382

    25.3.2 Gaseous Agents......................................................... 382

    25.4 Toxic Products of Combustion (TCP).................................... 387

    25.4.1 Introduction............................................................... 387

    25.4.2 Clinical Toxicity........................................................ 387

    25.5 Lacrimating Agents (Tear Gas).............................................. 389

    25.5.1 Introduction............................................................... 389

    25.5.2 Chemical Agents....................................................... 389

    25.6 Chemical Asphyxiants............................................................ 389

    25.7 Carbon Monoxide (CO).......................................................... 389

    25.7.1 Incidence................................................................... 389

    25.7.2 Chemical Characteristics and Sources of Exposure.....391

    25.7.3 Toxicokinetics........................................................... 391

    25.7.4 Mechanism of Toxicity.............................................. 391

    25.7.5 Signs and Symptoms of Acute Toxicity.................... 392

    25.7.6 Treatment of Acute Poisoning................................... 393

    25.8 Cyanide................................................................................... 394

    25.8.1 Chemical Characteristics, Occurrence, and Uses..... 394

    25.8.2 Mechanism of Toxicity.............................................. 394

    25.8.3 Toxicokinetics........................................................... 394

    25.8.4 Signs and Symptoms of Acute Toxicity.................... 395

    25.8.5 Treatment of Acute Poisoning................................... 395

    25.9 Methods Of Detection............................................................397

    References.........................................................................................397

    Suggested Readings...........................................................................397

    Review Articles................................................................................. 398

    Chapter 26 Metals................................................................................................ 401

    Anirudh J. Chintalapati and Frank A. Barile

    26.1 Introduction............................................................................ 401

    26.1.1 Background............................................................... 401

    26.1.2 Exposure and Applications....................................... 401

    26.1.3 Physiological Role of Metals.....................................402

    26.2 Chelation Therapy..................................................................402

    26.2.1 Description................................................................402

    26.2.2 Dimercaprol...............................................................404

    26.2.3 Ethylenediaminetetraacetic Acid (EDTA)................404

    26.2.4 Penicillamine.............................................................405

    26.2.5 Deferoxamine............................................................406

    26.2.6 Succimer....................................................................406

    26.2.7 Unithiol......................................................................407

    26.3 Antimony................................................................................407

    26.3.1 Physical and Chemical Properties.............................407

    26.3.2 Occurrence and Uses.................................................407

    26.3.3 Mechanism of Toxicity..............................................408

    26.3.4 Toxicokinetics...........................................................408

    26.3.5 Signs and Symptoms of Acute Poisoning.................408

    26.3.6 Treatment of Acute Poisoning...................................408

    26.4 Arsenic (As)............................................................................409

    26.4.1 Physical and Chemical Properties.............................409

    26.4.2 Occurrence and Uses.................................................409

    26.4.3 Mechanisms of Toxicity............................................409

    26.4.4 Toxicokinetics...........................................................409

    26.4.5 Signs and Symptoms of Acute Toxicity.................... 410

    26.4.6 Signs and Symptoms of Chronic Toxicity................. 410

    26.4.7 Treatment of Acute Poisoning................................... 410

    26.4.8 Treatment of Chronic Poisoning............................... 411

    26.4.9 Carcinogenesis.......................................................... 411

    26.5 Asbestos.................................................................................. 411

    26.5.1 Physical and Chemical Properties............................. 411

    26.5.2 Occurrence and Uses................................................. 411

    26.5.3 Mechanism of Toxicity.............................................. 412

    26.5.4 Toxicokinetics........................................................... 412

    26.5.5 Signs and Symptoms of Acute Toxicity.................... 412

    26.5.6 Signs and Symptoms of Chronic Toxicity................. 412

    26.5.7 Treatment of Acute Poisoning................................... 413

    26.5.8 Treatment of Chronic Poisoning............................... 413

    26.6 Cadmium................................................................................ 413

    26.6.1 Physical and Chemical Properties............................. 413

    26.6.2 Occurrence and Uses................................................. 413

    26.6.3 Mechanism of Toxicity.............................................. 414

    26.6.4 Toxicokinetics........................................................... 414

    26.6.5 Signs and Symptoms of Acute Toxicity.................... 414

    26.6.6 Signs and Symptoms of Chronic Toxicity................. 415

    26.6.7 Treatment of Acute Poisoning................................... 415

    26.6.8 Treatment of Chronic Poisoning............................... 415

    26.7 Cobalt..................................................................................... 415

    26.7.1 Physical and Chemical Properties............................. 415

    26.7.2 Occurrence and Uses................................................. 415

    26.7.3 Mechanism of Toxicity.............................................. 416

    26.7.4 Toxicokinetics........................................................... 416

    26.7.5 Signs and Symptoms of Acute Toxicity.................... 416

    26.7.6 Signs and Symptoms of Chronic Toxicity................. 416

    26.7.7 Treatment of Acute Poisoning................................... 417

    26.7.8 Treatment of Chronic Poisoning............................... 417

    26.8 Copper.................................................................................... 417

    26.8.1 Physical and Chemical Properties............................. 417

    26.8.2 Occurrence and Uses................................................. 417

    26.8.3 Mechanism of Toxicity.............................................. 418

    26.8.4 Toxicokinetics........................................................... 418

    26.8.5 Signs and Symptoms of Acute Toxicity.................... 419

    26.8.6 Signs and Symptoms of Chronic Toxicity................. 419

    26.8.7 Treatment of Acute Poisoning................................... 419

    26.8.8 Treatment of Chronic Poisoning............................... 419

    26.9 Iron (Fe2+, Fe3+)....................................................................... 420

    26.9.1 Physical and Chemical Properties............................. 420

    26.9.2 Occurrence and Uses................................................. 420

    26.9.3 Mechanism of Toxicity.............................................. 420

    26.9.4 Toxicokinetics........................................................... 421

    26.9.5 Signs and Symptoms of Acute Toxicity.................... 422

    26.9.6 Signs and Symptoms of Chronic Toxicity................. 422

    26.9.7 Treatment of Acute Poisoning................................... 422

    26.9.8 Treatment of Chronic Poisoning............................... 423

    26.9.9 Clinical Monitoring................................................... 423

    26.10 Lead........................................................................................ 423

    26.10.1 Physical and Chemical Properties............................. 423

    26.10.2 Occurrence and Uses................................................. 423

    26.10.3 Mechanism of Toxicity..............................................424

    26.10.4 Toxicokinetics...........................................................424

    26.10.5 Signs and Symptoms of Acute Toxicity.................... 426

    26.10.6 Signs and Symptoms of Chronic Toxicity................. 426

    26.10.7 Treatment of Acute Poisoning................................... 426

    26.10.8 Treatment of Chronic Poisoning............................... 427

    26.10.9 Clinical Monitoring................................................... 427

    26.11 Mercury (Hg).......................................................................... 427

    26.11.1 Physical and Chemical Properties............................. 427

    26.11.2 Occurrence and Uses................................................. 427

    26.11.3 Occupational and Environmental Exposure............. 429

    26.11.4 Mechanism of Toxicity.............................................. 429

    26.11.5 Toxicokinetics........................................................... 429

    26.11.6 Signs and Symptoms of Acute Toxicity

    (Inhalation and Ingestion)......................................... 430

    26.11.7 Signs and Symptoms of Subacute or Chronic

    Poisoning................................................................... 431

    26.11.8 Clinical Management of Hg Poisoning..................... 431

    26.12 Selenium (Se).......................................................................... 431

    26.12.1 Physical and Chemical Properties............................. 431

    26.12.2 Occurrence and Uses................................................. 431

    26.12.3 Physiological Role..................................................... 432

    26.12.4 Mechanism of Toxicity.............................................. 432

    26.12.5 Toxicokinetics........................................................... 432

    26.12.6 Signs and Symptoms of Acute Toxicity.................... 433

    26.12.7 Signs and Symptoms of Chronic Toxicity................. 433

    26.12.8 Clinical Management of Poisoning........................... 433

    26.13 Silver (Ag).............................................................................. 433

    26.13.1 Physical and Chemical Properties............................. 433

    26.13.2 Occurrence and Uses................................................. 433

    26.13.3 Toxicokinetics........................................................... 434

    26.13.4 Argyria...................................................................... 434

    26.14 Zinc (Zn)................................................................................. 434

    26.14.1 Physical and Chemical Properties............................. 434

    26.14.2 Occurrence and Uses................................................. 434

    26.14.3 Physiological Role..................................................... 435

    26.14.4 Mechanism of Toxicity.............................................. 435

    26.14.5 Toxicokinetics........................................................... 435

    26.14.6 Signs and Symptoms of Acute Toxicity.................... 435

    26.14.7 Signs and Symptoms of Chronic Toxicity................. 436

    26.14.8 Clinical Management of Poisoning........................... 436

    References......................................................................................... 436

    Suggested Readings........................................................................... 436

    Review Articles................................................................................. 437

    Chapter 27 Aliphatic and Aromatic Hydrocarbons............................................. 439

    27.1 Introduction............................................................................ 439

    27.1.1 Aliphatic and Alicyclic Hydrocarbons...................... 439

    27.1.2 Aromatic HCs............................................................ 439

    27.1.3 General Signs and Symptoms of Acute Toxicity...... 439

    27.2 Petroleum Distillates.............................................................. 441

    27.2.1 Occurrence and Uses................................................. 441

    27.2.2 Mechanism of Toxicity.............................................. 441

    27.3 Aromatic Hydrocarbons......................................................... 441

    27.3.1 Occurrence and Uses................................................. 441

    27.3.2 Mechanism of Toxicity.............................................. 441

    27.4 Halogenated Hydrocarbons....................................................443

    27.4.1 Occurrence and Uses.................................................443

    27.4.2 Mechanism of Toxicity..............................................444

    27.5 Methods Of Detection............................................................448

    References.........................................................................................448

    Suggested Readings...........................................................................448

    Review Articles.................................................................................449

    Chapter 28 Insecticides........................................................................................ 451

    28.1 Introduction............................................................................ 451

    28.2 Organophosphorus Compounds (Organophosphates, OP)..... 451

    28.2.1 Chemical Characteristics.......................................... 451

    28.2.2 Occurrence and Uses................................................. 452

    28.2.3 Mechanism of Toxicity.............................................. 453

    28.2.4 Signs and Symptoms of Acute Toxicity.................... 454

    28.2.5 Clinical Management of Acute Poisoning................ 455

    28.3 Carbamates............................................................................. 456

    28.3.1 Chemical Characteristics, Occurrence, and Uses..... 456

    28.3.2 Mechanism of Toxicity.............................................. 456

    28.3.3 Signs and Symptoms of Acute Toxicity.................... 456

    28.3.4 Clinical Management of Acute Poisoning................ 456

    28.4 Organochlorine (OC) Insecticides.......................................... 456

    28.4.1 Chemical Characteristics.......................................... 456

    28.4.2 Occurrence and Uses................................................. 458

    28.4.3 Mechanism of Toxicity.............................................. 458

    28.4.4 Signs and Symptoms of Acute Toxicity.................... 458

    28.4.5 Clinical Management of Acute Poisoning................460

    28.5 Miscellaneous Insecticides..................................................... 461

    28.5.1 Pyrethroid Esters....................................................... 461

    28.5.2 Nicotine..................................................................... 461

    28.5.3 Boric Acid (H3BO3)...................................................462

    28.5.4 Rotenone....................................................................462

    28.5.5 Diethyltoluamide (DEET).........................................463

    28.6 Methods of Detection.............................................................463

    References.........................................................................................464

    Suggested Readings...........................................................................464

    Review Articles.................................................................................465

    Chapter 29 Herbicides..........................................................................................467

    29.1 Introduction............................................................................ 467

    29.2 Chlorphenoxy Compounds..................................................... 467

    29.2.1 Chemical Characteristics.......................................... 467

    29.2.2 Occurrence and Uses.................................................469

    29.2.3 Signs and Symptoms and Mechanism of Acute

    Toxicity......................................................................469

    29.2.4 Clinical Management of Acute Poisoning................ 470

    29.3 Bipyridyl Herbicides............................................................... 470

    29.3.1 Chemical Characteristics, Occurrence, and Uses..... 470

    29.3.2 Toxicokinetics........................................................... 470

    29.3.3 Mechanism of Toxicity.............................................. 471

    29.3.4 Signs and Symptoms of Acute Toxicity.................... 472

    29.3.5 Clinical Management of Acute Poisoning................ 472

    29.4 Miscellaneous Herbicides....................................................... 473

    29.5 Methods of Detection............................................................. 473

    References......................................................................................... 475

    Suggested Readings........................................................................... 475

    Review Articles................................................................................. 476

    Chapter 30 Rodenticides...................................................................................... 477

    30.1 Introduction............................................................................ 477

    30.2 Anticoagulants........................................................................ 477

    30.2.1 Chemical Characteristics.......................................... 477

    30.2.2 Commercial and Clinical Use................................... 479

    30.2.3 Toxicokinetics...........................................................480

    30.2.4 Mechanism of Toxicity..............................................480

    30.2.5 Signs and Symptoms of Acute Toxicity....................480

    30.2.6 Clinical Management of Acute Poisoning................ 481

    30.3 Phosphorus (P)........................................................................482

    30.3.1 Chemical Characteristics, Occurrence, and Uses.....482

    30.3.2 Toxicokinetics...........................................................482

    30.3.3 Mechanism and Signs and Symptoms of Acute

    Toxicity......................................................................482

    30.3.4 Clinical Management of Acute Poisoning................483

    30.4 Red Squill...............................................................................483

    30.4.1 Chemical Characteristics, Occurrence and Uses......483

    30.4.2 Mechanism and Signs and Symptoms of Acute

    Toxicity......................................................................484

    30.4.3 Clinical Management of Acute Poisoning................484

    30.5 Metals: Thallium, Barium......................................................484

    30.5.1 Thallium (Tl).............................................................484

    30.5.2 Barium (Ba)...............................................................485

    30.6 Methods Of Detection............................................................485

    References.........................................................................................486

    Suggested readings............................................................................486

    Review Articles.................................................................................487

    Chapter 31 Chemical Carcinogenesis and Mutagenesis......................................489

    31.1 Introduction............................................................................489

    31.2 Mechanisms Of Chemical Carcinogenesis............................. 491

    31.2.1 Metabolism................................................................ 491

    31.2.2 Chemistry.................................................................. 491

    31.2.3 Free Radicals and Reactive Oxygen Species............ 491

    31.2.4 Mutagenesis...............................................................492

    31.2.5 DNA Repair...............................................................494

    31.2.6 Epigenetic Carcinogenesis........................................494

    31.3 Multistage Carcinogenesis......................................................494

    31.3.1 Tumor Initiation......................................................... 495

    31.3.2 Tumor Promotion...................................................... 495

    31.3.3 Tumor Progression....................................................497

    31.4 Carcinogenic Characteristics..................................................497

    31.4.1 Classification............................................................. 498

    31.4.2 Identification.............................................................. 498

    31.4.3 Carcinogenic Potential..............................................499

    31.4.4 Carcinogenic Risk Assessment.................................499

    31.4.5 Carcinogenic and Genotoxic Agents......................... 501

    31.5 Cancer Chemoprevention....................................................... 501

    31.5.1 General Considerations............................................. 501

    31.5.2 Cancer Chemopreventive Agents..............................502

    31.5.3 Mechanisms Underlying Cancer Chemoprevention...... 502

    References.........................................................................................502

    Suggested Readings...........................................................................502

    Review Articles.................................................................................504

    Chapter 32 Reproductive and Developmental Toxicity.......................................505

    Anirudh J. Chintalapati and Frank A. Barile

    32.1 Introduction............................................................................505

    32.2 History and Development.......................................................506

    32.3 Summary of Maternal–Fetal Physiology...............................506

    32.3.1 Definitions.................................................................506

    32.3.2 First Trimester...........................................................507

    32.3.3 Second and Third Trimesters....................................508

    32.4 Mechanisms of Developmental Toxicity................................508

    32.4.1 Susceptibility.............................................................508

    32.4.2 Dose–Response and Threshold.................................508

    32.5 Drugs Affecting Embryonic and Fetal Development.............509

    32.5.1 Classification.............................................................509

    32.5.2 Drug Classes.............................................................509

    32.6 Endocrine Disrupting Chemicals (Edcs)................................ 513

    32.6.1 Mechanism of Toxicity.............................................. 514

    32.6.2 Effects of EDCs on Female Reproductive System.... 515

    32.6.3 Effects of EDCs on Male Reproductive System....... 518

    32.6.4 Management of EDC Exposure................................. 519

    References......................................................................................... 519

    Suggested Readings........................................................................... 519

    Review Articles................................................................................. 520

    Chapter 33 Radiation Toxicity............................................................................. 523

    33.1 Principles Of Radioactivity.................................................... 523

    33.2 Ionizing Radiation.................................................................. 524

    33.2.1 Biological Effects of Ionizing Radiation................... 524

    33.2.2 Sources...................................................................... 524

    33.2.3 Clinical Manifestations............................................. 525

    33.2.4 Nuclear Terrorism and Health Effects...................... 527

    33.3 Ultraviolet (UV) Radiation..................................................... 527

    33.3.1 Biological Effects of Ultraviolet Radiation............... 527

    33.3.2 Sources...................................................................... 528

    33.3.3 Clinical Manifestations............................................. 528

    33.4 Nonionizing Radiation........................................................... 531

    33.4.1 Sources...................................................................... 531

    33.4.2 Biological Effects and Clinical Manifestations........ 531

    References......................................................................................... 532

    Suggested Readings........................................................................... 532

    Review Articles................................................................................. 532

    Chapter 34 Chemical and Biological Threats to Public Safety........................... 535

    34.1 Introduction............................................................................ 535

    34.2 Biological Pathogenic Toxins as Threats to Public Safety..... 536

    34.2.1 Anthrax (Bacillus anthracis)..................................... 537

    34.2.2 Botulism.................................................................... 541

    34.2.3 Plague (Yersinia pestis)............................................. 541

    34.2.4 Brucellosis (Brucella suis)........................................ 542

    34.2.5 Salmonellosis (Salmonella species).......................... 543

    34.2.6 Typhoid Fever............................................................ 545

    34.2.7 Shigellosis (Shigella Species)....................................546

    34.2.8 Escherichia coli O157:H7.........................................546

    34.2.9 Cholera (Vibrio cholerae).......................................... 547

    34.2.10 Smallpox....................................................................548

    34.2.11 Tularemia (Francisella tularensis), Q Fever

    (Coxiella burnetti), and Viral Hemorrhagic

    Fevers (VHF)............................................................549

    34.3 Chemical Agents As Threats To Public Safety...................... 550

    34.3.1 Nerve Gases............................................................... 550

    34.3.2 Vesicants, Chemical Asphyxiants, and

    Pulmonary Irritants................................................... 551

    34.3.3 Ricin (Ricinus communis)......................................... 551

    References......................................................................................... 552

    Suggested Readings........................................................................... 552

    Review Articles................................................................................. 553

    Index....................................................................................................................... 555

    Biography

    Frank A. Barile

    "The stated audience is undergraduate and graduate students, which is appropriate. The book will be a good starting point for understanding basic information on a large number of chemical toxicities."

    -Udayan Apte, PhD, DABT (University of Kansas Medical Center)
    DOODY'S PUBLISHERS' CLUB