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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…mehr
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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.
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.
Produktdetails
- Produktdetails
- Verlag: CRC Press / Taylor & Francis
- 3. Aufl.
- Seitenzahl: 624
- Erscheinungstermin: 14. Mai 2019
- Englisch
- Abmessung: 240mm x 161mm x 38mm
- Gewicht: 1038g
- ISBN-13: 9781498765305
- ISBN-10: 1498765300
- Artikelnr.: 55982706
- Herstellerkennzeichnung
- Books on Demand GmbH
- In de Tarpen 42
- 22848 Norderstedt
- info@bod.de
- 040 53433511
- Verlag: CRC Press / Taylor & Francis
- 3. Aufl.
- Seitenzahl: 624
- Erscheinungstermin: 14. Mai 2019
- Englisch
- Abmessung: 240mm x 161mm x 38mm
- Gewicht: 1038g
- ISBN-13: 9781498765305
- ISBN-10: 1498765300
- Artikelnr.: 55982706
- Herstellerkennzeichnung
- Books on Demand GmbH
- In de Tarpen 42
- 22848 Norderstedt
- info@bod.de
- 040 53433511
Frank A. Barile
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 beta-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...............................................
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 beta-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...............................................
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 beta-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...............................................
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 beta-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...............................................