clinical toxicology textbook

His book, A Small Dose of Toxicology- The Health Effects of Common Chemicals was published in 2004 and the 2nd edition is available for free as an E-book (www.asmalldoseoftoxicology.org). Preface...................................................................................................................xxxi, Acknowledgments............................................................................................... xxxiii, Author...................................................................................................................xxxv, Contributors........................................................................................................xxxvii, 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, 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, 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. 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