Barile’s Clinical Toxicology

Frank A. Barile, PhD, is Professor in the Toxicology Division and past chairmanof the Department of Pharmaceutical Sciences, St. John’s University College ofPharmacy and Health Sciences, New York.Dr. Barile received his BS in Pharmacy, MS in Pharmacology, and PhD inToxicology at St. John’s University. After doing a postdoctoral fellowship inPulmonary Pediatrics at the Albert Einstein College of Medicine, Bronx, NY, hemoved to the Department of Pathology, Columbia University—St. Luke’s RooseveltHospital, NY, as a research associate. In these positions, he investigated the role ofpulmonary toxicants in collagen metabolism in cultured lung cells. In 1984, he wasappointed assistant professor in the Department of Health Sciences at City Universityof NY. Sixteen years later, he rejoined St. John’s University in the Department ofPharmaceutical Sciences in the College of Pharmacy.Dr. Barile holds memberships in several professional associations, including theU.S. Society of Toxicology, the American Association of University Professors, theAmerican Association for the Advancement of Science, the American Society ofHospital Pharmacists, New York City Pharmacists Society, New York Academy ofSciences, and New York State Council of Health System Pharmacists. He is pastpresident of the In Vitro and Alternative Methods Specialty Section of the U.S.Society of Toxicology and a former member of the Scientific Advisory Committeefor Alternative Toxicological Methods, the National Institute of EnvironmentalHealth Sciences, U.S. National Institutes of Health (NIH). He is former editor ofToxicology in Vitro and Journal of Pharmacological & Toxicological Methods, publishedby Elsevier Ltd.Dr. Barile is the recipient of Public Health Service research grants from theNational Institute of General Medical Sciences, the National Institutes of Health,and grants from private foundations dedicated to alternatives to animal testing.He has authored approximately 100 original research manuscripts, review articles,research abstracts, and conference proceedings in peer-reviewed toxicology and biomedicaljournals. He has also published several books and related chapters in thefield. He contributed original in vitro toxicology data to the international MulticenterEvaluation for In Vitro Cytotoxicity program. He lectures regularly to pharmacy andtoxicology undergraduate and graduate students in clinical and basic pharmaceuticaland toxicological sciences and was awarded “Professor of the Year” for the Collegeof Pharmacy by the St. John’s University Student Government Association (2003).Dr. Barile has served on several U.S. government advisory committees, including:Toxicology Assessment Peer Review Committee, U.S. Environmental ProtectionAgency; National Institutes of Health Review Panel, Study Section Reviewer (2013);Scientific Advisory Committee on Alternative Toxicological Methods (SACATM,2005–2009); National Toxicology Program (NTP) Interagency Center for theEvaluation of Alternative Toxicological Methods, Support Contract Reviewer (2014);U.S. Food and Drug Administration (U.S. FDA), National Center for ToxicologyResearch, Systems Biology Subcommittee (2016); National Institute for OccupationalSafety and Health (NIOSH) and Oak Ridge Associated Universities, SK ProfilesReview Group (2014); U.S. Food and Drug Administration advisory committee onalternative toxicological methods (2013); and has served as vice president of theDermal Toxicology Specialty Section for the Society of Toxicology (2013–2014).Dr. Barile received the Faculty Recognition Award, American Association ofUniversity Professors Faculty Association Award, St. John’s University, in 2003,2004–2005, 2013–2014, and 2015–2016 and received the prestigious Public HealthService Medallion from the director of the National Institute of EnvironmentalHealth Sciences, Dr. Linda Birnbaum, for contributions to the Scientific AdvisoryCommittee for Alternative Toxicological Methods (2009).Dr. Barile continues original research on the cytotoxic effects of therapeuticdrugs, environmental chemicals, and controlled substances on cultured mammalianembryonic stem cells and human induced pluripotent stem cells and has dedicatedhis professional life to the advancement of in vitro alternative methods to reduce,replace and refine animal toxicology testing.

"The stated audience is undergraduate and graduate students, which is appropriate. The book will be a good starting point for understanding basic information on a large number of chemical toxicities."-Udayan Apte, PhD, DABT (University of Kansas Medical Center)DOODY'S PUBLISHERS' CLUB

• ContentsPreface...................................................................................................................xxxiAcknowledgments............................................................................................... xxxiiiAuthor...................................................................................................................xxxvContributors........................................................................................................xxxviiSection I □Introduction to BasicToxicological PrinciplesChapter 1 Introduction...........................................................................................31.1 Introduction................................................................................31.2 Basic Definitions.........................................................................41.2.1 Toxicology.....................................................................41.2.2 Clinical Toxicology.......................................................41.3 Types of Toxicology...................................................................51.3.1 General Toxicology.......................................................51.3.2 Mechanistic Toxicology................................................51.3.3 Regulatory Toxicology..................................................51.3.4 Descriptive Toxicology..................................................61.4 Types of Toxicologist..................................................................71.4.1 Forensic Toxicologist.....................................................71.4.2 Clinical Toxicologist.....................................................81.4.3 Research Toxicologist....................................................81.4.4 Regulatory Toxicologist................................................8References.............................................................................................8Suggested Readings...............................................................................8Review Articles.....................................................................................9Chapter 2 Risk Assessment and Regulatory Toxicology..................................... 112.1 Risk Assessment....................................................................... 112.1.1 Introduction................................................................. 112.1.2 Hazard Identification/Risk Assessment (HIRA)......... 112.1.3 Dose–Response Evaluation......................................... 112.1.4 Exposure Assessment and Assessment Modeling....... 122.1.5 Risk Characterization.................................................. 142.2 Regulatory Toxicology............................................................. 162.2.1 Nuclear Regulatory Commission (NRC).................... 162.2.2 Environmental Protection Agency (EPA)................... 172.2.3 The Food and Drug Administration (FDA)................ 182.2.4 Drug Enforcement Administration (DEA).................. 192.2.5 Consumer Products Safety Commission (CPSC)........202.2.6 Occupational Safety and Health Administrations(OSHA)........................................................................22References...........................................................................................23Suggested Readings.............................................................................23Review Articles...................................................................................23Chapter 3 Therapeutic Monitoring of Adverse Drug Reactions (ADRs).............273.1 Adverse Drug Reactions (ADRs) in Clinical Practice.............273.1.1 The Joint Commission (TJC)......................................273.1.2 Growing Medication Safety Concerns........................283.1.3 National Patient Safety Goals (NPSG).......................283.2 Factors that Contribute to Adverse Drug Reactions (ADRs)...293.2.1 Inadequate Monitoring of Prescribed Drugs..............293.2.2 Improper Adherence to Prescribed Directions........... 323.2.3 Over-Prescribing and Overuse of Medications........... 323.2.4 Drug–Drug and Drug–Disease Interactions............... 323.2.5 Allergic Reactions....................................................... 323.2.6 Medication Warnings.................................................. 333.2.7 Medication Errors....................................................... 333.2.8 Adverse Drug Reactions (ADRS)............................... 333.3 Treatment of ADRs and Poisoning in Patients......................... 353.3.1 History......................................................................... 353.3.2 Poison Control Centers (PCCs)................................... 353.3.3 Clinical Management of ADRs...................................363.3.4 Clinical Management of Toxicologic Emergencies.....363.4 Drug Identification and Methods of Detection......................... 41References...........................................................................................44Suggested Readings.............................................................................44Review Articles................................................................................... 45Chapter 4 Classification of Toxins in Humans.................................................... 474.1 Introduction.............................................................................. 474.2 Target Organ Classification...................................................... 474.2.1 Agents Affecting the Hematopoietic System.............. 474.2.2 Immunotoxic Agents...................................................484.2.3 Hepatotoxic Agents.....................................................484.2.4 Nephrotoxic Agents.....................................................494.2.5 Pulmonary Toxic Agents............................................. 524.2.6 Agents Affecting the Nervous System........................544.2.7 Agents Affecting the Cardiovascular (CV) System.... 554.2.8 Dermatotoxic Agents................................................... 554.2.9 Agents Affecting the Reproductive System................ 594.2.10 Agents Affecting the Endocrine System..................... 594.3 Classification According to use in the Public Domain.............604.3.1 Insecticides, Herbicides, Fungicides, andRodenticides (Pesticides).............................................604.3.2 Food and Color Additives........................................... 614.3.3 Therapeutic Drugs.......................................................634.3.4 By-Products of Combustion........................................634.4 Classification According to Source..........................................634.4.1 Botanical.....................................................................634.4.2 Environmental.............................................................634.5 Classification According to Effects..........................................644.5.1 Pathologic....................................................................644.5.2 Teratogenic, Mutagenic, and Carcinogenic.................644.6 Classification According to Physical State...............................644.6.1 Solids...........................................................................644.6.2 Liquids.........................................................................644.6.3 Gases...........................................................................654.7 Classification According to Biochemical Properties................654.7.1 Chemical Structure.....................................................654.7.2 Mechanism of Action or Toxicity................................65References...........................................................................................65Suggested Readings.............................................................................65Review Articles...................................................................................65Chapter 5 Exposure..............................................................................................695.1 Introduction..............................................................................695.2 Route of Exposure....................................................................695.2.1 Oral..............................................................................695.2.2 Intranasal..................................................................... 705.2.3 Inhalation.................................................................... 715.2.4 Parenteral.................................................................... 715.3 Duration and Frequency........................................................... 725.3.1 Acute Exposure........................................................... 725.3.2 Chronic Exposure........................................................ 735.3.3 Single- or Repeated-Dose Exposure........................... 735.4 Accumulation........................................................................... 735.4.1 According to Physiological Compartment.................. 745.4.2 According to Chemical Properties.............................. 745.4.3 According to Other Biological Factors........................ 74References........................................................................................... 76Suggested Readings............................................................................. 76Review Articles................................................................................... 76Chapter 6 Effects.................................................................................................. 796.1 General Classification............................................................... 796.1.1 Introduction to Principles of Immunology.................. 796.1.2 Chemical Allergies...................................................... 796.1.3 Idiosyncratic Reactions...............................................866.1.4 Immediate versus Delayed Effects..............................866.1.5 Reversible versus Irreversible Reactions.....................866.1.6 Local versus Systemic Effects.....................................866.1.7 Target Therapeutic Effects..........................................876.2 Chemical Interactions...............................................................876.2.1 Potentiation..................................................................876.2.2 Additive.......................................................................876.2.3 Synergistic...................................................................886.2.4 Antagonistic................................................................88References...........................................................................................88Suggested Readings.............................................................................88Review Aricles.....................................................................................89Chapter 7 Dose–Response................................................................................... 917.1 General Assumptions............................................................... 917.1.1 Types of Dose–Response Relationships...................... 917.1.2 Concentration–Effect and Presence at theReceptor Site...............................................................937.1.3 Criteria for Measurement............................................937.2 LD50 (Lethal Dose 50%)...........................................................937.2.1 Definition.....................................................................937.2.2 Experimental Protocol................................................937.2.3 Factors That Influence the LD50..................................947.3 ED50 (Effective Dose 50%), TD50 (Toxic Dose 50%), andTI (Therapeutic Index).............................................................957.3.1 Relationship to LD50....................................................957.3.2 Assumptions Using the TI...........................................957.4 IC50 (Inhibitory Concentration 50%)........................................967.4.1 Definition.....................................................................967.4.2 Experimental Determination.......................................977.4.3 For In Vitro Systems....................................................97References...........................................................................................97Suggested Readings.............................................................................97Review Articles...................................................................................98Chapter 8 Descriptive Animal Toxicity Tests......................................................998.1 Correlation with Human Exposure...........................................998.1.1 Human Risk Assessment.............................................998.1.2 Predictive Toxicology and Extrapolation toHuman Toxicity...........................................................998.2 Species Differentiation.............................................................998.2.1 Selection of a Suitable Animal Species......................998.2.2 Cost-Effectiveness..................................................... 1008.2.3 Institutional Animal Care and Use Committee(IACUC).................................................................... 1008.3 Descriptive Tests..................................................................... 1018.3.1 Required LD50 and Two Routes............................... 1018.3.2 Chronic and Subchronic Exposure............................ 1018.3.3 Types of Tests............................................................ 101References......................................................................................... 102Suggested Readings........................................................................... 102Review Aricles................................................................................... 103Chapter 9 In Vitro Alternatives to Animal Toxicity.......................................... 1059.1 In Vitro Methods.................................................................... 1059.1.1 Cell Culture Methods................................................ 1059.1.2 Organ System Cytotoxicity....................................... 1059.1.3 Applications to Clinical Toxicology.......................... 1069.1.4 Relationship to Animal Experiments........................ 1079.2 Correlation with Human Exposure......................................... 1079.2.1 Risk Assessment........................................................ 1079.2.2 Extrapolation to Human Toxicity.............................. 1079.2.3 Predictive Toxicology................................................ 108References......................................................................................... 108Suggested Readings........................................................................... 108Review Articles................................................................................. 108Chapter 10 Toxicokinetics................................................................................... 11110.1 Toxicokinetics......................................................................... 11110.1.1 Relationship to Pharmacokinetics............................. 11110.1.2 One-Compartment Model......................................... 11110.1.3 Two-Compartment Model......................................... 11210.1.4 Application to Clinical Toxicology........................... 11210.2 Absorption.............................................................................. 11210.2.1 Ionic and Nonionic Principles................................... 11210.2.2 Henderson–Hasselbalch Equation and Degree ofIonization................................................................... 11410.2.3 Route of Administration and Solubility.................... 11810.2.4 Absorption in Nasal and Respiratory Mucosa.......... 11910.2.5 Transport of Molecules............................................. 12010.3 Distribution............................................................................. 12110.3.1 Fluid Compartments.................................................. 12110.3.2 Ionic and Nonionic Principles................................... 12210.3.3 Plasma Protein Binding............................................. 12310.3.4 Lipids......................................................................... 12510.3.5 Liver and Kidney....................................................... 12510.3.6 Blood–Brain Barrier.................................................. 12510.3.7 Placenta..................................................................... 12510.3.8 Other Factors Affecting Distribution........................ 12610.4 Biotransformation (Metabolism)............................................ 12610.4.1 Principles of Detoxification....................................... 12610.4.2 Phase I Reactions...................................................... 12710.4.3 Phase II Reactions..................................................... 12810.5 Elimination............................................................................. 13110.5.1 Urinary...................................................................... 13110.5.1.1 First-Order Elimination............................. 13210.5.1.2 Zero-Order Elimination............................. 13410.5.2 Fecal.......................................................................... 13510.5.3 Pulmonary................................................................. 13510.5.4 Mammary Glands..................................................... 13610.5.5 Secretions.................................................................. 136References......................................................................................... 136Suggested Readings........................................................................... 136Review Articles................................................................................. 137Chapter 11 Chemical– and Drug–Receptor Interactions..................................... 139Zacharoula Konsoula11.1 Types of Chemical and Drug Receptors................................. 13911.1.1 Ion Channels.............................................................. 13911.1.2 G-Protein-Coupled Receptors................................... 14211.1.3 Kinases and Enzyme-Coupled Receptors................. 14311.1.4 Intracellular Receptors.............................................. 14511.2 Signal Transduction................................................................ 148References......................................................................................... 150Suggested Readings........................................................................... 150Review Articles................................................................................. 150Chapter 12 Toxicogenomics................................................................................. 151Anirudh J. Chintalapati, Zacharoula Konsoula, and Frank A. Barile12.1 Introduction............................................................................ 15112.2 Human Genomic Variation..................................................... 15112.2.1 Genomic Variation in Target Molecules................... 15212.2.2 Genomic Variation in Drug Metabolism................... 15412.3 Gene Structure and Function.................................................. 15412.3.1 DNA Alterations and Genotoxic Effects................... 15512.3.2 DNA Repair Mechanisms......................................... 15712.3.3 Experimental Monitoring for Genetic Toxicity......... 15912.3.4 Clinical Monitoring for Genetic Toxicity.................. 15912.4 Epigenetic Toxicology............................................................ 16012.4.1 Mechanisms of Epigenetic Toxicity.......................... 16112.4.1.1 DNA Methylation...................................... 16112.4.1.2 Posttranslational Modifications ofHistone Proteins......................................... 16212.4.1.3 Noncoding RNA........................................ 16212.4.2 Epigenetics and Disease............................................ 163Referenes........................................................................................... 163Suggested Readings........................................................................... 163Review Articles................................................................................. 164Section II Toxicity of Therapeutic AgentsChapter 13 Sedative/Hypnotics............................................................................ 167Frank A. Barile and Anirudh J. Chintalapati13.1 Barbiturates............................................................................ 16713.1.1 History and Classification......................................... 16713.1.2 Epidemiology............................................................ 16713.1.3 Medicinal Chemistry................................................. 16713.1.4 Pharmacology and Clinical Use................................ 16813.1.5 Toxicokinetics and Metabolism................................ 16813.1.6 Mechanism of Toxicity.............................................. 16913.1.7 Signs and Symptoms of Acute Toxicity.................... 16913.1.8 Emergency Guidelines.............................................. 17113.1.9 Clinical Management of Acute Overdose................. 17113.1.10 Tolerance and Withdrawal......................................... 17213.1.11 Methods of Detection................................................ 17213.2 Benzodiazepines (BZ)............................................................ 17213.2.1 Epidemiology............................................................ 17213.2.2 Medicinal Chemistry................................................. 17313.2.3 Pharmacology and Mechanism of Toxicity............... 17313.2.4 Toxicokinetics........................................................... 17313.2.5 Signs and Symptoms of Acute Toxicity.................... 17413.2.6 Emergency Guidelines.............................................. 17413.2.7 Clinical Management of Acute Overdose................. 17413.2.8 Tolerance and Withdrawal......................................... 17413.2.9 Methods of Detection................................................ 17413.3 Miscellaneous Sedative/Hypnotics........................................ 17613.3.1 Chloral Hydrate......................................................... 17613.3.2 Meprobamate (Miltown®, Equanil®)......................... 17613.3.3 Zolpidem tartrate (Ambien®)..................................... 17713.3.4 Buspirone (Buspar®).................................................. 17713.3.5 Flunitrazepam (Rohypnol®)...................................... 17713.3.6 Gamma-hydroxybutyrate (GHB)............................... 17813.3.7 Ethchlorvynol (Placidyl®), Methaqualone(Quaalude®), Glutethimide (Doriden®),Methyprylon (Noludar®)............................................ 17813.4 Methods of Detection and Laboratory Tests for S/H............. 179References......................................................................................... 179Suggested Readings........................................................................... 180Review Articles................................................................................. 181Chapter 14 Opioids and Related Agents.............................................................. 18314.1 Opioids.................................................................................... 18314.1.1 U.S. Public Health and Historical Use...................... 18314.1.2 Neonatal Abstinence Syndrome (NAS).................... 18514.1.3 Classification............................................................. 18614.1.4 Medicinal Chemistry................................................. 18914.1.5 Mechanism of Toxicity.............................................. 18914.1.6 Brain Chemistry........................................................ 19114.1.7 Toxicokinetics........................................................... 19114.1.8 Mechanism of Toxicity.............................................. 19114.1.9 Signs and Symptoms of Clinical Toxicity................. 19214.1.10 Clinical Management of Acute Overdose................. 19214.1.11 Tolerance and Withdrawal......................................... 19314.1.12 Clinical Management of Addiction........................... 19514.2 Specific Opioid Derivatives.................................................... 19514.2.1 Codeine..................................................................... 19514.2.2 Diphenoxylate............................................................ 19614.2.3 Fentanyl..................................................................... 19614.2.4 Meperidine................................................................ 19614.2.5 Pentazocine............................................................... 19714.2.6 Propoxyphene............................................................ 19714.2.7 Hydrocodone/Oxycodone.......................................... 19714.2.8 Tramadol................................................................... 19814.2.9 Clonidine................................................................... 19914.3 Methods of Detection............................................................. 199References.........................................................................................200Suggested Readings...........................................................................200Review Articles................................................................................. 201Chapter 15 Sympathomimetics............................................................................20315.1 Amphetamines and Amphetamine-like Agents.....................20315.1.1 Incidence...................................................................20315.1.2 Classification.............................................................20315.1.3 Medicinal Chemistry.................................................20415.1.4 Pharmacology and Clinical Use................................20415.1.5 Toxicokinetics...........................................................20615.1.6 Effects and Mechanism of Toxicity...........................20615.1.7 Chronic Methamphetamine Use...............................20815.1.8 Tolerance and Withdrawal.........................................20815.1.9 Clinical Management of Amphetamine Addiction...20815.1.10 Methods of Detection................................................20915.2 Cocaine...................................................................................20915.2.1 Incidence and Occurrence.........................................20915.2.2 Medicinal Chemistry................................................. 21015.2.3 Pharmacology and Clinical Use................................ 21015.2.4 Toxicokinetics........................................................... 21115.2.5 Signs and Symptoms of Acute Toxicity.................... 21215.2.6 Clinical Management of Acute Overdose................. 21215.2.7 Tolerance and Withdrawal......................................... 21315.2.8 Clinical Management of Cocaine Addiction............. 21315.2.9 Methods of Detection................................................ 21315.3 Xanthine Derivatives.............................................................. 21315.3.1 Source and Medicinal Chemistry.............................. 21315.3.2 Occurrence................................................................ 21415.3.3 Pharmacology and Clinical Use................................ 21415.3.4 Toxicokinetics........................................................... 21615.3.5 Signs and Symptoms and Clinical Managementof Caffeine Toxicity................................................... 21615.3.6 Signs and Symptoms and Clinical Managementof Theophylline Toxicity........................................... 21715.3.7 Tolerance and Withdrawal......................................... 21715.4 Other Specific Sympathomimetic Agents.............................. 21715.4.1 Strychnine................................................................. 21715.4.2 Nicotine..................................................................... 21815.4.3 Ephedrine.................................................................. 21915.4.4 Phenylpropranolamine..............................................22015.4.5 Pseudoephedrine.......................................................220References.........................................................................................220Suggested Readings...........................................................................220Review Articles................................................................................. 221Chapter 16 Hallucinogenic Agents......................................................................22516.1 History and Description.........................................................22516.2 Ergot Alkaloids.......................................................................22516.2.1 Incidence and Occurrence.........................................22516.2.2 Medicinal Chemistry.................................................22616.2.3 Pharmacology and Clinical Use................................22616.2.4 Signs and Symptoms of Acute Toxicity....................22716.2.5 Clinical Management of Acute Overdose.................22716.3 Lysergic Acid Diethylamide (LSD)........................................22816.3.1 Incidence and Occurrence.........................................22816.3.2 Mechanism of Toxicity..............................................22816.3.3 Hallucinogenic Effects..............................................22816.3.4 Toxicokinetics...........................................................22916.3.5 Signs and Symptoms of Acute Toxicity....................22916.3.6 Clinical Management of Acute Overdose.................22916.3.7 Tolerance and Withdrawal.........................................23016.3.8 Methods of Detection................................................23016.4 Tryptamine Derivatives..........................................................23016.4.1 Incidence and Occurrence.........................................23016.4.2 Mechanism of Toxicity..............................................23016.4.3 Signs and Symptoms of Acute Toxicity.................... 23116.4.4 Clinical Management of Acute Overdose................. 23116.4.5 Tolerance and Withdrawal......................................... 23116.4.6 Methods of Detection................................................ 23116.5 Phenethylamine Derivatives................................................... 23216.5.1 Incidence and Occurrence......................................... 23216.5.2 Medicinal Chemistry................................................. 23216.5.3 Mescaline.................................................................. 23216.5.4 DOM (2,5-dimethoxy-4-methylamphetamine,STP) and MDA (3,4-methylenedioxyamphetamine)...............................23416.5.5 MDMA (3,4-methylenedioxymethamphetamine,ecstasy)......................................................................23416.5.6 Methods of Detection................................................ 23516.6 Phencyclidine (1-Phenylcyclohexyl Piperidine; PCP)............ 23516.6.1 Incidence and Occurrence......................................... 23516.6.2 Toxicokinetics........................................................... 23516.6.3 Signs and Symptoms of Acute Toxicity....................23616.6.4 Clinical Management of Acute Overdose.................23616.6.5 Tolerance and Withdrawal......................................... 23716.6.6 Methods of Detection................................................ 23716.7 Marijuana............................................................................... 23716.7.1 Incidence and Occurrence......................................... 23716.7.2 Medicinal Chemistry.................................................24016.7.3 Receptor Pharmacology and Toxicology..................24016.7.4 Clinical Use and Effects............................................ 24116.7.5 Toxicokinetics...........................................................24216.7.6 Acute Toxicity and Clinical Management.................24216.7.7 Tolerance, Withdrawal, and Chronic Effects............24216.7.8 Clinical Management of Chronic Addiction............. 24316.7.9 Methods of Detection................................................ 24316.8 Miscellaneous Hallucinogenic Agents................................... 24316.8.1 Ketamine (Special K, Vitamin K)............................. 24316.8.2 Gamma-hydroxybutyrate (GHB; Xyrem®)................24516.8.3 NBOMe.....................................................................246References.........................................................................................246Suggested Readings...........................................................................246Review Articles................................................................................. 247Chapter 17 Anticholinergic and Neuroleptic Drugs............................................ 25117.1 Introduction to Drugs Possessing Anticholinergic Effects........25117.2 Antihistamine, Gastrointestinal, and Antiparkinson Drugs.......25117.2.1 Incidence................................................................... 25117.2.2 Medicinal Chemistry, Pharmacology, andClinical Use............................................................... 25317.2.3 Signs and Symptoms of Acute Toxicity.................... 25317.2.4 Clinical Management of Acute Overdose.................25417.2.5 Methods of Detection................................................25417.3 Tricyclic Antidepressants (TCA)............................................ 25517.3.1 Incidence................................................................... 25517.3.2 Medicinal Chemistry................................................. 25517.3.3 Pharmacology and Clinical Use................................ 25517.3.4 Toxicokinetics........................................................... 25517.3.5 Mechanism of Toxicity..............................................25617.3.6 Signs and Symptoms of Acute Toxicity....................25617.3.7 Clinical Management of Acute Overdose.................25617.3.8 Tolerance and Withdrawal......................................... 25917.3.9 Methods of Detection................................................ 25917.4 Phenothiazine, Phenylbutylpiperidine, and ThioxanthineAntipsychotics........................................................................ 25917.4.1 Classification and Indications................................... 25917.4.2 Pharmacology and Clinical Use................................26017.4.3 Toxicokinetics...........................................................26017.4.4 Mechanism and Signs and Symptoms of AcuteToxicity......................................................................26017.4.5 Clinical Management of Acute Overdose................. 26217.4.6 Tolerance and Withdrawal......................................... 26217.4.7 Methods of Detection................................................ 26217.5 Selective Serotonin Reuptake Inhibitors (SSRIS).................. 26217.5.1 Classification and Clinical Use................................. 26217.5.2 Pharmacology and Receptor Activity.......................26317.5.3 Toxicokinetics...........................................................26417.5.4 Side Effects and Adverse Reactions..........................26517.5.5 Signs and Symptoms of Acute Toxicity....................26617.5.6 Clinical Management of Acute Overdose (O.D.)......26617.5.7 Tolerance and Withdrawal......................................... 26717.5.8 Methods of Detection................................................ 267References......................................................................................... 267Suggested Readings........................................................................... 267Review Articles.................................................................................268Chapter 18 Acetaminophen, Salicylates, and Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)........................................................ 27118.1 History and Description......................................................... 27118.2 Acetaminophen (N-Acetyl-Para-Aminophenol,APAP, Paracetamol)............................................................... 27118.2.1 Incidence................................................................... 27118.2.2 Medicinal Chemistry and Pharmacology................. 27218.2.3 Clinical Use............................................................... 27218.2.4 Metabolism and Mechanism of Toxicity................... 27218.2.5 Signs and Symptoms of Acute Toxicity.................... 27418.2.6 Clinical Management of Acute Overdose................. 27418.3 Salicylates and Acetylsalicylic Acid (ASPIRIN, ASA).......... 27618.3.1 Incidence and Clinical Use....................................... 27618.3.2 Toxicokinetics...........................................................27718.3.3 Mechanism of Toxicity..............................................27718.3.4 Signs and Symptoms of Acute Toxicity.................... 27818.3.5 Clinical Management of Toxicity.............................. 27918.4 Nonsteroidal Anti-Inflammatory Agents (NSAIDS)............. 28118.4.1 History and Description............................................ 28118.4.2 Classification, Pharmacology, and Clinical Use.......28218.4.3 Signs and Symptoms of Acute Toxicity....................28218.4.4 Clinical Management of Acute Overdose.................28218.5 Methods of Detection.............................................................284References.........................................................................................284Suggested Readings...........................................................................284Review Articles.................................................................................285Chapter 19 Anabolic–Androgenic Steroids.........................................................28719.1 The Endocrine System...........................................................28719.2 Neuroendocrine Physiology...................................................28719.2.1 Description................................................................28719.3 Anabolic–Androgenic Steroids (AAS)...................................28819.3.1 Definition and Incidence...........................................28819.3.2 Pharmacology and Clinical Use................................28919.3.3 Adverse reactions......................................................28919.3.4 Addiction and Withdrawal Syndrome.......................29319.3.5 Treatment of the Consequences of ChronicSteroid Use................................................................29319.4 Estrogen and Progestins.........................................................29319.4.1 Physiology.................................................................29319.4.2 Pharmacology and Clinical Use................................29419.4.3 Clinical Toxicity of Prolonged Estrogen and/orProgestin Administration..........................................294References.........................................................................................297Suggested Readings...........................................................................297Review Articles.................................................................................297Chapter 20 Cardiovascular Toxicology................................................................29920.1 Epidemiology..........................................................................29920.2 Cardiovascular (CV) Physiology............................................29920.2.1 CV Functions.............................................................29920.2.2 Cardiac Circulation...................................................30020.2.3 Electrophysiology......................................................30020.2.4 The Conducting System............................................ 30120.2.5 Electrocardiography..................................................30220.3 Digitalis Glycosides................................................................30320.3.1 Medicinal Chemistry.................................................30320.3.2 Pharmacology and Clinical Use................................30420.3.3 Toxicokinetics...........................................................30420.3.4 Clinical Manifestations of Toxicity...........................30520.3.5 Mechanisms of Toxicity............................................30520.3.6 Clinical Management of Intoxication........................30620.3.7 Methods of Detection................................................30720.4 Beta-Adrenergic Receptor Antagonists..................................30720.4.1 β-Adrenergic Receptor System..................................30720.4.2 Pharmacology and Clinical Use................................30720.4.3 Clinical Manifestations of Toxicity...........................30820.4.4 Clinical Management of Intoxication........................30820.5 Calcium Channel Antagonists (Ca2+ Channel Blockers)........30920.5.1 Pharmacology and Clinical Use................................30920.5.2 Clinical Manifestations of Toxicity........................... 31020.5.3 Clinical Management of Intoxication........................ 31020.6 Other CV Drugs..................................................................... 31020.6.1 Angiotensin-Converting Enzyme (ACE)Inhibitors................................................................... 31120.6.2 Direct Vasodilators.................................................... 31220.6.3 Antiarrhythmic Drugs............................................... 313References......................................................................................... 314Suggested Readings........................................................................... 314Review Articles................................................................................. 315Chapter 21 Antineoplastic Agents....................................................................... 31721.1 Description............................................................................. 31721.2 Review of the Cell Cycle........................................................ 31721.3 Antimetabolites...................................................................... 31821.3.1 Pharmacology and Clinical Use................................ 31821.3.2 Acute Toxicity........................................................... 31921.3.3 Clinical Management of Acute Overdose................. 31921.4 Alkylating Agents................................................................... 32021.4.1 Pharmacology and Clinical Use................................ 32021.4.2 Acute Toxicity........................................................... 32021.4.3 Clinical Management of ADRs................................. 32121.5 Miscellaneous Chemotherapeutic Drugs............................... 32121.5.1 Natural Products........................................................ 32121.5.2 Hormones and Antagonists....................................... 32321.5.3 Platinum Coordination Complexes...........................32421.5.4 Substituted Urea........................................................324References......................................................................................... 325Suggested Readings........................................................................... 325Review Articles................................................................................. 325Chapter 22 Vitamins............................................................................................ 32922.1 Introduction............................................................................ 32922.2 Fat-Soluble Vitamins.............................................................. 33122.2.1 Vitamin A and Retinoic Acid Derivatives................ 33122.2.2 Vitamin D.................................................................. 33222.2.3 Vitamin E.................................................................. 33522.2.4 Vitamin K.................................................................. 33522.3 Water-Soluble Vitamins.......................................................... 33622.3.1 Thiamine................................................................... 33622.3.2 Riboflavin.................................................................. 33622.3.3 Niacin........................................................................ 33622.3.4 Folic Acid.................................................................. 33822.3.5 Cyanocobalamin (Vitamin B12)................................. 33822.3.6 Ascorbic Acid (Vitamin C)....................................... 33822.3.7 Pyridoxine (Vitamin B6)........................................... 33922.3.8 Pantothenic Acid (Vitamin B5)................................. 339References.........................................................................................340Suggested Readings...........................................................................340Review Articles.................................................................................340Chapter 23 Herbal Remedies............................................................................... 34323.1 Introduction............................................................................ 34323.2 Nomenclature and Classification............................................34423.2.1 Nomenclature............................................................34423.2.2 Therapeutic Category................................................ 34523.3 Indications.............................................................................. 34523.4 Other Therapeutic and Toxicologic Information onHerbal Products...................................................................... 345References......................................................................................... 356Suggested Readings........................................................................... 356Review Articles................................................................................. 357Section III Toxicity of Nontherapeutic AgentsChapter 24 Alcohols and Aldehydes.................................................................... 36124.1 Ethanol.................................................................................... 36124.1.1 Incidence and Occurrence......................................... 36124.1.2 Chemical Characteristics.......................................... 36124.1.3 Toxicokinetics........................................................... 36224.1.4 Calculation of Blood Alcohol Concentrations(BAC)........................................................................ 36324.1.5 Mechanisms of Toxicity............................................36424.1.6 Clinical Manifestations of Acute Toxicity................36624.1.7 Management of Acute Intoxication...........................36824.1.8 Clinical Manifestations of Chronic Toxicity.............36824.1.9 Management of Chronic Intoxication....................... 37024.1.10 Fetal Alcohol Syndrome (FAS)................................. 37124.1.11 Tolerance, Dependence, and Withdrawal.................. 37124.1.12 Methods of Detection................................................ 37224.2 Methanol................................................................................. 37324.2.1 Incidence and Occurrence......................................... 37324.2.2 Toxicokinetics........................................................... 37324.2.3 Mechanism of Toxicity.............................................. 37324.2.4 Clinical Manifestations of Acute Intoxication.......... 37424.2.5 Management of Acute Intoxication........................... 37424.3 Isopropanol............................................................................. 37424.3.1 Toxicokinetics........................................................... 37524.3.2 Mechanisms of Toxicity............................................ 37524.3.3 Clinical Manifestations of Acute Toxicity................ 37524.3.4 Management of Acute Intoxication........................... 37524.4 Formaldehyde......................................................................... 37524.4.1 Incidence and Occurrence......................................... 37624.4.2 Toxicokinetics........................................................... 37624.4.3 Mechanisms of Toxicity............................................ 37724.4.4 Clinical Manifestations of Acute Intoxication.......... 37724.4.5 Management of Acute Intoxication........................... 377References......................................................................................... 377Suggested Readings........................................................................... 377Review Articles................................................................................. 378Chapter 25 Gases................................................................................................. 38125.1 Introduction............................................................................ 38125.2 Pulmonary Irritants................................................................ 38125.3 Simple Asphyxiants................................................................ 38225.3.1 Introduction............................................................... 38225.3.2 Gaseous Agents......................................................... 38225.4 Toxic Products of Combustion (TCP).................................... 38725.4.1 Introduction............................................................... 38725.4.2 Clinical Toxicity........................................................ 38725.5 Lacrimating Agents (Tear Gas).............................................. 38925.5.1 Introduction............................................................... 38925.5.2 Chemical Agents....................................................... 38925.6 Chemical Asphyxiants............................................................ 38925.7 Carbon Monoxide (CO).......................................................... 38925.7.1 Incidence................................................................... 38925.7.2 Chemical Characteristics and Sources of Exposure.....39125.7.3 Toxicokinetics........................................................... 39125.7.4 Mechanism of Toxicity.............................................. 39125.7.5 Signs and Symptoms of Acute Toxicity.................... 39225.7.6 Treatment of Acute Poisoning................................... 39325.8 Cyanide................................................................................... 39425.8.1 Chemical Characteristics, Occurrence, and Uses..... 39425.8.2 Mechanism of Toxicity.............................................. 39425.8.3 Toxicokinetics........................................................... 39425.8.4 Signs and Symptoms of Acute Toxicity.................... 39525.8.5 Treatment of Acute Poisoning................................... 39525.9 Methods Of Detection............................................................397References.........................................................................................397Suggested Readings...........................................................................397Review Articles................................................................................. 398Chapter 26 Metals................................................................................................ 401Anirudh J. Chintalapati and Frank A. Barile26.1 Introduction............................................................................ 40126.1.1 Background............................................................... 40126.1.2 Exposure and Applications....................................... 40126.1.3 Physiological Role of Metals.....................................40226.2 Chelation Therapy..................................................................40226.2.1 Description................................................................40226.2.2 Dimercaprol...............................................................40426.2.3 Ethylenediaminetetraacetic Acid (EDTA)................40426.2.4 Penicillamine.............................................................40526.2.5 Deferoxamine............................................................40626.2.6 Succimer....................................................................40626.2.7 Unithiol......................................................................40726.3 Antimony................................................................................40726.3.1 Physical and Chemical Properties.............................40726.3.2 Occurrence and Uses.................................................40726.3.3 Mechanism of Toxicity..............................................40826.3.4 Toxicokinetics...........................................................40826.3.5 Signs and Symptoms of Acute Poisoning.................40826.3.6 Treatment of Acute Poisoning...................................40826.4 Arsenic (As)............................................................................40926.4.1 Physical and Chemical Properties.............................40926.4.2 Occurrence and Uses.................................................40926.4.3 Mechanisms of Toxicity............................................40926.4.4 Toxicokinetics...........................................................40926.4.5 Signs and Symptoms of Acute Toxicity.................... 41026.4.6 Signs and Symptoms of Chronic Toxicity................. 41026.4.7 Treatment of Acute Poisoning................................... 41026.4.8 Treatment of Chronic Poisoning............................... 41126.4.9 Carcinogenesis.......................................................... 41126.5 Asbestos.................................................................................. 41126.5.1 Physical and Chemical Properties............................. 41126.5.2 Occurrence and Uses................................................. 41126.5.3 Mechanism of Toxicity.............................................. 41226.5.4 Toxicokinetics........................................................... 41226.5.5 Signs and Symptoms of Acute Toxicity.................... 41226.5.6 Signs and Symptoms of Chronic Toxicity................. 41226.5.7 Treatment of Acute Poisoning................................... 41326.5.8 Treatment of Chronic Poisoning............................... 41326.6 Cadmium................................................................................ 41326.6.1 Physical and Chemical Properties............................. 41326.6.2 Occurrence and Uses................................................. 41326.6.3 Mechanism of Toxicity.............................................. 41426.6.4 Toxicokinetics........................................................... 41426.6.5 Signs and Symptoms of Acute Toxicity.................... 41426.6.6 Signs and Symptoms of Chronic Toxicity................. 41526.6.7 Treatment of Acute Poisoning................................... 41526.6.8 Treatment of Chronic Poisoning............................... 41526.7 Cobalt..................................................................................... 41526.7.1 Physical and Chemical Properties............................. 41526.7.2 Occurrence and Uses................................................. 41526.7.3 Mechanism of Toxicity.............................................. 41626.7.4 Toxicokinetics........................................................... 41626.7.5 Signs and Symptoms of Acute Toxicity.................... 41626.7.6 Signs and Symptoms of Chronic Toxicity................. 41626.7.7 Treatment of Acute Poisoning................................... 41726.7.8 Treatment of Chronic Poisoning............................... 41726.8 Copper.................................................................................... 41726.8.1 Physical and Chemical Properties............................. 41726.8.2 Occurrence and Uses................................................. 41726.8.3 Mechanism of Toxicity.............................................. 41826.8.4 Toxicokinetics........................................................... 41826.8.5 Signs and Symptoms of Acute Toxicity.................... 41926.8.6 Signs and Symptoms of Chronic Toxicity................. 41926.8.7 Treatment of Acute Poisoning................................... 41926.8.8 Treatment of Chronic Poisoning............................... 41926.9 Iron (Fe2+, Fe3+)....................................................................... 42026.9.1 Physical and Chemical Properties............................. 42026.9.2 Occurrence and Uses................................................. 42026.9.3 Mechanism of Toxicity.............................................. 42026.9.4 Toxicokinetics........................................................... 42126.9.5 Signs and Symptoms of Acute Toxicity.................... 42226.9.6 Signs and Symptoms of Chronic Toxicity................. 42226.9.7 Treatment of Acute Poisoning................................... 42226.9.8 Treatment of Chronic Poisoning............................... 42326.9.9 Clinical Monitoring................................................... 42326.10 Lead........................................................................................ 42326.10.1 Physical and Chemical Properties............................. 42326.10.2 Occurrence and Uses................................................. 42326.10.3 Mechanism of Toxicity..............................................42426.10.4 Toxicokinetics...........................................................42426.10.5 Signs and Symptoms of Acute Toxicity.................... 42626.10.6 Signs and Symptoms of Chronic Toxicity................. 42626.10.7 Treatment of Acute Poisoning................................... 42626.10.8 Treatment of Chronic Poisoning............................... 42726.10.9 Clinical Monitoring................................................... 42726.11 Mercury (Hg).......................................................................... 42726.11.1 Physical and Chemical Properties............................. 42726.11.2 Occurrence and Uses................................................. 42726.11.3 Occupational and Environmental Exposure............. 42926.11.4 Mechanism of Toxicity.............................................. 42926.11.5 Toxicokinetics........................................................... 42926.11.6 Signs and Symptoms of Acute Toxicity(Inhalation and Ingestion)......................................... 43026.11.7 Signs and Symptoms of Subacute or ChronicPoisoning................................................................... 43126.11.8 Clinical Management of Hg Poisoning..................... 43126.12 Selenium (Se).......................................................................... 43126.12.1 Physical and Chemical Properties............................. 43126.12.2 Occurrence and Uses................................................. 43126.12.3 Physiological Role..................................................... 43226.12.4 Mechanism of Toxicity.............................................. 43226.12.5 Toxicokinetics........................................................... 43226.12.6 Signs and Symptoms of Acute Toxicity.................... 43326.12.7 Signs and Symptoms of Chronic Toxicity................. 43326.12.8 Clinical Management of Poisoning........................... 43326.13 Silver (Ag).............................................................................. 43326.13.1 Physical and Chemical Properties............................. 43326.13.2 Occurrence and Uses................................................. 43326.13.3 Toxicokinetics........................................................... 43426.13.4 Argyria...................................................................... 43426.14 Zinc (Zn)................................................................................. 43426.14.1 Physical and Chemical Properties............................. 43426.14.2 Occurrence and Uses................................................. 43426.14.3 Physiological Role..................................................... 43526.14.4 Mechanism of Toxicity.............................................. 43526.14.5 Toxicokinetics........................................................... 43526.14.6 Signs and Symptoms of Acute Toxicity.................... 43526.14.7 Signs and Symptoms of Chronic Toxicity................. 43626.14.8 Clinical Management of Poisoning........................... 436References......................................................................................... 436Suggested Readings........................................................................... 436Review Articles................................................................................. 437Chapter 27 Aliphatic and Aromatic Hydrocarbons............................................. 43927.1 Introduction............................................................................ 43927.1.1 Aliphatic and Alicyclic Hydrocarbons...................... 43927.1.2 Aromatic HCs............................................................ 43927.1.3 General Signs and Symptoms of Acute Toxicity...... 43927.2 Petroleum Distillates.............................................................. 44127.2.1 Occurrence and Uses................................................. 44127.2.2 Mechanism of Toxicity.............................................. 44127.3 Aromatic Hydrocarbons......................................................... 44127.3.1 Occurrence and Uses................................................. 44127.3.2 Mechanism of Toxicity.............................................. 44127.4 Halogenated Hydrocarbons....................................................44327.4.1 Occurrence and Uses.................................................44327.4.2 Mechanism of Toxicity..............................................44427.5 Methods Of Detection............................................................448References.........................................................................................448Suggested Readings...........................................................................448Review Articles.................................................................................449Chapter 28 Insecticides........................................................................................ 45128.1 Introduction............................................................................ 45128.2 Organophosphorus Compounds (Organophosphates, OP)..... 45128.2.1 Chemical Characteristics.......................................... 45128.2.2 Occurrence and Uses................................................. 45228.2.3 Mechanism of Toxicity.............................................. 45328.2.4 Signs and Symptoms of Acute Toxicity.................... 45428.2.5 Clinical Management of Acute Poisoning................ 45528.3 Carbamates............................................................................. 45628.3.1 Chemical Characteristics, Occurrence, and Uses..... 45628.3.2 Mechanism of Toxicity.............................................. 45628.3.3 Signs and Symptoms of Acute Toxicity.................... 45628.3.4 Clinical Management of Acute Poisoning................ 45628.4 Organochlorine (OC) Insecticides.......................................... 45628.4.1 Chemical Characteristics.......................................... 45628.4.2 Occurrence and Uses................................................. 45828.4.3 Mechanism of Toxicity.............................................. 45828.4.4 Signs and Symptoms of Acute Toxicity.................... 45828.4.5 Clinical Management of Acute Poisoning................46028.5 Miscellaneous Insecticides..................................................... 46128.5.1 Pyrethroid Esters....................................................... 46128.5.2 Nicotine..................................................................... 46128.5.3 Boric Acid (H3BO3)...................................................46228.5.4 Rotenone....................................................................46228.5.5 Diethyltoluamide (DEET).........................................46328.6 Methods of Detection.............................................................463References.........................................................................................464Suggested Readings...........................................................................464Review Articles.................................................................................465Chapter 29 Herbicides..........................................................................................46729.1 Introduction............................................................................ 46729.2 Chlorphenoxy Compounds..................................................... 46729.2.1 Chemical Characteristics.......................................... 46729.2.2 Occurrence and Uses.................................................46929.2.3 Signs and Symptoms and Mechanism of AcuteToxicity......................................................................46929.2.4 Clinical Management of Acute Poisoning................ 47029.3 Bipyridyl Herbicides............................................................... 47029.3.1 Chemical Characteristics, Occurrence, and Uses..... 47029.3.2 Toxicokinetics........................................................... 47029.3.3 Mechanism of Toxicity.............................................. 47129.3.4 Signs and Symptoms of Acute Toxicity.................... 47229.3.5 Clinical Management of Acute Poisoning................ 47229.4 Miscellaneous Herbicides....................................................... 47329.5 Methods of Detection............................................................. 473References......................................................................................... 475Suggested Readings........................................................................... 475Review Articles................................................................................. 476Chapter 30 Rodenticides...................................................................................... 47730.1 Introduction............................................................................ 47730.2 Anticoagulants........................................................................ 47730.2.1 Chemical Characteristics.......................................... 47730.2.2 Commercial and Clinical Use................................... 47930.2.3 Toxicokinetics...........................................................48030.2.4 Mechanism of Toxicity..............................................48030.2.5 Signs and Symptoms of Acute Toxicity....................48030.2.6 Clinical Management of Acute Poisoning................ 48130.3 Phosphorus (P)........................................................................48230.3.1 Chemical Characteristics, Occurrence, and Uses.....48230.3.2 Toxicokinetics...........................................................48230.3.3 Mechanism and Signs and Symptoms of AcuteToxicity......................................................................48230.3.4 Clinical Management of Acute Poisoning................48330.4 Red Squill...............................................................................48330.4.1 Chemical Characteristics, Occurrence and Uses......48330.4.2 Mechanism and Signs and Symptoms of AcuteToxicity......................................................................48430.4.3 Clinical Management of Acute Poisoning................48430.5 Metals: Thallium, Barium......................................................48430.5.1 Thallium (Tl).............................................................48430.5.2 Barium (Ba)...............................................................48530.6 Methods Of Detection............................................................485References.........................................................................................486Suggested readings............................................................................486Review Articles.................................................................................487Chapter 31 Chemical Carcinogenesis and Mutagenesis......................................48931.1 Introduction............................................................................48931.2 Mechanisms Of Chemical Carcinogenesis............................. 49131.2.1 Metabolism................................................................ 49131.2.2 Chemistry.................................................................. 49131.2.3 Free Radicals and Reactive Oxygen Species............ 49131.2.4 Mutagenesis...............................................................49231.2.5 DNA Repair...............................................................49431.2.6 Epigenetic Carcinogenesis........................................49431.3 Multistage Carcinogenesis......................................................49431.3.1 Tumor Initiation......................................................... 49531.3.2 Tumor Promotion...................................................... 49531.3.3 Tumor Progression....................................................49731.4 Carcinogenic Characteristics..................................................49731.4.1 Classification............................................................. 49831.4.2 Identification.............................................................. 49831.4.3 Carcinogenic Potential..............................................49931.4.4 Carcinogenic Risk Assessment.................................49931.4.5 Carcinogenic and Genotoxic Agents......................... 50131.5 Cancer Chemoprevention....................................................... 50131.5.1 General Considerations............................................. 50131.5.2 Cancer Chemopreventive Agents..............................50231.5.3 Mechanisms Underlying Cancer Chemoprevention...... 502References.........................................................................................502Suggested Readings...........................................................................502Review Articles.................................................................................504Chapter 32 Reproductive and Developmental Toxicity.......................................505Anirudh J. Chintalapati and Frank A. Barile32.1 Introduction............................................................................50532.2 History and Development.......................................................50632.3 Summary of Maternal–Fetal Physiology...............................50632.3.1 Definitions.................................................................50632.3.2 First Trimester...........................................................50732.3.3 Second and Third Trimesters....................................50832.4 Mechanisms of Developmental Toxicity................................50832.4.1 Susceptibility.............................................................50832.4.2 Dose–Response and Threshold.................................50832.5 Drugs Affecting Embryonic and Fetal Development.............50932.5.1 Classification.............................................................50932.5.2 Drug Classes.............................................................50932.6 Endocrine Disrupting Chemicals (Edcs)................................ 51332.6.1 Mechanism of Toxicity.............................................. 51432.6.2 Effects of EDCs on Female Reproductive System.... 51532.6.3 Effects of EDCs on Male Reproductive System....... 51832.6.4 Management of EDC Exposure................................. 519References......................................................................................... 519Suggested Readings........................................................................... 519Review Articles................................................................................. 520Chapter 33 Radiation Toxicity............................................................................. 52333.1 Principles Of Radioactivity.................................................... 52333.2 Ionizing Radiation.................................................................. 52433.2.1 Biological Effects of Ionizing Radiation................... 52433.2.2 Sources...................................................................... 52433.2.3 Clinical Manifestations............................................. 52533.2.4 Nuclear Terrorism and Health Effects...................... 52733.3 Ultraviolet (UV) Radiation..................................................... 52733.3.1 Biological Effects of Ultraviolet Radiation............... 52733.3.2 Sources...................................................................... 52833.3.3 Clinical Manifestations............................................. 52833.4 Nonionizing Radiation........................................................... 53133.4.1 Sources...................................................................... 53133.4.2 Biological Effects and Clinical Manifestations........ 531References......................................................................................... 532Suggested Readings........................................................................... 532Review Articles................................................................................. 532Chapter 34 Chemical and Biological Threats to Public Safety........................... 53534.1 Introduction............................................................................ 53534.2 Biological Pathogenic Toxins as Threats to Public Safety..... 53634.2.1 Anthrax (Bacillus anthracis)..................................... 53734.2.2 Botulism.................................................................... 54134.2.3 Plague (Yersinia pestis)............................................. 54134.2.4 Brucellosis (Brucella suis)........................................ 54234.2.5 Salmonellosis (Salmonella species).......................... 54334.2.6 Typhoid Fever............................................................ 54534.2.7 Shigellosis (Shigella Species)....................................54634.2.8 Escherichia coli O157:H7.........................................54634.2.9 Cholera (Vibrio cholerae).......................................... 54734.2.10 Smallpox....................................................................54834.2.11 Tularemia (Francisella tularensis), Q Fever(Coxiella burnetti), and Viral HemorrhagicFevers (VHF)............................................................54934.3 Chemical Agents As Threats To Public Safety...................... 55034.3.1 Nerve Gases............................................................... 55034.3.2 Vesicants, Chemical Asphyxiants, andPulmonary Irritants................................................... 55134.3.3 Ricin (Ricinus communis)......................................... 551References......................................................................................... 552Suggested Readings........................................................................... 552Review Articles................................................................................. 553Index....................................................................................................................... 555