Contributors xxv Preface xxix PART A Basics of Toxicologic Pathology Toxicologic Pathology: An Introduction Colin G. Rousseaux Wanda M. Haschek Matthew A. Wallig An Overview of Toxicologic Pathology 3(2) What Is Toxicologic Pathology? 3(1) The Philosophy of Toxicologic Pathology 4(1) The Need for Toxicologic Pathology in Modern Society 5(4) What Led to the Need for Toxicologic Pathology? 5(4) The Value of Toxicologic Pathology 9(1) The Future of Toxicologic Pathology 9(5) Animals and Toxicologic Pathology 9(1) The ``Practitioner of Toxicologic Pathology 10(1) The ``Researcher in Toxicologic Pathology 11(1) The ``Consultant in Toxicologic Pathology 12(1) The ``Manager in Toxicologic Pathology 12(1) Training Future Toxicologic Pathologists 13(1) Summary 14(1) Suggested Reading 14(1) Biochemical Basis of Toxicity Elizabeth H. Jeffery Introduction 15(1) Absorption 16(2) Passage across Membranes 16(1) Absorption Routes 17(1) Distribution 18(2) Volume of Distribution 18(1) Storage 18(2) Barriers 20(1) Biotransformation 20(3) Detoxification and Bioactivation 20(3) Role of Enzyme Location in Toxicity 23(1) Excretion 23(4) Urinary Excretion 23(1) Mechanisms of Urinary System Toxicity 24(1) Biliary Excretion 25(1) Pulmonary Excretion 26(1) Other Excretory Mechanisms 26(1) Factors Causing Variation in Handling 27(2) Genetic Factors 27(1) Environmental Factors 28(1) Interaction of Agent and Organism 29(1) Site Specificity 29(1) Dose Dependency and Site of Action 29(1) Critical Organ for Toxicity 30(1) Temporal Outcome of Interaction 30(1) Site-Specific Interactions 30(3) Receptors and Enzymes 30(2) Mechanisms of Site-Specific Toxicities 32(1) Nonspecific Interaction 33(2) Electrophiles and Covalent Binding 33(1) Free Radicals and Lipid Peroxidation 34(1) Loss of Calcium Homeostasis 34(1) Mechanisms of Protection 35(4) Prevention of Toxicity 35(1) Adaptation of the Organism 35(1) Reversibility of Toxic Injury 36(1) Suggested Reading 37(2) Morphologic Manifestation of Toxic Cell Injury Matthew A. Wallig Introduction 39(4) Key Cellular Components in Cell Injury 39(1) Factors Influencing Injury 39(2) Reaction of the Body to Injury 41(1) Adaptation 41(2) Reversible Cell Injury 43(5) Cell Swelling 45(1) Fatty Change 46(2) Irreversible Cell Injury 48(15) Oncotic Necrosis 49(7) Apoptotic Necrosis 56(2) Sequelae 58(5) Concluding Comments 63(4) Suggested Reading 64(3) Organelle Biochemistry and Regulation of Cell Death Myrtle A. Davis Elizabeth H. Jeffery Overview and Nomenclature 67(1) Cell Membrane 68(1) Introduction 68(1) Membrane Integrity and Signals for Engulfment during Apoptosis 68(1) Receptors Associated with the Cell Membrane 68(1) Cytoskeleton 69(2) Actin Microfilaments 70(1) Microtubules 70(1) Intermediate Filaments 71(1) Structure Meets Gene Expression and Cell Signaling 71(1) Mitochondrion 71(3) Mitochondrial Compartments and Membranes: History and Function 71(1) Permeability Transition Pore (Mitochondrial Megachannel Port) 72(1) Mitochondrial Swelling, Permeability, and Mechanism of Cell Death 72(1) Mitochondrial Protein Translocation and Apoptosis 73(1) Mitochondrial Energy Transport and Cell Death 73(1) Endoplasmic Reticulum 74(1) The ``Unfolded Protein Response to ER Stress 74(1) ER Stress and Calcium 75(1) Caspase 12 Specifically Responds to ER Stress 75(1) Nucleus 75(4) A Review of Nuclear Structure during Cell Death 76(1) Nuclear Structure during Cell Death 76(1) Regulation of Cell Death by Nuclear Transcription Factors 77(1) DNA Tumor Viruses and Regulation of Apoptosis 78(1) Extracellular Matrix 79(1) Integrins: Cell-Matrix Interaction 79(1) Matrix Proteases in Cell Death 80(1) Summary 80(3) Suggested Reading 80(3) Carcinogenesis Stephen Mastorides R. R. Maronpot Introduction 83(1) The Spectrum of Proliferative Lesions 84(6) Quantitative Cell Proliferation 84(2) Qualitative Cell Proliferation 86(1) Preneoplasia 87(1) Neoplastic Cell Proliferation 88(1) Diagnostic Distinction among Preneoplasia, Benign Neoplasia, and Malignant Neoplasia 89(1) Steps in the Neoplastic Process 90(7) Overview 90(1) Multiple Steps in the Neoplastic Process 91(6) Hypotheses of Mode of Action of Chemical Carcinogens 97(9) Overview 97(1) Mutational Genetic Hypothesis of Chemical Carcinogenesis 98(2) Nonmutational Genetic Hypothesis of Chemical Carcinogenesis 100(1) Epigenetic Hypothesis of Chemical Carcinogenesis 101(3) Viral Hypothesis of Carcinogenesis 104(2) Oncogenes and Tumor Suppressor Genes in Chemical Carcinogenesis 106(4) Genes and Tumor Suppressor Genes in Chemical Carcinogenesis 106(1) Protooncogene Function 106(1) Protooncogene Activation 107(1) Protooncogene Activation in Chemical Carcinogenesis 108(2) Tumor Suppressor Genes and Carcinogenesis 110(1) Cell Cycle Control and Carcinogenesis 110(2) Tests for Carcinogenic Potential of Chemicals 112(11) In Vivo Chronic Rodent Carcinogenicity Studies (Rodent Bioassays) 113(2) Additional in Vivo Tests for Carcinogenicity 115(4) In Vivo Short-Term Tests 119(1) Suggested Reading 119(4) Applied Clinical Pathology in Preclinical Toxicology Testing G. S. Smith R. L. Hall R. M. Walker Introduction 123(2) Hematology 125(6) Parameters Generally Included in Study Protocols 125(1) Interpretative Hematology 126(5) Clinical Chemistry 131(9) Cholesterol, Triglycerides, and Glucose 131(1) Serum Proteins 132(3) Indicators of Hepatic Integrity and Function 135(3) Indicators of Renal Function 138(1) Electrolytes 139(1) Calcium and Inorganic Phosphate 139(1) Enzymes of Muscle Origin 139(1) Microsomal Enzyme Induction 140(1) Urinalysis 141(1) Clinical Pathology Study Design Considerations 142(1) Clinical Pathology Result Interpretation 143(7) Potential Effects of Factors Unrelated to Test Article Treatment 143(3) Comparators: Concurrent Controls Reference Ranges 146(1) Statistical Analyses 146(1) Treatment-Related versus Incidental Findings 147(1) Direct versus Indirect Effects 148(1) Pharmacologic versus Toxic Effects 149(1) Biologic Importance of Treatment-Related Effects 149(1) Reporting of Clinical Pathology Findings 150(7) Overall Result Reporting 151(1) Summary 151(1) Suggested Reading 152(5) Nomenclature Ronald A. Herbert James R. Hailey John C. Seely Cynthia C. Shackelford Michael P. Jokinen Jeffrey C. Wolf Gregory S. Travlos Introduction 157(1) Terminology Issues 157(5) Training 158(1) Multiple Pathologists 158(1) Diagnostic Drift 159(1) Lesion Complexity 159(1) The Need for Standardized Nomenclature 160(1) Data Collection 160(2) Suggested Practices 162(3) Summary 165(6) Suggested Reading 166(5) PART B The Practice of Toxicologic Pathology Basic Techniques Thomas J. Bucci Introduction 171(1) Factors Influencing the Evaluation of Altered Morphology 172(10) Collection and Processing of Tissue 174(2) Factors Intrinsic to the Animal 176(2) Factors Related to the Environment 178(2) Factors Related to Nomenclature 180(2) Summary 182(5) Suggested Reading 183(4) Managing Pitfalls in Toxicologic Pathology Peter C. Mann Jerry F. Hardisty Mary D. Parker Introduction 187(1) Study Design 187(2) Necropsy 189(1) Histology 190(12) Specialized Histologic Techniques 192(1) Artifacts versus Lesions 193(3) Lesion Interpretation 196(6) Computer Systems 202(3) Peer Review 205(1) Study Review 205(1) Pathology Working Groups 205(1) Conclusions 206(1) Suggested Reading 206(1) Special Techniques in Toxicologic Pathology N. Gillett C. Chan C. Farman P. Lappin Introduction 207(1) Immunohistochemistry in Toxicologic Pathology 207(10) Introduction 207(1) Technical Considerations 208(2) Applications of Immunohistochemistry in Toxicologic Pathology 210(6) Conclusion 216(1) In Situ Hybridization 217(4) Introduction 217(1) Technical Considerations 217(2) Applications of ISH in Toxicologic Pathology 219(2) Conclusions 221(1) Flow Cytometry 221(6) Introduction 221(1) Application of Flow Cytometry in Toxicologic Pathology 222(4) Limitation of Flow Cytometry 226(1) Laser Scanning Cytometry 227(1) Conclusions 227(1) In Situ Polymerase Chain Reaction (PCR)/in Situ Reverse Transcriptase-PCR 227(3) Introduction 227(1) Technical Considerations 228(1) Controls 229(1) Limitations 229(1) Laser Capture Microdissection 230(1) Confocal Microscopy 231(1) Stereology 232(11) Suggested Reading 233(10) Application of New Technologies to Toxicologic Pathology Bruce D. Car Paul J. Ciaccio Nancy R. Contel Introduction 243(1) Genomics: High-Density Nucleic Acid Microarrays 244(2) Proteomics 246(1) Metabonomics: Pattern Recognition Nuclear Magnetic Resonance Specroscopy 247(1) Laser Capture Microscopy 248(1) Computational Modeling 249(1) Summary 249(2) Suggested Reading 249(2) Issues in Laboratory Animal Science for the Toxicologic Pathologist Jeffrey I. Everitt David C. Dorman Introduction 251(1) Regulatory Issues 252(2) Overview of Rules and Regulations 252(1) Institutional Animal Care and Use Committee 253(1) Methods of Euthanasia 254(1) Selection of Animal Models 254(4) Overview 254(1) Genetic Issues 255(1) Issues Involving the Use of Historical Databases 256(1) Challenges of Genetically Engineered Rodents 257(1) Animal Health Considerations 258(2) Adventitious Agents 258(1) Sentinel Monitoring Programs 259(1) Microbial Effects on Toxicity 259(1) Housing and Hubandry Issues 260(2) Role of Environment in Lesion Production 260(1) Study Design Consideration 261(1) The Role of Diet in Toxicology Studies 262(3) Introduction 262(1) Types of Diets 263(1) Contaminant Issues 264(1) Dietary Optimization 264(1) Summary 265(4) Suggested Reading 265(4) New Animal Models in Toxicology Eugenia Floyd Many Strains of Genetically Engineered Rodents Are Available for Use in Toxicology 269(1) Genetically Engineered Mice Can Be Used for in Vivo Genetic Toxicity Testing 270(3) Mutamouse and Big Blue Transgenic Mice 270(1) Aprt-Deficient Mice 271(1) Pun Mutant Mice 272(1) Other New Models for Mutagenicity Testing 272(1) Advantages and Disadvantages of Gene-Altered Mice for Genetic Toxicology 272(1) Genetically Engineered Mice Can Be Used to Study Mechanisms of Toxicity in Vivo 273(6) Role of Xenobiotic Receptors in Toxicity 273(1) Role of Cytochrome P450 Enzymes in Toxicity and Carcinogenesis 274(1) Role of Phase II and Other Metabolic Enzymes in Toxicity and Carcinogenesis 275(1) Role of Oxidative Stress in Toxicity 276(1) In Vivo Study of Redundancy in Antioxidant Pathways 277(1) Role of Cytokines and Other Mediators of Inflammation in Toxicity 278(1) Genetically Modified Mice Can Be Used for Special or Customized Toxicity Testing 279(2) Altered Phenotypes Reflecting Toxicity 279(1) Identifying Activity-Related Toxicity 280(1) Characterizing Human-Target-Specific Toxicity 281(1) Genetically Engineered Mice Can Be Useful for Short-Term Carcinogenicity Testing 281(12) Multistep Theory of Cancer as Basis for New Models 281(1) Global Collaboration to Evaluate Models for Short-Term Carcinogenicity Testing 282(1) The Trp53 Hemizygous Model 282(4) The TG.AC Mouse 286(3) The RasH2 Mouse 289(2) Xpa-null and Xpa-null/Trp53 Hemizyogous Mice 291(1) The Neonatal Mouse Assay and Other Alternative Carcinogenicity Assays 292(1) Current and Future Use of Genetically Modified Mice for Short-Term Carcinogenicity 293(1) Caveats Apply to the Use of Genetically Engineered Mice in Research 293(3) Effects of Genetic Background on Phenotype 294(1) Effects of Genetic Technologies on Phenotype 294(1) Importance of Genetic Quality Control 295(1) New Gene-Altering Technologies Will Produce More Sophisticated Mouse Models 296(11) Models with Multiple Genetic Alterations 296(1) Inducible Transgene Systems 296(1) Tissue-Specific Genetic Alterations 297(1) Future Models for Use in Toxicology 298(1) Suggested Reading 299(8) Pathology Issues in the Design of Toxicology Studies Ricardo Ochoa Introduction 307(1) Toxicology Studies and Their Utility 307(1) Landmarks in Compound Development 308(1) Approval for Human Clinical Trials 308(1) Application for a License to Market a Drug 308(1) The Role of the Pathologist in Compound Development 309(4) Discovery Studies 310(3) Regulatory Studies 313(1) Studies to Support First in Human Exposure 313(1) Studies to Support Longer Exposures in Humans 313(1) Length of Studies 313(1) General Consideration for the Use of Pathology in Regulatory Studies 314(2) What Is in a Diagnosis? 314(1) Peer Reviews and Quality Control 315(1) Sharing Studies 316(1) Recutting and Restaining 316(1) Evaluating Only High-Dose and Control Groups 316(1) Studies to Support First in Human Exposure 316(8) Acute Toxicity Studies 317(1) Alternative Studies to Support ``First in Human Exposure 318(1) Subacute, Subchronic, and Chronic Toxicity Studies 318(1) Carcinogenicity Studies 319(5) Clinical Pathology 324(1) Reproductive Toxicology 324(1) Pediatric Populations 325(1) Special Studies 325(2) Animal Health Products 325(1) Suggested Reading 326(1) Use and Misuse of Statistics in the Design and Interpretation of Studies Shayne C. Gad Colin G. Rousseaux Introduction 327(6) Research and the Toxicologic Pathologist 328(3) Observations and Measurements 331(2) Prerequisites to Statistical Analysis 333(11) Biological Variation 333(2) Describing Data 335(5) Biological and Statistical Significance 340(4) Functions of Statistical Analyses 344(3) Hypothesis Testing and Probability (P) Values 345(1) Multiple Comparisons 346(1) Estimating the Size of the Effect 346(1) An Overview of Experimental Design 347(8) Control 347(1) Bias and Change 348(1) Basic Principles of Experimental Design 348(1) Detecting Treatment Effects 349(4) Censoring 353(1) Impacts of Sample Size 353(1) Considerations Made before Designing the Experiment 354(1) Designs Commonly Used in Toxicologic Studies 355(2) Completely Randomized Design 355(1) Completely Randomized Block Design 356(1) Latin Square Design 356(1) Factorial Design 356(1) Nested Design 357(1) Managing Data 357(3) Bias 357(2) Bias and the Toxicologic Pathologist 359(1) Statistical Methods 360(48) Statistical Analysis: General Considerations 361(9) Methods for Data Examination and Preparation 370(6) Exploratory Data Analysis 376(2) Hypothesis Testing of Categorical Data 378(3) Hypothesis Testing of Ordinal Data 381(4) Hypothesis Testing on Univariate Parameters 385(5) Hypothesis Testing on Multivariate Parameters 390(2) Modeling 392(7) Methods for the Reduction of Dimensionality 399(5) Meta-analysis 404(2) Bayesian Inference 406(2) Data Analysis Application in Toxicologic Pathology 408(6) Body and Organ Weights 409(2) Clinical Chemistry 411(1) Hematology 412(1) Incidence of Histopathologic Findings 412(1) Carcinogenesis 413(1) Summary and Conclusions 414(5) Suggested Reading 415(4) Preparation of the Report for a Toxicology/Pathology Study Hugh E. Black Introduction 419(1) Clients 419(1) Impact of a Poorly Written Report 420(1) Preparation of the Final Report for a Toxicology Study 421(1) Organization of the Report 422(11) Title Page 422(1) Information/Signature Page 422(1) Table of Contents 423(1) Quality Assurance Statement 423(1) Summary 423(1) Evaluation 423(1) Body of the Report 424(7) Things to Avoid in Preparing a Final Report 431(2) Conclusion 433(4) PART C Selected Topics in Toxicologic Pathology Risk Assessment: The Changing Paradigm Stephen K. Durham James A. Swenberg Introduction 437(1) Traditional Risk Assessment 438(2) The Changing Paradigm 440(1) Examples of Mechanistically Based Risk Assessment 441(2) α2μ-Globulin Nephropathy 441(1) Peroxisome Proliferators 442(1) Butadiene 442(1) Future Implications and Methodologies for Toxicology 443(4) Suggested Reading 444(3) Principles of Risk Communication: Building Trust and Credibility with the Public Ronald W. Brecher Terry Flynn Introduction 447(1) The Risk Communication Perspective 448(1) Risk Communication and Public Involvement 448(1) Challenges and Obstacles to Effective Risk Communication 449(2) Data versus Information 450(1) The Publics Expectations of Science 450(1) Contradictory Expert Opinions 450(1) Perception and Acceptance of Risk 451(1) Likelihood (Size) of the Adverse Effect 451(1) ``Dread Factor 451(1) Permanent or Reversible Nature of the Adverse Effect 451(1) Voluntary Acceptance of Risks 451(1) Who Benefits from Acceptance of a Risk? 451(1) Jargon and Technical Terms 451(1) Age and Sex of the Risk Taker 452(1) Source of Information 452 Assessing the Issue: ``Is There a Risk? 451(2) Problem Formulation 452(1) Exposure Assessment 452(1) Toxicity Assessment 453(1) Risk Characterization 453(1) How Can Risks Be Managed? 453(3) How Do People Feel about the Risk? 454(1) Involving Stakeholders in Issue Definition 455(1) Putting It All Together 456(1) Summary 456(3) Suggested Reading 456(3) Biomedical Devices and Biomaterials Mary E. P. Goad Dale L. Goad Introduction 459(1) Definition of Biomaterial and Biomedical Devices 459(2) Types of Biomaterials 460(1) Uses of Biomaterials 461(1) Biomedical Devices 461(10) Soft Tissue Defects and Injury Repair 461(1) Bones and Joints 462(7) Heart Valves and Vessels 469(1) Silicone Implants 470(1) Bioengineered Implants and Delivery Systems 471(1) Safety Evaluation of Biomaterials and Devices 471(8) Assessment of Lesions 471(3) Carcinogenicity 474(1) FDA and ISO Guidelines 475(1) Suggested Reading 476(3) Biotechnology and Its Products Anne M. Ryan Timothy G. Terrell Introduction 479(1) Biopharmaceuticals 480(11) Biopharmaceuticals versus Small Molecule Therapeutics 481(1) Classes of Biopharmaceuticals 481(4) Recently Approved Biopharmaceuticals 485(3) Toxicologic Pathology Findings with Biopharmaceuticals 488(3) Safety Evaluation of Biopharmaceuticals 491(4) Regulatory Resources 491(1) Study Design Issues 492(2) Other Studies 494(1) Summary and Conclusions 495(6) Suggested Reading 496(5) Endocrine Disruptors Paul S. Cooke Richard E. Peterson Rex A. Hess Introduction 501(1) Mechanisms of Endocrine Disruption 502(2) Target Organs 504(1) Classes of Compounds with Endocrine Disrupting Activity 504(15) Estrogens 504(7) Androgens and Antiandrogens 511(1) Effects of Endocrine Disruptors on Progesterone Signaling 512(1) Disruption of Endocrine Homeostasis through Other Steroid Receptors 512(1) Disruptors of Thyroid Hormone Homeostasis 513(1) Aryl Hydrocarbon Receptor (AhR) Agonists 514(2) Phytoestrogens 516(3) Exposure to Endocrine Disruptors: Are There Risks? 519(2) Wildlife Populations 519(1) Human Health 519(2) Techniques for Screening Endocrine Disruptors 521(1) Conclusions, Controversy, and Questions 522(7) Suggested Reading 523(6) Radiation and Heat Stephen A. Benjamin Barbara E. Powers Fletcher F. Hahn Donna F. Kusewitt Introduction 529(3) Sources and Occurrence 530(2) Ionizing Radiation 532(47) Nature and Action of Ionizing Radiation 532(4) Mechanisms of Ionizing Radiation Injury 536(9) Response to Injury Induced by Ionizing Radiation 545(34) Ultraviolet Radiation 579(10) Nature and Action of Ultraviolet Radiation 579(1) Mechanisms of Ultraviolet Radiation Injury 579(2) Response to Injury Induced by Ultraviolet Radiation 581(8) Hyperthermia 589(6) Clinical Use of Hyperthermia 589(1) Mechanisms of Hyperthermia-Induced Injury 589(1) Response to Injury Induced by Hyperthermis 590(2) Suggested Reading 592(3) Nutritional Toxicologic Pathology Elizabeth H. Jeffery Matthew A. Wallig M. E. Tumbleson Introduction 595(2) Macronutrients 597(6) Proteins 597(3) Carbohydrates 600(1) Fats 601(1) Fiber 602(1) Micronutrients 603(24) Vitamins 603(11) Minerals 614(13) Dietary Contaminants 627(4) Suggested Reading 629(2) Phycotoxins Philip F. Solter Val R. Beasley Introduction 631(1) Diarrhaeic Shellfish Poisoning 631(2) Paralytic Shellfish Poisoning 633(1) Amnesic Shellfish Poisoning 634(1) Ciguatera Fish Poisoning 635(1) Pfiesteria Toxicoses 636(1) Cyanbacterial Toxins 636(9) Neurotoxins 636(1) Hepatotoxins 637(4) Suggested Reading 641(4) Selected Mycotoxins Affecting Animal and Human Health Wanda M. Haschek Kenneth A. Voss Val R. Beasley Introduction 645(5) Aflatoxins 650(6) Source/Occurrence 650(1) Toxicology 651(2) Clinical Signs and Pathology 653(2) Human Risk 655(1) Diagnosis, Treatment, and Control 656(1) Ochratoxins 656(6) Source/Occurrence 656(1) Toxicology 657(1) Clinical Signs and Pathology 658(1) Human Risk 659(3) Diagnosis, Treatment, and Prevention 662(1) Trichothecene Mycotoxins 662(8) Sources/Occurrence 662(1) Toxicology 662(2) Clinical Signs and Pathology 664(4) Human Risk 668(2) Diagnosis, Treatment, and Prevention 670(1) Zearalenone 670(2) Sources/Occurrence 670(1) Toxicology 670(1) Clinical Signs and Pathology 671(1) Human Risk 672(1) Diagnosis, Treatment, and Prevention 672(1) Fumonisins 672(11) Sources/Occurrence 672(1) Toxicology 673(3) Clinical Signs and Pathology 676(6) Human Risk 682(1) Diagnosis, Treatment, and Prevention 683(1) Ergot Alkaloids 683(7) Sources/Occurrence 683(1) Toxicology 684(3) Clinical Signs and Pathology 687(2) Human Risk 689(1) Diagnosis, Treatment, and Prevention 690(1) Summary/Conclusion 690(11) Suggested Reading 691(10) Heavy Metals Sharon M. Gwaltney-Brant Introduction 701(1) Cadmium 701(6) Sources and Exposure 701(1) Kinetics 702(1) Mechanism of Action 703(1) Acute Toxicity 704(1) Chronic Toxicity 704(2) Carcinogenicity 706(1) Mercury 707(5) Sources and Exposure 707(1) General Mechanism of Action 707(1) Elemental Mercury 708(1) Inorganic Mercury 709(1) Organic Mercury 710(1) Carcinogenicity 711(1) Lead 712(4) Sources and Exposure 712(1) Kinetics 712(1) Mechanism of Action 713(1) Acute Toxicity 714(1) Chronic Toxicity 715(1) Carcinogenicity 716(1) Arsenic 716(5) Chemical Forms 716(1) Inorganic Arsenic 717(3) Phenylarsonics 720(1) Arsine 720(1) Uranium and Plutonium 721(2) Uranium 721(1) Plutonium 722(1) Thallium 723(2) Sources and Exposure 723(1) Kinetics 723(1) Mechanism of Action 723(1) Toxicity 723(2) Carcinogenicity 725(1) Bismuth 725(1) Sources and Exposure 725(1) Kinetics 725(1) Mechanism of Action 725(1) Toxicity 725(1) Teratogenicity and Carcinogenicity 726(1) Antimony 726(1) Sources and Exposure 726(1) Kinetics and Mechanism of Action 726(1) Toxicity 727(1) Carcinogenicity 727(1) Beryllium 727(3) Sources and Exposure 727(1) Kinetics 728(1) Acute Toxicity 728(1) Chronic Toxicity 728(2) Carcinogenicity 730(1) Summary and Conclusions 730(1) Suggested Reading 730
