Volume one in this expanded second edition addresses general pathology and is divided into three parts: basics of toxicologic pathology, the practice of toxicologic pathology, and selected topics, such as principles of risk communication, biotechnology and its products, nutritional toxicological pathology, and heavy metals. Volume two covers organ-specific toxicologic pathology. A number of new chapters address new technological developments such as laser capture dissection and new imaging modalities. Chapters related to the practice of toxicologic pathology discuss topics such as how to avoid pitfalls by paying attention to study design and taking advantage of peer review; issues in laboratory animal science, including regulatory issues, animal health considerations, and the role of diet in toxicological studies; new animal models, including the many strains of genetically engineered rodents available; and the use and misuse of statistics in the design and interpretation of studies. Two of the editors, Wanda Haschek and Matthew Wallig are affiliated with the College of Veterinary Medicine at the U. of Illinois, Urbana-Champaign; Colin Rousseaux is from the University of Ottowa's Department of Cellular and Molecular Medicine. Annotation c. Book News, Inc., Portland, OR (booknews.com)
A comprehensive understanding of toxicologic pathology is essential for those in industry, academia, and government who make decisions concerning the safety and efficacy of drugs and chemicals. Toxicologic Pathology relies heavily on the fields of both toxicology and pathology, which are well covered individually in various texts and references; however, there are few texts that address the field of toxicologic pathology. The Handbook of Toxicology Pathology fills this void and is thus essential for all health professionals within or interacting with the field of toxicologic pathology.
This two-volume set provides the reader with a single reference for toxicologic pathology. In volume I, the book covers toxicologic pathology in its basic aspects, including its definition, the basic biochemical and morphologic mechanisms underlying the discipline, the basic practice of toxicologic pathology (including special techniques) and issues essential to the understanding of toxicologic pathology such as risk assessment, experimental design, and statistical analysis. Next, the book moves to specific issues affecting the "practice" toxicologic pathology, including issues such as knowledge management, regulatory affairs and writing pathology reports. Finally, Volume I closes with several chapters that deal with specific classes of environmental
toxicants such as endocrine disruptors and heavy metals. Volume II addresses the toxicologic pathology in a thoroughly standardized systems manner, addressing the basic structure and function of a particular organ system, its response to toxic injury, mechanisms of injury and methods of evaluation of such injury.
Key Features
* Easy to find, up-to-date reference information
* Graphic and photographic plates
* Current hot topics and anticipated changes in toxicologic pathology
* Standardized chapter format
* Topics that are addressed in both a broad and deep manner, resulting in a stand alone text
* Added coverage of important environmental toxicants
* Chapters authored by internationally recognized experts and peer-reviewed
Recenzijas
"The 2 volumes are excellent companions that complement each other as a "1,2" punch! This publication should be on the bookshelf of clinical toxicologists, environmental professionals and laboratory investigators..." --VETERINARY AND HUMAN TOXICOLOGY (October 2002)
"...gives an excellent overview of the numerous processes associated with toxicologic pathology as used in risk assessment. It stands alone as a classic textbook in toxicology, or would be an excellent supplement to other such books. ...Its readability will allow acceptance to all scientists ranging from undergraduate to experienced industry/regulatory professional." --Paul Baldrick for THE BRITISH TOXICOLOGY SOCIETY NEWSLETTER (Spring 2002)
"...very readable, well-referenced, and current... an excellent book for research training." --DOODY'S
"[ W]ell illustrated with good quality diagrams, colour and black and white photographs. [ A]n excellent, eminently readable book to have as a study or reference book, covering the essential basics and providing a good overview for any toxicological pathologist, toxicologist or research scientist with an interest in the pathological changes seen in toxicological studies." --British Toxicology Society Newsletter
Papildus informācija
Key Features * Easy to find, up-to-date reference information * Graphic and photographic plates * Current hot topics and anticipated changes in toxicologic pathology * Standardized chapter format * Topics that are addressed in both a broad and deep manner, resulting in a stand alone text * Added coverage of important environmental toxicants * Chapters authored by internationally recognized experts and peer-reviewed
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 Organ-Specific Toxicologic Pathology: An Introduction 1(936) Colin G. Rousseaux Wanda M. Haschek Matthew A. Walling Respiratory System Wanda M. Haschek Hanspeter R. Witschi Kristen J. Nikula Introduction 3(1) Structure and Cell Biology 4(25) Macroscopic and Microscopic Anatomy 4(15) Physiology and Functional Considerations 19(5) Xenobiotic Exposure, Metabolism, and Excretion 24(5) Mechanisms of Toxicity 29(7) Direct Toxicity 30(1) Metabolic Activation 31(2) Immune-Mediated Toxicity 33(1) Toxicity and Responses to Inhaled Particles 34(1) Xenobiotic Interactions 35(1) Modifying Factors in Toxicity 36(1) Response to Injury 36(32) Injury, Regeneration, and Repair 37(2) Nasopharyngeal and Laryngeal Responses to Injury 39(7) Airway Response to Injury 46(5) Pulmonary Parenchymal Response to Injury 51(17) Testing for Toxicity 68(17) Methods for Testing 69(3) Evaluation of Toxicity 72(6) Animal Models 78(1) Suggested Reading 79(6) Skin and Oral Mucosa Andres J. P. Klein-Szanto Claudio J. Conti Skin 85(27) Introduction 85(1) Structure and Function of Skin 85(9) Mechanisms of Cutaneous Toxicity 94(4) Response of Skin to Injury 98(11) Evaluation of Cutaneous Toxicity 109(3) Oral Mucosa 112(9) Introduction 112(1) Structure and Function of Oral Mucosa 112(1) Mechanisms of Mucosal Toxicity 113(1) Response of Oral Mucosa to Injury 113(2) Evaluation of Oral Toxicity 115(1) Suggested Reading 116(5) Gastrointestinal Tract T. A. Bertram Introduction 121(1) Structure and Function of the Gastrointestinal Tract 122(21) Macroscopic and Microscopic Structure and Function 122(11) Enteric Lymphoid System 133(2) Enteric Nervous System 135(2) Biotransformation 137(3) Bacterial Metabolism 140(1) Enterohepatic Circulation 141(2) Mechanisms of Gastrointestinal Toxicity 143(12) Intestinal Barrier Function 143(1) Intestinal Malabsorption 144(1) Hypoxia 145(1) Mucosal Barrier Damage and Cytotoxicity 146(4) Hypersensitivity 150(1) Acetylcholinesterase Inhibitors 151(1) Perturbation of Enteric Microflora 151(1) Carcinogenicity 152(3) Response of Gastrointestinal Tract to Injury 155(14) Pathophysiological Response 155(3) Inflammatory Response 158(6) Organ-Specific Response 164(5) Evaluation of Gastrointestinal Toxicity 169(18) In Vitro Strategies 169(1) In Vivo Strategies 170(1) Molecular Pathology 170(1) Morphological Methods 171(7) Animal Models 178(6) Suggested Reading 184(3) Liver Russell C. Cattley James A. Popp Introduction 187(1) Structure and Function 187(3) Gross Anatomy 188(1) Cell Components 188(2) Xenobiotic Metabolism 190(1) Cellular Mechanisms of Toxicity 190(1) Nonneoplastic Responses to Injury 190(22) Histologic Types of Hepatic Necrosis 192(6) Hepatic Lipidosis 198(1) Infiltration and Pigments 199(1) Pathology of Transcription and Translation 200(2) Cholestasis 202(1) Hepatocellular Adaptive Responses 202(2) Hepatocellular Proliferation 204(1) Bile Ductular Lesions 205(4) Nonparenchymal Cell Toxicity 209(2) Hepatitis 211(1) Cirrhosis 211(1) Hepatic Neoplasia 212(6) Hepatocellular Neoplasia 212(3) Bile Duct Neoplasms 215(2) Endothelial Neoplasms 217(1) Kupffer Cell Neoplasms 218(1) Testing for Toxicity 218(4) Whole Animal 218(3) Perfused Liver Preparations 221(1) Cultured Hepatocytes 221(1) Liver Slices 221(1) Use of Animals as Models 222(1) Summary and Conclusions 222(5) Suggested Reading 222(5) Pancreas Daniel S. Longnecker Glenn L. Wilson Overview 227(1) Exocrine Pancreas 227(14) Introduction 227(1) Normal Structure of the Exocrine Pancreas 227(3) Physiology of the Exocrine Pancreas 230(1) Mechanisms of Toxicity in Exocrine Pancreas 230(1) Response of the Exocrine Pancreas to Injury 231(6) Evaluation of Exocrine Pancreatic Toxicity 237(4) Summary and Conclusions 241(1) Endocrine Pancreas 241(14) Structure of Endocrine Pancreas 241(2) Physiology of Endocrine Pancreas 243(1) Mechanisms of Endocrine Pancreatic Toxicity 244(4) Response to Injury 248(3) Evaluation of Endocrine Pancreatic Toxicity 251(1) Summary and Conclusions 252(1) Suggested Reading 252(3) Kidney Kanwar Nasir M. Khan Carl L. Alden Introduction 255(1) Renal Structure and Function 256(15) Gross, Microscopic, and Ultrastructural Anatomy 256(9) Physiology 265(6) Molecular Pathology of the Kidney 271(7) Growth Factors, Protooncogenes, Chemokines, and Heat Shock Proteins 271(1) Molecular Targets of Emerging Novel Therapeutics 272(5) Genetically Modified Rodent Models 277(1) Mechanisms of Toxicity 278(34) Overview and Classification 278(2) Glomerular Injury 280(5) Proximal Tubular Injury 285(17) Other Sites of Injury 302(3) Renal Carcinogenesis 305(7) Response to Injury 312(11) Introduction 312(2) Glomerulus 314(1) Proximal Tubule 315(3) Renal Papilla 318(1) Tubular Hyperplasia and Neoplasia 318(4) Predictors of Carcinogenesis 322(1) Testing for Kidney Toxicity 323(6) Routine Screening of New Chemicals 323(1) Methodology for Refinement of the Risk Assessment 324(3) Spontaneous Renal Disease 327(2) Conclusion 329(8) Suggested Reading 330(7) Lower Urinary Tract Samuel M. Cohen Hideaki Wanibuchi Shoji Fukushima Introduction 337(1) Structure and Function 337(3) Kidney Pelvis 337(1) Ureters 338(1) Urinary Bladder 338(1) Urethra 338(1) Urothelium 339(1) Mechanisms of Toxicity 340(6) Urinary Chemistry 340(1) Urinary Solids 341(3) Chronic Injury 344(1) Carcinogenesis 344(2) Response to Injury 346(6) Nonneoplastic Lesions 346(4) Epithelial Neoplasms 350(1) Urothelial Carcinoma 350(2) Mesenchymal Tumors 352(1) Testing for Toxicity 352(11) Evaluation of Urine 352(4) Morphologic Evaluations 356(2) Animal Models 358(1) Suggested Reading 359(4) Cardiovascular and Skeletal Muscle Systems John F. Van Vleet Victor J. Ferrans Eugene Herman Heart 363(47) Introduction 363(1) Structure and Function 363(10) Mechanisms of Toxicity 373(9) Response to Injury 382(18) Testing for Toxicity 400(10) Vessels 410(19) Introduction 410(1) Structure and Function 410(5) Mechanisms of Toxicity 415(4) Response to Injury 419(6) Evaluation of Vasotoxic Effects 425(4) Skeletal Muscle 429(28) Introduction 429(1) Structure and Function 430(3) Mechanisms of Toxicity 433(2) Response to Injury 435(4) Evaluation of the Effects of Xenobiotics on Skeletal Muscle 439(7) Suggested Reading 446(11) Bones and Joints J. C. Woodard J. E. Burkhardt W. Lee Introduction 457(1) Skeletal Structure and Composition 457(4) Formation and Development 457(3) Blood Supply and Nerves 460(1) Composition of Bone 460(1) Species Differences in Composition and Changes with Age 461(1) Bone Physiology and Function 461(5) Modeling and Remodeling of Bone 461(1) Biomechanics 462(1) Mineral Homeostasis 462(1) Regulation of Bone Cell Function 463(3) Mechanisms of Toxicity 466(10) Bone Toxicity 466(9) Joint Toxicity 475(1) Response of the Skeleton to Toxic Injury 476(18) Bone 476(13) Joints 489(5) Evaluation of Skeletal Toxicity 494(9) Testing for Skeletal Toxicity 494(1) Morphologic Evaluation 495(6) Biochemical Evaluation 501(1) Animal Models of Skeletal Disease 502(1) Summary 503(6) Suggested Reading 503(6) Nervous System David C. Dorman Karrie A. Brenneman Brad Bolon Introduction 509(1) Structure and Function of the Nervous System 510(7) Macroscopic Structure 510(1) Microscopic Anatomy 511(1) Specialized Anatomical Features 512(1) Select Functions 513(4) Mechanisms of Disease and Classification of Neurotoxic Diseases 517(11) Neuronopathies 518(3) Axonopathies 521(2) Myelinopathies 523(2) Toxicants Affecting Vascular Integrity 525(1) Developmental Neurotoxicants 525(2) Neurocarcinogens 527(1) Testing for Neurotoxicity 528(7) Animal Testing 528(6) Use of in Vitro Systems in Neurotoxicity Testing 534(1) Conclusions 535(4) Suggested Reading 535(4) The Eye Herbert E. Whiteley Robert L. Peiffer Introduction 539(1) Development of the Eye 540(2) Structure, Function, and Cell Biology 540(1) Mechanisms of Toxicity 540(2) Cornea 542(11) Structure, Function, and Cell Biology 542(7) Mechanisms of Toxicity 549(4) Lens 553(4) Structure and Function 554(1) Mechanisms of Toxicity 555(2) Retina and Retinal Pigment Epithelium 557(14) Structure and Function 557(4) Mechanisms of Toxicity 561(9) Summary 570(1) Toxicologic, Clinical, and Pathologic Evaluation 571(3) Animal Models: Which Ones? 571(1) Clinical Opthalmic Examination 571(1) Other Clinical Diagnostic Techniques 572(1) Morphologic Evaluation 573(1) Ocular Toxicity Testing 574(3) Ocular Irritation: Draize Test 574(2) Alternative to the Draize Test 576(1) Models of Retinal Toxicity 577(1) Other in Vitro Models 577(1) Conclusions 577(8) Suggested Reading 578(7) Immune System C. Frieke Kuper Emile de Heer Henk Van Loveren Joseph G. Vos Introduction 585(1) Structure and Function of the Immune System 585(19) Function of the Immune System 585(7) Structure of the Immune System 592(12) Mechanisms of Immune Toxicity 604(17) Introduction 604(3) Examples of Immunotoxic Agents 607(13) Immune Derangements and Neoplasia 620(1) Response of Lymphoid Tissue to Toxic Injury 621(14) Decreased Cellularity, Depletion, Atrophy, and Involution 622(10) Increased Cellularity, Hyperplasia, Germinal Center Development, and Macrophage Accumulations 632(3) Neoplasia 635(1) Inflammation in Nonlymphoid Organs: Autoimmune Disease and Allergy 635(6) Testing for Immunotoxicity 641(2) Introduction 641(2) Animal Models 643(1) Summary 643(4) Suggested Reading 644(3) Hematopoietic System V. E. Valli J. P. McGrath I. Chu Introduction 647(1) Phylogeny and Ontogeny of the Hematopoietic and Lymphoid Systems 647(1) Structure and Function 648(14) Gross and Microscopic Anatomy 648(7) Hematopiesis 655(5) Cellular Kinetics 660(2) Hematopoietic Assessment 662(1) Interpreting Changes in Blood and Hematopoietic Tissues 663(9) Maturation Index of Myeloproliferation 666(6) Hematotoxic Agents and Mechanisms 672(5) Summary and Future Direction 677(4) Suggested Reading 677(4) Endocrine System Charles C. Capen Ronald A. DeLellis John T. Yarrington Introduction 681(1) Adrenal Cortex 681(18) Structure and Function 681(5) Mechanisms of Toxicity 686(1) Response to Injury 687(10) Testing for Toxicity 697(2) Use of Animals as Models 699(1) Adrenal Medulla Structure and Function 699(1) Mechanisms of Toxicity 700(1) Response to Injury 701(5) Testing for Toxicity 706(1) Pituitary Gland 706(13) Structure and Function 706(4) Mechanisms of Toxicity 710(3) Response to Injury 713(5) Testing for Toxicity 718(1) Thyroid C Cells Structure and Function 719(2) Mechanisms of Toxicity 721(1) Response to Injury 721(4) Thyroid Follicular Cells 725(30) Structure and Function 725(7) Mechanisms of Toxicity 732(11) Response to Injury 743(7) Evaluation of Toxicity 750(5) Parathyroid Gland 755(30) Introduction 755(1) Structure and Function 755(5) Mechanisms of Toxicity 760(5) Response of Parathyroid Chief Cells to Injury 765(5) Evaluation of Toxicity 770(1) Suggested Reading 771(14) Male Reproductive System Dianne M. Creasy Paul M. D. Foster Introduction 785(1) Structure and Cell Biology 785(23) Embryological Derivation of the Reproductive Tract 785(1) Development of the Reproductive Tract 786(1) Structure of the Testes 787(5) Physiology and Functional Consideration of the Testes 792(13) Structure and Function of the Epididymis and Excurrent Ducts 805(1) Structure and Function of Accessory Sex Organs 806(1) Penis and Ejaculation 807(1) Mechanisms of Toxicity 808(14) Role of Metabolism 809(1) Cell-Specific Toxicity in the Testes 810(6) Vascular Effects and Indirect Toxicity to the Testes 816(1) Epididymal and Sperm Toxicity 817(1) Secondary Sex Organs 818(1) Hormone Disruption 818(2) Toxicity to the Developing Male Reproductive Tract 820(2) Responses to Injury 822(15) Disruption of Spermatogenesis 822(6) Tubular Dilatation and Tubular Shrinkage 828(1) Tubular and Testicular Necrosis 828(1) Leydig Cell Response 828(2) Disruption of Sperm Maturation 830(1) Epididymal Response 830(1) Response to Alternations in Hormone Balance 831(5) Reversibility 836(1) Testing for Toxicity 837(7) Detecting Toxicity 837(1) Characterization of Male Reproductive Toxicity 838(3) Functional Characterization 841(2) Testing for Toxicity of the Developing Male Reproductive Tract 843(1) Conclusions 844(3) Suggested Reading 844(3) Female Reproductive System Yang-Dar Yuan George L. Foley Introduction 847(1) Structure and Functional Physiology 848(17) Structure 848(11) Functional Physiology 859(6) Mechanisms of Toxicity 865(7) General Toxicity: Ovary, Uterus, and Vagina as a Unit 865(5) Local Vaginal Toxicity 870(1) Carcinogenesis 871(1) Response to Injury 872(14) General Responses: Overy, Uterus, and Vagina as a Unit 872(6) Local Inflammation of Vagina 878(2) Neoplasia 880(6) Testing for Toxicity 886(3) General Toxicity 886(2) Local Vaginal Toxicity 888(1) Summary 889(6) Suggested Reading 889(6) Embryo and Fetus Ronald D. Hood Colin G. Rousseaux Patricia M. Blakley Introduction 895(1) Overview of Fetal Toxicologic Pathology 895(1) Basic Principles of Developmental Toxicology 895(1) Incidence of Congenital Anomalies 896(1) Normal Morphologic Development 896(5) Fertilization and Blastocyst Formation 897(1) Gastrulation 897(1) Organogenesis 897(3) Histogenesis and Functional Maturation 900(1) Mechanisms of Toxicity 901(5) Critical Phase of Intrauterine Development 901(1) Modifying Factors 902(4) Response to Injury 906(8) Death 906(1) Malformations 907(3) Intrauterine Growth Retardation 910(1) Perinatal Toxicology 911(1) Endocrine Disruption 912(1) Congenital Neoplasia 912(2) How Dose Relates to Manifestation of Abnormal Development 914(1) Selected Malformations 914(13) Central Nervous System 914(6) Craniofacial Structures 920(2) Cardiovascular System 922(1) Respiratory System 923(1) Gastrointestinal System 924(1) Urinary System 924(1) Reproductive System 925(1) Skeletal System 925(2) Developmental Toxicity Testing and Risk Assessment 927(10) Hazard Identification and Dose-Response Analysis 927(5) Dose---Response Evaluation 932(1) Risk Characterization 933(1) Conclusions 933(1) Suggested Reading 933(4) Index 937
Professor Haschek-Hock has served as president of the Society of Toxicologic Pathology and the Society of Toxicologys Comparative and Veterinary Specialty Section, as well as Councilor of the American College of Veterinary Pathologists, board member of the American Board of Toxicology; as Associate Editor for Toxicological Sciences and for Toxicologic Pathology; as Editorial Board member for Fundamental and Applied Toxicology, Veterinary Pathology and Toxicologic Pathology. She has served as a member on the USFDA Veterinary Medicine Advisory Committee for the Center for Veterinary Medicine, the EPAs FIFRA Science Advisory Panel, and National Academy of Sciences Committee. She currently serves on the Board of Directors of the C.L. Davis Foundation for the Advancement of Veterinary and Comparative Pathology. She was awarded the Society of Toxicologic Pathologys Achievement Award in 2007 and the Midwest Regional Chapter Society of Toxicologys Kenneth DuBois Award in 2011. Colin G. Rousseaux, BVSc, Ph.D., DABT, FIATP, is also a Fellow of the Royal College of Pathology (FRCPath) and Fellow of the Academy of Toxicological Sciences (FATS). He is a Professor (Adjunct) in the Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Ottawa, Canada. He has over 35 years of experience in comparative and toxicologic pathology with a research focus on herbal remedies, fetal development and teratology, and environmental pollutants. He has described, investigated, and evaluated numerous toxicologic pathology issues associated with pharmaceuticals, pesticides, and agrochemicals. He has served on the editorial board of Toxicologic Pathology. He is a former President of the STP. Colin served as an Editor for the three editions of the Fundamentals of Toxicologic Pathology and Haschek and Rousseauxs Handbook of Toxicologic Pathology. Matthew A. Wallig, DVM, Ph.D., DACVP, is Professor Emeritus in the Department of Pathobiology, College of Veterinary Medicine, the Department of Food Science and Human Nutrition, as well as the Division of Nutritional Sciences at the University of Illinois. His research has focused on the chemoprotective properties and mechanisms of phytochemicals in the diet, in particular those in cruciferous vegetables, soy, and tomatoes. His current interests have expanded to include defining morphologic parameters for diagnostic quantitative ultrasound in pancreatitis, pancreatic and hepatic neoplasia, metastatic disease, and chronic hepatic diseases such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Matt has served as an Editor for the last two editions of the Fundamentals of Toxicologic Pathology and Haschek and Rousseauxs Handbook of Toxicologic Pathology. Brad Bolon, DVM, MS, Ph.D., DAVCP, DABT, FATS, FIATP, FRCPath, has worked [ sic] as an experimental and toxicologic pathologist in several settings: academia, a contract research organization, pharmaceutical companies (in both biomolecule and traditional small molecule settings), and private consulting. His main professional interests are the pathology of genetically engineered mice (especially embryos, fetuses, and placentas) and toxicologic neuropathology to assess the efficacy and safety of many therapeutic entities (biomolecules, cell and gene therapies, medical devices, and small molecules). He is a former President of the STP and a Member of the American College of Toxicology (ACT), British Society of Toxicological Pathology (BSTP), and European Society of Toxicologic Pathology (ESTP). Brad served as an Editor for the third edition of the Fundamentals of Toxicologic Pathology and an Associate Editor for the third edition of Haschek and Rousseauxs Handbook of Toxicologic Pathology.
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