Non-pathologists, such as toxicologists and study personnel, can find it difficult to understand the data they receive from pathologists. Toxicological pathologists write long, detailed and highly technical reports. Study personnel are under daily pressure to decide whether lesions described in pathology reports are treatment-related and thus important to the pharmaceutical company or whether the lesions are background changes and thus of little significance.Written by experienced toxicological pathologists, Pathology for Toxicologists: Principles and Practices of Laboratory Animal Pathology for Study Personnel serves to bridge the gap in the understanding of pathology data, enabling non-pathologists to more easily comprehend pathology reports, better integrate pathology data into final study reports and ask pathologists relevant questions about the test compound.This succinct, fully referenced, full colour book is suitable for toxicologists at all stages of their training or career who want to know more about the pathology encountered in laboratory animals used in safety studies. Key features include important chapters on spontaneous and target organ lesions in rats, mice, non-human primates, mini pigs, rabbits and beagle dogs as well as information on general pathology, macroscopic target organ lesions, ancillary pathology techniques, haematology, biochemistry and adversity.Pathology for Toxicologists: Principles and Practices of Laboratory Animal Pathology for Study Personnel includes:* Colour diagrams explaining how lesions are caused by either external compounds or spontaneously* The anatomic variations and background lesions of laboratory animals* Advice on sampling tissues, necropsy, ancillary pathology techniques and recording data* A chapter on the haematology and biochemistry of laboratory animals* Full colour photographs of common macroscopic lesions encountered in laboratory animals* A comprehensive glossary

List of Contributors xiPreface xiii1 An Introduction to Pathology Techniques 1Elizabeth McInnes1.1 Animal Considerations 21.2 Necropsy 21.3 Lung Inflation with Fixative 51.4 Fixation 51.5 Making Glass Slides 61.5.1 Trimming 61.5.2 Tissue Processing 91.5.3 Embedding 91.5.4 Microtoming 91.5.5 Staining 91.5.6 Quality Control 111.6 Special Histochemical Stains 121.7 Decalcification 131.8 Immunohistochemistry 131.9 Tissue Crossreactivity Studies 151.10 Electron Microscopy 151.11 In Situ Hybridisation 161.12 Laser Capture Microscopy 161.13 Confocal Microscopy 161.14 Image Analysis 171.15 Digital Imaging 171.16 Spermatocyte Analysis 171.17 Good Laboratory Practice 171.18 Inhalation Studies 181.19 Continuous?]Infusion Studies 181.20 Carcinogenicity 191.21 Biologicals 191.22 The Pathology Report 201.23 Conclusion 20References 202 Recording Pathology Data 23Cheryl L. Scudamore2.1 What is a Pathology Finding? 242.2 Standardisation of Pathology Findings 242.2.1 Semiquantitative Analysis 242.2.2 Nomenclature/Controlled Terminology 262.2.3 Ontological Approach 282.3 'Inconsistencies' in Pathology Recording 282.3.1 Diagnostic Drift 282.3.2 Thresholds 282.3.3 Lumping versus Splitting 292.4 Blind Review 302.5 Historical Control Data: Pros and Cons 302.6 The Use of Peer Review in Pathology 32References 323 General Pathology and the Terminology of Basic Pathology 35Elizabeth McInnes3.1 Cellular Responses to Insults 353.2 Inflammation 413.3 Circulatory Disturbances 463.4 Disorders of Tissue Growth 523.5 Tissue Repair and Healing 533.6 Neoplasia 543.7 Immune System 55References 574 Common Spontaneous and Background Lesions in Laboratory Animals 59Elizabeth McInnes4.1 Rats 624.2 Mice 634.3 Dogs 664.4 Minipigs 664.5 Non?]Human Primates 674.6 Rabbits 674.7 Experimental Procedures 674.8 Causes of Death in Rats and Mice 674.9 Conclusion 68References 695 Target Organ Pathology 72Elizabeth McInnes5.1 Skin 725.2 Eye 765.3 Gastrointestinal Tract 785.4 Liver 835.5 Respiratory System 855.6 Urinary System 895.7 Lymphoreticular System 945.8 Musculoskeletal System 955.9 Cardiovascular System 975.10 Endocrine System 995.11 Reproductive System 1025.12 Central and Peripheral Nervous System 1045.13 Ear 106References 1066 Clinical Pathology 112Barbara von Beust6.1 Clinical Pathology in Study Phases and Good Laboratory Practice 1126.1.1 Preanalytic Phase: Study Plan 1136.1.2 Analytic Phase: Data Generation 1146.1.3 Postanalytic Phase: Data Interpretation and Reporting 1146.1.4 Good Laboratory Practice 1146.2 What is Measured in Clinical Pathology? 1156.2.1 Interference by Haemolysis, Lipaemia and Icterus 1166.3 Haematology 1176.3.1 Manual and Automated Techniques in Haematology 1186.3.2 Haematocrit and Red Blood Cell Mass 1196.3.3 Blood Cells 1206.3.3.1 Red Blood Cells 1206.3.3.2 White Blood Cells 1226.3.3.3 Platelets 1246.3.4 The Standard Haematology Profile 1246.3.5 Bone Marrow 1256.4 Coagulation 1256.4.1 Standard Coagulation Profile 1266.4.2 Prothrombin Time 1276.4.3 Activated Partial Thromboplastin Time 1276.4.4 Fibrinogen 1276.5 Clinical Chemistry 1276.5.1 Metabolites 1276.5.1.1 Carbohydrate Metabolism 1276.5.1.2 Protein Metabolism 1286.5.1.3 Lipid Metabolism 1286.5.1.4 Metabolism of Haemoglobin 1296.5.2 Enzymes 1296.5.3 Electrolytes and Minerals 1296.5.3.1 Potassium 1306.5.3.2 Sodium and Chloride 1306.5.3.3 Calcium and Phosphorus 1306.5.4 Standard Chemistry Profiles 1306.5.4.1 Assessment of Liver Function 1306.5.4.2 Assessment of Kidney Function 1306.5.4.3 Assessment of Gastrointestinal Function 1316.6 Urinalysis 1316.7 Acute?]Phase Proteins 1316.8 The Biomarker Concept 1326.9 Reference Intervals 1336.10 Instrumentation, Validation and Quality Control 1336.11 Data Analysis and Interpretation 1346.12 Reporting 1356.13 Food Consumption and Body Weight (Gain) 1366.14 Organ Weights 1366.15 Examples of Typical Clinical Pathology Profile Changes in Toxicologic Clinical Pathology 1366.15.1 Reduced Red Blood Cell Mass due to Chronic Disease 1386.15.2 Stress Response 1396.15.3 Reduced Red Blood Cell Mass due to Excessive Blood Sampling 1396.15.4 Common Artefacts 1396.15.4.1 Coagulation 1406.15.4.2 Haemolysis and Increased Potassium Concentration 1406.15.4.3 Blood in Urine 1406.16 Microsampling 1406.17 Conclusion 141Acknowledgments 141References 1417 Adversity: A Pathologist's Perspective 145Bhanu Singh7.1 LOAEL, NOEL and NOAEL: Definition 1467.2 Adversity 1477.3 Determining Adversity using Pathology Findings: Factors to Consider 1497.3.1 Severity 1497.3.2 Functional Effect 1507.3.3 Primary versus Secondary Effects 1517.3.4 Physiological Adaptability 1527.3.5 Reversibility of the Lesion 1527.3.6 Pharmacological Effect 1537.4 Communicating NOAEL in Toxicity Studies 1537.5 Conclusion 154References 1548 Limitations of Pathology and Animal Models 157Natasha Neef8.1 Limitations of In Vivo Animal Models 1578.1.1 Traditional Laboratory Species Used as General Toxicology Models 1578.1.2 The Test Article May Not have Sufficient Pharmacological Activity in Routine Toxicology Species 1588.1.3 The Model May Not Identify Hazards Related to Causation or Exacerbation of Pathology that is Unique to Humans or Undetectable in Animals 1598.1.4 The Model May Not Identify Hazards with Low Incidence/Low Severity 1598.1.5 Potential for Misinterpretation of Reversibility/Recovery for Low?]Incidence Findings 1608.1.6 Potential for Over?] or Underestimation of the Relationship to Test Article of Findings that have High Spontaneous Incidence in Laboratory Species, but are Relatively Rare in Humans 1608.1.7 Exclusive Use of Young, Healthy Animals Kept in Ideal Conditions Gives Limited Predictivity for Aged/Diseased Human Populations 1618.2 Efficacy/Disease Models as Toxicology Models 1628.3 Limitations of Efficacy/Disease Models as Toxicology Models 1648.3.1 Lack of Validation as Safety/Toxicology Models 1648.3.2 Disease Models Rarely Have All the Elements of the Equivalent Human Disease 1658.3.3 Limited Sensitivity Produced by Increased Interanimal Variability amongst Diseased Animals and/or Low Animal Numbers 1658.3.4 Lack of Historical Data 1668.3.5 Risk Associated with Nonregulated Laboratory Conditions 1668.4 Limitations of Pathology within In Vivo Toxicology Models 1678.4.1 Anatomic Pathology Evaluation Will Not Identify Hazards with No Morphological Correlates 1678.4.2 Limitations of Pathology when Evaluating Moribund Animals or Animals Found Dead on Study 1688.4.3 Limitations of Anatomic and/or Clinical Pathology End Points within other Types of In Vivo Preclinical Safety Study 1688.4.4 Limitations of Histopathology Related to Sampling Error 1698.4.5 Limitations of Quantitative Anatomic Pathology 1708.4.6 Limitations of Pathology Related to Subjectivity and Pathologist Error 1738.4.7 Anatomic Pathology Error/Missed Findings 1738.4.8 Subjectivity and Pathologist Variability 1758.5 Managing Risk Associated with Subjectivity and the Potential for Pathologist Error 1768.5.1 Choice of Study Pathologist 1768.5.2 Peer Review 1768.5.3 Review of the Anatomic Pathology Data 1778.5.4 Review of Anatomic Pathology Data Interpretation 177References 179Glossary 184Index 187