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Pathology and GLPs, Quality Control, and Quality Assurance

1 Introduction Good Laboratory Practice (GLP) standards were authored by the United States Food and Drug Administration (FDA) to ensure sound and repeatable nonclinical safety assessment studies. They set the standard by which studies are planned, conducted, monitored, reported, and archived to assure reproducibility, accuracy, and consistency. Similar guidelines were later developed by the United States Environmental Protection Agency (EPA) and internationally by the Organisation for…

Pathology Peer Review

1 Introduction In vivo regulatory-type animal toxicity studies that include pathology endpoints are generally not hypothesis-driven experiments. Instead, these studies are meant to gather information using multiple, medical diagnostic endpoints, assessed both antemortem (i.e., in life) and postmortem, to discover or characterize the toxicity profile that results from the administration of relatively high doses of a test article to animals. Characterizing the toxicity profile necessitates integration of…

Nomenclature and Diagnostic Resources in Anatomic Toxicologic Pathology

Acknowledgments The authors acknowledge previous authors of this chapter, Drs. Amy Brix and Ron Herbert. This work was supported in part by the NIH, National Institute of Environmental Health Sciences. 1 Introduction In general nonclinical toxicology studies conducted for hazard evaluation and/or safety assessment, toxicologic pathologists document nonneoplastic and neoplastic morphological changes from laboratory animals to identify potential treatment-related effects of a test article (see ;…

Alternative Models in Biomedical Research: In Silico, In Vitro, Ex Vivo, and Nontraditional In Vivo Approaches

1 Introduction In 2007, the U.S. National Research Council (NRC) formally introduced a new paradigm in safety assessment and toxicity testing on behalf of a joint consortium of U.S. federal government agencies ( ; ). This “Tox 21” initiative highlighted both a vision and a strategy for assessing the safety of underevaluated agents. For example, at present, the U.S. Environmental Protection Agency (EPA) Toxic Substances Control…

Genetically Engineered Animal Models in Toxicologic Research

Acknowledgments Some passages in this chapter were taken directly or slightly modified from the predecessor chapter entitled “Genetically Engineered Animals in Product Discovery and Development” as printed in Haschek and Rousseaux's Handbook of Toxicologic Pathology , 3rd edition, by permission of the Publisher. Accordingly, the authors gratefully salute that chapter's authors—Dr. Elizabeth J. Galbreath, Dr. Carl A. Pinkert, and the incomparable Dr. Daniel Morton—for their contributions…

Animal Models in Toxicologic Research: Nonmammalian

Acknowledgments The authors would like to sincerely thank the following for their assistance in obtaining and preparing materials presented in this chapter: John Friel, Cornell University Museum of Vertebrates, Ithaca, New York, USA; Christiana Grim, OSCP/EPA, USA; Shelley Gruntz, EPL, Inc., Sterling, Virginia, USA; Ron Hardman, Duke University, Durham, North Carolina, USA; David Hinton, Duke University, Durham, North Carolina, USA; Michael Kent, Oregon State University, Corvallis,…

Animal Models in Toxicologic Research: Nonhuman Primate

1 Introduction At the time of writing this chapter, the Coronavirus (COVID-19/SARS CoV-2) pandemic of 2020 was in full progress without vaccines or viable treatments available to the public. Meanwhile, multiple research and toxicology studies involving nonhuman primates (NHPs) were already underway in the race to fill this unmet medical need. This situation emphasized use of the NHP as an essential element to the advancement of…

Animal Models in Toxicologic Research: Pig

1 Introduction The choice of animal species in nonclinical research should always be carefully considered and justified. Pigs and minipigs are considered good models for humans because they share many important characteristics. Swine exhibit particularly close resemblance to humans with respect to the anatomy of the skin, cardiovascular system, the majority of the gastrointestinal tract, and urogenital system ( ). In addition, similarities are often found in…

Animal Models in Toxicologic Research: Dog

1 Introduction In order to develop new agrochemicals, industrial chemicals, and pharmaceutical products, regulatory agencies worldwide require preclinical safety evaluation trials in order to determine toxicity and pharmacokinetics. International guidelines typically recommend studies in at least two species, one rodent and one nonrodent. These studies establish target organ toxicity and are used to set acceptable exposure limits of chemicals for subsequent risk assessment and management of…

Animal Models in Toxicologic Research: Rabbit

1 Introduction Throughout modern biomedical research, the rabbit has remained a core laboratory animal species. Studies using rabbits have provided important insights into toxicology, immunology, reproduction, and other fields. Interestingly, despite their common use, many key factors about rabbit biology, physiology, and disease are either poorly documented or difficult to identify in the literature. This chapter will cover some of those lesser-documented topics, as well as recommend…

Animal Models in Toxicologic Research: Rodents

Acknowledgments Noah's Arkive images are provided by courtesy of the Charles Louis Davis and Samuel Wesley Thompson DVM Foundation for the Advancement of Veterinary and Comparative Pathology (hosted at ) and are reproduced under a Creative Commons BY-NC-SA license. 1 Introduction Laboratory rodents—especially the mouse (primarily Mus musculus ), rat ( Rattus norvegicus ), hamster (particularly the Syrian [or golden] variant, Mesocricetus auratus ), Hartley…

Experimental Design and Statistical Analysis for Toxicologic Pathologists

1 Introduction General texts concerning statistics ( ; ; ; ; ; ; ; ; ) are available; however, this chapter has been written as a practical guide to common statistical problems encountered when using differing research strategies in toxicologic pathology, and to provide the methodologies available to solve them. First, core issues in mathematical decision-making are discussed, followed by details concerning some of the principles…

Toxicogenomics: A Primer for Toxicologic Pathologists

Acknowledgments We would like to acknowledge the work of the authors in the previous edition of this chapter “The Application of Toxicogenomics to the interpretation of Toxicologic Pathology” by William R. Foster, Donald G. Robertson, and Bruce D. Car in 3rd ed. W. M. Haschek, C. G. Rousseaux and M. A. Wallig, eds. (2013) Academic Press. We would also like to express our appreciation for the…

Biomarkers: Discovery, Qualification, and Application

1 Introduction Biomarker discovery has rapidly progressed from a classical empirical approach to a high-priority, technology-supported research activity. According to the Food and Drug Administration's (FDA) Biomarkers, EndpointS and other Tools glossary ( ), a biomarker is a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions. Within this characterization,…

In Vivo Small Animal Imaging: A Comparison to Gross and Histopathologic Observations in Animal Models

Acknowledgments The authors are grateful for figure contributions for this chapter. We would like to thank Dr. Robert Maronpot and Dr. Robert Sills of NIEHS, Dr. Alan Johnson of the Duke University Center for In vivo Microscopy, Dr. Marty Pomper, Dr. Hal Dietz, and Dr. Jennifer Habashi of Johns Hopkins University, School of Medicine. From Baylor University, we would like to thanks Dr. Roger Price and Dr.…

Digital Pathology and Tissue Image Analysis

1 Introduction The age of digitalization has arrived in light microscopy. While the current practice of toxicologic pathology remains largely based on the light microscopic evaluation of stained tissue sections, it is no longer limited to it. Thanks to the availability of whole-slide imaging (WSI), histopathologic evaluation can now be accomplished via a computer screen ( ; ; ). Substituting a computer monitor for a traditional…

Special Techniques in Toxicologic Pathology

1 Introduction Advances in cell and molecular biology have engendered a wide range of techniques to investigate mechanisms of disease or toxicity that can be used to augment traditional morphologic tools used in toxicity testing. In the team-oriented scientific world of today, pathologists should be familiar with the technical basis and utility of these varied techniques, some of which are slide based and others that are…

Clinical Pathology in Nonclinical Toxicity Testing

1 Introduction 1.1 Value of Clinical Pathology Testing Clinical pathology testing is a key component of nonclinical safety studies that evaluate the potential toxicity of test articles including therapeutic agents (new chemical entities and biologics), pesticides, and industrial chemicals to which humans and/or animals may be exposed. Clinical pathology data are used to detect treatment-related effects; monitor the onset, temporal progression, and reversibility of these effects;…

Basic Approaches in Anatomic Toxicologic Pathology

1 Introduction Traditionally trained veterinary and medical pathologists often encounter unanticipated challenges during their transition from diagnostic pathology to the regulatory-driven environment of toxicologic pathology. During their initial years of training and diagnostic effort, pathologists typically serve both clinical and public health functions. Pathologists in diagnostic, hospital, or private laboratory settings serve the clinical community to support therapeutic approaches and disease prognoses. These laboratories are generally…

Carcinogenesis: Mechanisms and Evaluation

Acknowledgments The authors would like to thank David Sabio and Experimental Pathology Laboratories for assistance with figure generation. We foresee cancer research as an increasingly logical science, in which complexities are manifestations of a small set of underlying organizing principles. Hanahan and Weinberg, 2011 1 Introduction Cancer is a major cause of morbidity and mortality throughout the world, caused by the accumulation of genetic and epigenetic…