Emmanuelle Balme, Bernd Baier, Katja Hempel, Susanne Mueller, Sydney Mukaratirwa, Thomas Nolte
{"title":"Microscopic Findings in Seminal Vesicles of Control Rats Mated to Females From Fertility and Early Embryonic Development Studies.","authors":"Emmanuelle Balme, Bernd Baier, Katja Hempel, Susanne Mueller, Sydney Mukaratirwa, Thomas Nolte","doi":"10.1177/01926233251375447","DOIUrl":"https://doi.org/10.1177/01926233251375447","url":null,"abstract":"<p><p>Male reproductive organs are rarely examined microscopically in developmental and reproductive toxicity (DART) studies. Therefore, few background histopathological data exist for breeding animals. Yet, toxicologic pathologists must be able to recognize spontaneous lesions in a particular organ or tissue so that these changes are not incorrectly attributed to the test item. Inflammation of the secondary sex organs is described as a common background finding in laboratory rats and mice. Breeding activity may increase the risk of infection of the male accessory glands. In the present communication, we report microscopic changes in seminal vesicles observed in Control rats mated to Control females from three fertility and early embryonic development (FEED) studies. Acute inflammation, inflammatory cell infiltrate, hypertrophy, and increased apoptosis of the glandular epithelium were frequent findings.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233251375447"},"PeriodicalIF":1.8,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bob Thoolen, Alys Bradley, Nikolas Stathonikos, Paul J van Diest
{"title":"Toxicologic Pathology Forum*: Opinion on the Future of Histopathology Using Whole Slide Images in Toxicologic Pathology of Preclinical Studies and Its Successful Implementation in Compliance With Good Laboratory Practice-Yes, We Are There!","authors":"Bob Thoolen, Alys Bradley, Nikolas Stathonikos, Paul J van Diest","doi":"10.1177/01926233251366270","DOIUrl":"https://doi.org/10.1177/01926233251366270","url":null,"abstract":"<p><p>Digital pathology (DP) for the purpose of primary reads has emerged as a transformative tool in the practice of histopathology and has already proved to be suitable, bringing numerous advantages over traditional light microscopy (LM). This position paper promotes the adoption of DP, particularly whole slide imaging (WSI), within toxicologic pathology, emphasizing its applicability in Good Laboratory Practice (GLP)-compliant nonclinical safety assessments. With established benefits such as efficiency, remote collaboration, data security, and compatibility with artificial intelligence AI-based tools, DP represents a reliable and advanced alternative. This paper offers a counterpoint to recent skepticism expressed in the literature on the readiness of DP including discussion of implementation strategies, technical requirements, and the growing body of validation evidence supporting DP's utility in toxicologic pathology.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233251366270"},"PeriodicalIF":1.8,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stefania-Alexandra Iakab, Heike Antje Marxfeld, Florian M Richter, Alexander Geisel, Yasemin Ucal, Tobias Bausbacher, Christina Henser, Sibylle Gröters, Carsten Hopf
{"title":"Reliable Identification of Alpha2u-Globulin and Lysozyme Accumulation in Rat Kidney by Label-Free MALDI Mass Spectrometry Imaging.","authors":"Stefania-Alexandra Iakab, Heike Antje Marxfeld, Florian M Richter, Alexander Geisel, Yasemin Ucal, Tobias Bausbacher, Christina Henser, Sibylle Gröters, Carsten Hopf","doi":"10.1177/01926233251368855","DOIUrl":"https://doi.org/10.1177/01926233251368855","url":null,"abstract":"<p><p>The molecular identification of alpha2 urinary protein in male rat kidneys is crucial in distinguishing human relevant from rat-specific cases of nephropathy caused by protein accumulation. As protein accumulation in the kidney presents uniformly as hyaline eosinophilic droplets, the identification of the causative protein can be very difficult, especially if suitable antibodies are lacking. We describe the successful identification of two morphologically similar protein accumulations (alpha2u protein and lysozyme) in rat kidneys by the matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MSI). The potential benefits of MSI may extend to other areas of toxicologic pathology, including instances where the protein accumulation must be characterized and the initial steps are unclear or the composition is unknown.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233251368855"},"PeriodicalIF":1.8,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145030506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Daniel B Woodburn, Jeremy J Bearss, Camille M Lake, Natalie L Twilley, Whitney L Do, Joshua R Porter, Jing Qin, Kevin Footer, Sean Bartlinski, Joe Croghan
{"title":"Calculating Veterinary Clinical Pathology Reference Intervals for Research at the Integrated Research Facility, NIAID: A Practical Application of Data Partitioning and Statistical Methodology.","authors":"Daniel B Woodburn, Jeremy J Bearss, Camille M Lake, Natalie L Twilley, Whitney L Do, Joshua R Porter, Jing Qin, Kevin Footer, Sean Bartlinski, Joe Croghan","doi":"10.1177/01926233251352495","DOIUrl":"https://doi.org/10.1177/01926233251352495","url":null,"abstract":"<p><p>The veterinary research community requires statistically robust reference intervals in which to contextualize the results of laboratory tests obtained in research studies. While published reference intervals are available for veterinary clinical practice, they typically do not account for differences in animal husbandry, variations in analytical equipment, and the diverse range of species encountered in a research setting. In addition, existing guidelines for statistical calculation of reference intervals do not address commonly encountered issues with data quality, sample size, research-induced population biases, and other impediments. In this manuscript, we document our pipeline to extract, partition, analyze, and statistically summarize in-house clinical pathology data for developing useful reference intervals to support research at the Integrated Research Facility at Fort Detrick (National Institute of Allergy and Infectious Diseases) and showcase a practical application of statistical methodology that can guide other facilities in their own determination of clinical pathology reference intervals.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233251352495"},"PeriodicalIF":1.8,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rebecca Kohnken, Amanda Wilsey, Brandan Bird, Olivera Antic, Geena Jasiek, C Michael Foley
{"title":"Histopathologic Findings in the Heart Associated With Telemetry Instrumentation in Beagle Dogs.","authors":"Rebecca Kohnken, Amanda Wilsey, Brandan Bird, Olivera Antic, Geena Jasiek, C Michael Foley","doi":"10.1177/01926233251364231","DOIUrl":"10.1177/01926233251364231","url":null,"abstract":"<p><p>Conscious telemetry-instrumented dogs are used during cardiovascular safety assessment in early drug development for the collection of cardiovascular function parameters such as electrocardiography (ECG), heart rate, mean arterial pressure, and cardiac contractility. To refine the use of animals for exploratory toxicology studies, these dogs may be repurposed into these studies following failure of their implanted device. Telemetry instrumentation involves surgical placement of a pressure catheter through the left ventricular apex of the heart. Slight variations in placement and extension of the catheter tip into the ventricular chamber lead to variability in cardiac pathology associated with the instrumentation. Reuse of these animals in toxicologic assessments therefore requires the pathologist to be aware of the spectrum of histologic changes that may occur because of telemetry instrumentation. This report describes cardiac findings in 12 telemetry-instrumented male dogs with implant duration ranging from 7 to 37 months and discusses considerations and recommendations for use of these animals.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233251364231"},"PeriodicalIF":1.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144875379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Toxicologic PathologyPub Date : 2025-08-01Epub Date: 2025-05-31DOI: 10.1177/01926233251341271
N K Tripathi, L Ramaiah, T Arndt, L Cregar, A O Adedeji, D Meyer, J Whalan, A E Schultze
{"title":"Toxicologic Pathology Forum*: Opinion on Qualitative Severity Descriptors to Express Magnitude of Changes in Clinical Pathology Endpoints in Nonclinical Toxicity Studies.","authors":"N K Tripathi, L Ramaiah, T Arndt, L Cregar, A O Adedeji, D Meyer, J Whalan, A E Schultze","doi":"10.1177/01926233251341271","DOIUrl":"10.1177/01926233251341271","url":null,"abstract":"<p><p>Clinical pathology endpoints are routinely assessed in nonclinical toxicity studies and the magnitude of test article-related changes is frequently expressed using quantitative and/or qualitative severity descriptors. Quantitative descriptors (ie, percent or fold change) are easily calculated to express numerical magnitude of a change but may not adequately convey biological relevance. A specific quantitative magnitude may be associated with vastly different levels of pathophysiologic relevance depending on several factors, including the nature of the endpoint, the animal species/strain, and the magnitude and direction of change. Qualitative descriptors (eg, minimal and mild) offer a succinct way to provide additional context to the pathophysiologic relevance but are more challenging to ascribe to a change. The assignment of qualitative descriptors often requires a subjective, comprehensive, and multifaceted approach using various factors in addition to numerical calculation. Because of the subjectivity involved, the qualitative severity descriptor assigned to a specific change may differ among clinical pathology endpoints, species/strain, contributing scientists, and studies/programs. Quantitative and qualitative severity descriptors may provide complementary information and may be used individually or in combination. This opinion piece primarily explains the process and discusses caveats and various factors taken into consideration by clinical pathologists while ascribing qualitative severity descriptors.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"561-570"},"PeriodicalIF":1.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Toxicologic PathologyPub Date : 2025-08-01Epub Date: 2025-05-15DOI: 10.1177/01926233251339116
Giulia Tosi, Elisavet Karamanavi, Zuhal Dincer, Michela Levi
{"title":"Uveodermatologic Syndrome in a Laboratory Beagle Dog: Histological and Immunohistochemical Features.","authors":"Giulia Tosi, Elisavet Karamanavi, Zuhal Dincer, Michela Levi","doi":"10.1177/01926233251339116","DOIUrl":"10.1177/01926233251339116","url":null,"abstract":"<p><p>This brief communication details the clinical, macroscopic, histological, and immunohistochemical features of a spontaneous case of uveodermatologic syndrome (UDS) in a laboratory beagle dog. A bilateral and symmetrical panuveitis, rich in macrophages and T lymphocytes, with distinctive extracellular clumped or phagocytised melanin pigment granules, and Dalen-Fuchs nodules was diagnosed following occurrence of ocular symptoms and subsequent blindness in a female peripubertal 9.5-month-old beagle dog. Although no macroscopic lesions were visible in the skin, microscopic examination revealed a histiocytic and lymphocytic lichenoid dermatitis with pigmentary incontinence. UDS has not been described as a background finding in laboratory beagle dogs before, although it is a well-known immune-mediated disease in certain canine breeds. Knowledge that UDS can occur in laboratory beagle dogs involved in preclinical studies, especially ocular studies, is essential for toxicologic pathologists.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"548-553"},"PeriodicalIF":1.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Toxicologic PathologyPub Date : 2025-08-01Epub Date: 2025-01-19DOI: 10.1177/01926233241311539
Michael Ly, Sandra Diaz-Garcia, Nathaniel Roscoe, Irina Ushach, Zhigang Hong, Monique França, Stephanie Schaffer, Tong-Yuan Yang, Mathieu Marella, Glenn Marsboom, Donna Klein, Tamar R Grossman, Vinicius Carreira, Michael Ollmann
{"title":"Multiplexed siRNA Immunoassay Unveils Spatial and Quantitative Dimensions of siRNA Function, Abundance, and Localization In Vitro and In Vivo.","authors":"Michael Ly, Sandra Diaz-Garcia, Nathaniel Roscoe, Irina Ushach, Zhigang Hong, Monique França, Stephanie Schaffer, Tong-Yuan Yang, Mathieu Marella, Glenn Marsboom, Donna Klein, Tamar R Grossman, Vinicius Carreira, Michael Ollmann","doi":"10.1177/01926233241311539","DOIUrl":"10.1177/01926233241311539","url":null,"abstract":"<p><p>Small interfering RNAs (siRNAs) have been successfully used as therapeutics to silence disease-causing genes when conjugated to ligands or formulated in lipid nanoparticles to target relevant cell types for efficacy while sparing other cells for safety. To support the development of new methods for delivery of siRNA therapeutics, we developed and characterized a panel of antibodies generated against chemically modified nucleotides used in therapeutic siRNA molecules, identifying a monoclonal antibody that detects a broad range of siRNA representing distinct sequences and modification patterns. By integrating this anti-siRNA antibody with additional reagents, we created a multiplex siRNA immunoassay that simultaneously quantifies siRNA uptake, trafficking, and silencing activity. Using immunohistochemistry (IHC), we applied our method on tissues from mice treated with unconjugated, GalNAc-conjugated, or cholesterol-conjugated siRNAs and quantitatively assessed the biodistribution and activity of siRNAs in various organs. In addition, we used high-content imaging (HCI) and applied our multiplex siRNA immunoassay in tissue culture to enable simultaneous quantification of siRNA uptake, activity, and intracellular colocalization with endosome markers. These methods provide a robust platform for testing nucleic acid delivery methods <i>in vitro</i> and <i>in vivo</i>, allowing precise analysis and visualization of the pharmacokinetics and pharmacodynamics of siRNA therapeutics with cellular and subcellular resolution.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"536-547"},"PeriodicalIF":1.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Toxicologic PathologyPub Date : 2025-08-01Epub Date: 2025-06-03DOI: 10.1177/01926233251340622
Gabriele Pohlmeyer-Esch, Charles Halsey, Julie Boisclair, Sripad Ram, Sarah Kirschner-Kitz, Brian Knight, Pierre Moulin, Anna-Lena Frisk
{"title":"Digital Pathology and Artificial Intelligence Applied to Nonclinical Toxicology Pathology-The Current State, Challenges, and Future Directions.","authors":"Gabriele Pohlmeyer-Esch, Charles Halsey, Julie Boisclair, Sripad Ram, Sarah Kirschner-Kitz, Brian Knight, Pierre Moulin, Anna-Lena Frisk","doi":"10.1177/01926233251340622","DOIUrl":"10.1177/01926233251340622","url":null,"abstract":"<p><p>Advancements in digital pathology and artificial intelligence (AI) have enormous transformative potential for nonclinical toxicologic pathology and are already changing the ways in which pathologists work. However, due to the rapid evolution of digital pathology and AI, the toxicologic pathology community would benefit from an update on these advancements, which can be used to aid drug development. Here we identify key articles published on the use of digital pathology and AI in the field and provide current regulatory statuses and guidelines. For digital pathology, we outline the requirements for equipment, validation processes, workflows, and archiving. Challenges to achieve system interoperability and to establish harmonization through Digital Imaging and Communications in Medicine compatibility are also discussed. For AI, we highlight considerations for model development, including the determination of ground truth, problems that may arise due to bias, and how the accuracy and precision of AI algorithms can be assessed. Finally, we discuss the challenges and potential for AI-assisted toxicologic pathology, picturing a future where technology and scientific expertise work hand-in-hand to improve the quality and efficiency of nonclinical drug safety evaluation. This publication is a deliverable of the European Innovative Medicines Initiative 2 Joint Undertaking, \"Bigpicture.\"</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"516-535"},"PeriodicalIF":1.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144209610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Deep Learning Methodology for Quantification of Normal Pancreas Structures.","authors":"Zhiyong Xie, Stephane Thibault, Norimitsu Shirai, Yutian Zhan, Lindsay Tomlinson","doi":"10.1177/01926233251341824","DOIUrl":"10.1177/01926233251341824","url":null,"abstract":"<p><p>Histopathologic evaluation plays a crucial role in assessing morphological tissue alterations in disease models and toxicology studies. Identifying small quantitative shifts in specific substructures of organs can be challenging due to the subjective nature of visual assessment and the pathologist's reliance on categorical measurements rather than continuous ones. The emergence of digital pathology and artificial intelligence (AI) provides the ability to quantify different organ substructures using automated methods. Here, we employed a deep learning method to integrate normal pancreatic substructures into an algorithm. We also included areas of abnormal pancreas in the deep learning model. Once the image analysis pipeline was developed, we tested its effectiveness on a disease model and a toxicity study. The quantitative measurements clearly differentiated between control animals and those in the disease model or treated with a test article. In the toxicity study, we observed a distinct dose-dependent change. This approach could be applied to other organs and different species.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"554-560"},"PeriodicalIF":1.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}