Yohei Inai, Takeshi Izawa, Tomomi Kamei, Sho Fujiwara, Miyuu Tanaka, Jyoji Yamate, Mitsuru Kuwamura
Iron overload has been recognized as a risk factor for liver disease; however, little is known about its pathological role in the modification of liver injury. The purpose of this study is to investigate the influence of iron overload on liver injury induced by two hepatotoxicants with different pathogenesis in rats. Rats were fed a control (Cont), 0.8% high-iron (0.8% Fe), or 1% high-iron diet (1% Fe) for 4 weeks and were then administered with saline, thioacetamide (TAA), or carbon tetrachloride (CCl4 ). Hepatic and systemic iron overload were seen in the 0...
March 25, 2024: Toxicologic Pathology
Debabrata Mahapatra, Robert Maronpot
Animals models are essential to understand the complex pathobiology of human diseases. George Box's aphorism based on statistics "All models are wrong, but some are useful" certainly applies to animal models of disease. In this session, the translational relevance of various animal models applicable to human liver disease was explored starting with a historic overview of the rodent cancer bioassay with emphasis on hepatocarcinogenesis from early work at the National Cancer Institute, refinement by the National Toxicology Program and contemporary efforts to identify potential mechanisms and their relevance to human cancer risk...
March 18, 2024: Toxicologic Pathology
Catherine Si, Kourtney Nickerson, Taylor Simmons, Parker Denton, M Russell Nichols, Robert C Dysko, Mark Hoenerhoff, Rinosh Mani, Cheryl Woods, Kenneth S Henderson, Zachary T Freeman
NOD.Cg- Prkdcscid Il2rgtm1Wjl /SzJ (NSG) mice, lacking many components of a mature immune system, are at increased risk of disease. General understanding of potential pathogens of these mice is limited. We describe a high mortality disease outbreak caused by an opportunistic bacterial infection in NSG mice. Affected animals exhibited perianal fecal staining, dehydration, and wasting. Histopathologic lesions included a primary necrotizing enterocolitis, with inflammatory and necrotizing lesions also occurring in the liver, kidneys, heart, and brain of some mice...
March 13, 2024: Toxicologic Pathology
Lars Mecklenburg, C Marc Luetjens, Annette Romeike, Rohit Garg, Pranab Samanta, Amogh Mohanty, Tijo Thomas, Gerhard Weinbauer
The indirect assessment of adverse effects on fertility in cynomolgus monkeys requires that tissue sections of the testis be microscopically evaluated with awareness of the stage of spermatogenesis that a particular cross-section of a seminiferous tubule is in. This difficult and subjective task could very much benefit from automation. Using digital whole slide images (WSIs) from tissue sections of testis, we have developed a deep learning model that can annotate the stage of each tubule with high sensitivity, precision, and accuracy...
March 11, 2024: Toxicologic Pathology
(no author information available yet)
No abstract text is available yet for this article.
March 7, 2024: Toxicologic Pathology
Charlotte Keenan, Muthafar Al-Haddawi, Jean-Guy Bienvenu, Alys Elizabeth Bradley, Paul Brown, Hepei Chen, Karyn Colman, Michael Elwell, Nicholas Gatto, Dawn Goodman, Binod Jacob, Lynda Lanning, LuAnn McKinney, Erin Muhlbradt, Rick Perry, Alessandro Piaia, Daniel Potenta, Karen S Regan, Benjamin Sefing, Michael Thibodeau, Erin Tibbs-Slone, Jochen Woicke, Craig M Zwickl
The Tumor Combination Guide was created at the request of the U. S. Food and Drug Administration (FDA) by a Working Group of biopharmaceutical experts from international societies of toxicologic pathology, the Food and Drug Administration (FDA), and members of the Standard for Exchange of Nonclinical Data (SEND) initiative, to assist pharmacology/toxicology reviewers and biostatisticians in statistical analysis of nonclinical tumor data. The guide will also be useful to study and peer review pathologists in interpreting the tumor data...
March 6, 2024: Toxicologic Pathology
Erin M Quist, Ronnie Chamanza, Amanda J Martinot, Allison Boone, Gregory A Krane, Martha E Hensel, Shawn V Lennix
The 2023 annual Division of Translational Toxicology (DTT) Satellite Symposium, entitled "Pathology Potpourri," was held in Summerlin, Nevada, at the Society of Toxicologic Pathology's 41st annual meeting. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers' talks along with select images that were used by the audience for voting and discussion. Various lesions and topics covered during the symposium included induced and spontaneous neoplastic and nonneoplastic lesions in the mouse liver, infectious and proliferative lesions in nonhuman primates, interesting presentations of mononuclear cell infiltrates in various animal models and a complex oral tumor in a rat...
March 6, 2024: Toxicologic Pathology
Eric Tien, Branka Grubor, Melissa Kirkland, Su Jing Chan, Nick van der Munnik, Wenlong Xu, Kate Henry, Stefan Hamann, Cong Wei, Wan-Hung Lee, Davide Gianni, Ashton Brennecke, Kalyani Nambiar, Jeron Chen, Bin Liu, Shen Shen, Claudine Tremblay, Edward D Plowey, Patrick Trapa, James Fikes, Junghae Suh, Dale Morris
Recombinant adeno-associated virus (AAV)-mediated degeneration of sensory neurons in the dorsal root ganglia (DRG) and trigeminal ganglia (TG) has been observed in non-human primates (NHPs) following intravenous (IV) and intrathecal (IT) delivery. Administration of recombinant AAV encoding a human protein transgene via a single intra-cisterna magna (ICM) injection in New Zealand white rabbits resulted in histopathology changes very similar to NHPs: mononuclear cell infiltration, degeneration/necrosis of sensory neurons, and nerve fiber degeneration of sensory tracts in the spinal cord and of multiple nerves...
February 22, 2024: Toxicologic Pathology
Dinesh S Bangari, Lisa G Lanigan, Sarah D Cramer, Jessica L Grieves, René Meisner, Arlin B Rogers, Elizabeth J Galbreath, Brad Bolon
Biotherapeutic modalities such as cell therapies, gene therapies, nucleic acids, and proteins are increasingly investigated as disease-modifying treatments for severe and life-threatening neurodegenerative disorders. Such diverse bio-derived test articles are fraught with unique and often unpredictable biological consequences, while guidance regarding nonclinical experimental design, neuropathology evaluation, and interpretation is often limited. This paper summarizes key messages offered during a half-day continuing education course on toxicologic neuropathology of neuro-targeted biotherapeutics...
February 21, 2024: Toxicologic Pathology
Adeyemi O Adedeji, Fiona Zhong, Janice Corpuz, Fangyao Hu, Xiaofeng Zhao, Dewakar Sangaraju, Catherine F Ruff, Noel Dybdal
In nonclinical toxicology studies, lab animals are fasted typically overnight, to reduce variability in some clinical pathology parameters. However, fasting adds undue stress, and this is particularly concerning in rodents given their fast metabolic rates. Furthermore, as rodents are nocturnal animals, an overnight fasting may cause a protracted negative metabolic state even when the fasting has technically ended, given their minimal activity and food consumption during the day. Therefore, to evaluate the impacts of different fasting durations (±DietGel supplementation) on rats' welfare, we assessed the traditional and ancillary clinical pathology parameters in Sprague-Dawley rats, along with body weight, organ weight, and histopathology...
February 20, 2024: Toxicologic Pathology
Armelle Grevot, Julie Boisclair, Magali Guffroy, Peter Hall, Gabriele Pohlmeyer-Esch, Matt Jacobsen, Ute Bach, Anna Lena Frisk, Noel Dybdal, Xavier Palazzi
In the last decade, numerous initiatives have emerged worldwide to reduce the use of animals in drug development, including more recently the introduction of Virtual Control Groups (VCGs) concept for nonclinical toxicity studies. Although replacement of concurrent controls (CCs) by virtual controls (VCs) represents an exciting opportunity, there are associated challenges that will be discussed in this paper with a more specific focus on anatomic pathology. Coordinated efforts will be needed from toxicologists, clinical and anatomic pathologists, and regulators to support approaches that will facilitate a staggered implementation of VCGs in nonclinical toxicity studies...
January 31, 2024: Toxicologic Pathology
Arun R Pandiri, Scott S Auerbach, Jim L Stevens, Eric A G Blomme
Toxicogenomic technologies query the genome, transcriptome, proteome, and the epigenome in a variety of toxicological conditions. Due to practical considerations related to the dynamic range of the assays, sensitivity, cost, and technological limitations, transcriptomic approaches are predominantly used in toxicogenomics. Toxicogenomics is being used to understand the mechanisms of toxicity and carcinogenicity, evaluate the translational relevance of toxicological responses from in vivo and in vitro models, and identify predictive biomarkers of disease and exposure...
January 30, 2024: Toxicologic Pathology
Brad Bolon
Existing nervous system sampling and processing "best practices" for nonclinical general toxicity studies (GTS) were designed to assess test articles with unknown, no known, or well-known neurotoxic potential. Similar practices are applicable to juvenile animal studies (JAS). In GTS and JAS, the recommended baseline sampling for all species includes brain (7 sections), spinal cord (cervical and lumbar divisions [cross and longitudinal sections for each]), and 1 nerve (sciatic or tibial [cross and longitudinal sections]) in hematoxylin and eosin-stained sections...
January 30, 2024: Toxicologic Pathology
Mei-Lan Chu, Xing-Yue M Ge, Jeffrey Eastham, Trung Nguyen, Reina N Fuji, Ruth Sullivan, Daniel Ruderman
Digital pathology workflows in toxicologic pathology rely on whole slide images (WSIs) from histopathology slides. Inconsistent color reproduction by WSI scanners of different models and from different manufacturers can result in different color representations and inter-scanner color variation in the WSIs. Although pathologists can accommodate a range of color variation during their evaluation of WSIs, color variability can degrade the performance of computational applications in digital pathology. In particular, color variability can compromise the generalization of artificial intelligence applications to large volumes of data from diverse sources...
January 30, 2024: Toxicologic Pathology
Amit Kumar, Marie Bockenstedt, Victoria Laast, Alok Sharma
Data collected from approximately 1800 male and 1800 female Sprague-Dawley (SD) rats used in 104-week carcinogenicity studies were archived in a historical control database at Labcorp Early Development, Inc, and the neoplastic microscopic observation data from these rats were retrospectively evaluated. Historical control data can provide useful information on the range and incidence of spontaneously occurring background neoplasms in the species and strain of the test animal used in different types of toxicity studies, including studies of differing lengths, delivery of test article, and test animal...
January 28, 2024: Toxicologic Pathology
Allison C Boone, Shakirat A Adetunji, Rebecca Kohnken, Kenji Koyama
This case study session of the hepatobiliary system was held during the 42nd Annual Society of Toxicologic Pathology Symposium in Summerlin, Nevada. The case studies highlighed potential hepatic and biliary toxicity liabilities. This article comprises several of the case studies that were presented during the session which included copper-associated hepatitis in a dog, sinusoidal obstruction syndrome in non-human primates, hepatic cytoplasmic alteration in mice and rats, and Kupffer cell hyperplasia/granulomatous inflammation in rats...
January 28, 2024: Toxicologic Pathology
(no author information available yet)
No abstract text is available yet for this article.
January 21, 2024: Toxicologic Pathology
Richard T Miller
Risk assessment of hepatobiliary toxicities represents one of the greatest challenges and, more often than not, one of the most rewarding activities in which toxicologic pathologists can partake, and often times lead. This is in part because each liver toxicity picture is a bit different, informed by a broad range and diversity of relevant data, and also in part because the heavily relied upon animal models are imperfect regarding predictivity of hepatic effects in humans. Following identification and characterization of a hepatotoxicity hazard, typically in nonclinical toxicology studies, a holistic and integrated assessment of liver-relevant endpoints is conducted that typically incorporates ADME (absorption, distribution, metabolism, and excretion) information (ideally, including extensive transporter data, exposure margins, and possibly concentration of parent/metabolite at region of injury), target expression/function, in silico prediction data, in vitro hepatocyte data, liver/circulating biomarkers, and importantly, species specificity of any of these data...
January 20, 2024: Toxicologic Pathology
Giulia Tosi, Jennifer Rachael Barnes
This brief communication describes a rare spontaneous background lesion in the lower urinary tract of two male laboratory beagles. Proliferative lesions comprising a constellation of histological features consistent with polypoid cystitis were observed in the bladder of two adolescent dogs from a routine preclinical toxicology study. Both animals were clinically asymptomatic and had only minor alterations in urinalysis parameters. While chronic polypoid cystitis is well-recognized in adult pet dogs, this is the first reported case in purpose-bred laboratory beagles...
January 9, 2024: Toxicologic Pathology
Lisa D Berman-Booty, Stephanie K Klein, Curt Mazur, Joseph Schroeder, Sven Korte, Florian T Ludwig, Annette Romeike, Brad Bolon, Jessica L Grieves
Direct delivery of therapeutics to the central nervous system (CNS) greatly expands opportunities to treat neurological diseases but is technically challenging. This opinion outlines principal technical aspects of direct CNS delivery via intracerebroventricular (ICV) or intrathecal (IT) injection to common nonclinical test species (rodents, dogs, and nonhuman primates) and describes procedure-related clinical and histopathological effects that confound interpretation of test article-related effects. Direct dosing is by ICV injection in mice due to their small body size, while other species are dosed IT in the lumbar cistern...
January 5, 2024: Toxicologic Pathology
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