Adeyemi O Adedeji, Tony Pourmohamad, Niraj Tripathi, Shelly Zhong, Kenna R Degner, Fiona Zhong, Dewakar Sangaraju, Kevin Williams, Noel Dybdal
During toxicology studies, fasting animals prior to clinical pathology blood collection is believed to reduce variability in some clinical chemistry analytes. However, fasting adds stress to animals that are already stressed from the administration of potentially toxic doses of the test article. The purpose of this study was to assess the impacts of different fasting durations on cynomolgus monkeys' welfare during toxicology studies. To this end, we assessed the cynomolgus monkeys traditional and ancillary clinical pathology endpoints at different fasting times...
September 13, 2023: Toxicologic Pathology
Alex A Gutsol, Taben M Hale, Jean-Francois Thibodeau, Chet E Holterman, Rania Nasrallah, Jose W N Correa, Rhian M Touyz, Chris R J Kennedy, Dylan Burger, Richard L Hébert, Kevin D Burns
Assessment of hypertensive tubulopathy for more than fifty animal models of hypertension in experimental pathology employs criteria that do not correspond to lesional descriptors for tubular lesions in clinical pathology. We provide a critical appraisal of experimental hypertension with the same approach used to estimate hypertensive renal tubulopathy in humans. Four models with different pathogenesis of hypertension were analyzed-chronic angiotensin (Ang) II-infused and renin-overexpressing (TTRhRen) mice, spontaneously hypertensive (SHR), and Goldblatt two-kidney one-clip (2K1C) rats...
August 26, 2023: Toxicologic Pathology
Brad Bolon
No abstract text is available yet for this article.
August 14, 2023: Toxicologic Pathology
Tracey L Papenfuss, Lauren Himmel, C Frieke Kuper, Sunish Mohanan, Johannes Harleman, Susan A Elmore
The evaluation of changes in the immune system serves to determine the efficacy and potential immunotoxicologic effects of new products under development. Toxicologic pathologists play critical roles in identifying immune system changes that drive the immunosafety determination. Standard pathology evaluations of therapies and chemicals remain similar; however, biopharmaceutical therapies have moved from simply affecting the immune system to being specifically developed to modify the immune system, which can impact interpretation...
August 14, 2023: Toxicologic Pathology
Bindu M Bennet, Ingrid D Pardo, Basel T Assaf, Elizabeth Buza, Sarah Cramer, LaTasha K Crawford, Jeffery A Engelhardt, Branka Grubor, James P Morrison, Tanasa S Osborne, Alok K Sharma, Brad Bolon
Certain biopharmaceutical products consistently affect dorsal root ganglia, trigeminal ganglia, and/or autonomic ganglia. Product classes targeting ganglia include antineoplastic chemotherapeutics, adeno-associated virus-based gene therapies, antisense oligonucleotides, and anti-nerve growth factor agents. This article outlines "points to consider" for sample collection, processing, evaluation, interpretation, and reporting of ganglion findings; these points are consistent with published best practices for peripheral nervous system evaluation in nonclinical toxicity studies...
July 25, 2023: Toxicologic Pathology
Josep M Monné Rodríguez, Anna-Lena Frisk, Robert Kreutzer, Thomas Lemarchand, Stephane Lezmi, Chandrassegar Saravanan, Birgit Stierstorfer, Céline Thuilliez, Enrico Vezzali, Grazyna Wieczorek, Seong-Wook Yun, Dirk Schaudien
In situ hybridization (ISH) is used for the localization of specific nucleic acid sequences in cells or tissues by complementary binding of a nucleotide probe to a specific target nucleic acid sequence. In the last years, the specificity and sensitivity of ISH assays were improved by innovative techniques like synthetic nucleic acids and tandem oligonucleotide probes combined with signal amplification methods like branched DNA, hybridization chain reaction and tyramide signal amplification. These improvements increased the application spectrum for ISH on formalin-fixed paraffin-embedded tissues...
July 14, 2023: Toxicologic Pathology
Diethilde Theil, Jens Kuhle, Dominique Brees, Elaine Tritto, François Pognan, Wilfried Frieauff, Kelley Penraat, Emily Meseck, Reginald Valdez, Andreas Hartmann
Branaplam is a splicing modulator previously under development as a therapeutic agent for Spinal Muscular Atrophy Type 1 and Huntington's disease. Branaplam increased the levels of survival motor neuron protein in preclinical studies and was well tolerated in early clinical studies; however, peripheral neurotoxicity was observed in a preclinical safety study in juvenile dogs. The aim of this study was to determine whether serum neurofilament light chain (NfL) concentrations in dogs could serve as a monitoring biomarker for branaplam-induced peripheral neurotoxicity...
July 12, 2023: Toxicologic Pathology
Allan D Rasmussen, Nathalie Truchot, Agnete Dyssegaard, Pierluigi Fant
In this study, we assessed the toxicity and toxicokinetics of racemic vigabatrin and its S- and R-enantiomers (vigabatrin consists of 50:50% of the two enantiomers) by administering doses of the three test articles to male Long Evans rats via oral gavage. The animals were housed under high-intensity light conditions and the study consisted of an escalating dose phase and a 21-day fixed-dose phase. Systemic toxicity of vigabatrin appears to be due to the Vig-S-enantiomer only, as increasing doses of Vig-S or Vig-RS caused body weight loss, decreased food consumption, and affected activity...
July 4, 2023: Toxicologic Pathology
Xavier Palazzi, Erio Barale-Thomas, Bhupinder Bawa, Jonathan Carter, Kyathanahalli Janardhan, Heike Marxfeld, Abraham Nyska, Chandrassegar Saravanan, Dirk Schaudien, Vanessa L Schumacher, Robert H Spaet, Simone Tangermann, Oliver C Turner, Enrico Vezzali
The European Society of Toxicologic Pathology (ESTP) initiated a survey through its Pathology 2.0 workstream in partnership with sister professional societies in Europe and North America to generate a snapshot of artificial intelligence (AI) usage in the field of toxicologic pathology. In addition to demographic information, some general questions explored AI relative to (1) the current status of adoption across organizations; (2) technical and methodological aspects; (3) perceived business value and finally; and (4) roadblocks and perspectives...
June 2023: Toxicologic Pathology
(no author information available yet)
No abstract text is available yet for this article.
May 9, 2023: Toxicologic Pathology
Heather Kowalski, Debie Hoivik, Michael Rabinowitz
Vadadustat is an investigational oral hypoxia-inducible factor (HIF) prolyl-4-hydroxylase inhibitor to treat anemia due to chronic kidney disease (CKD). Some studies suggest that HIF activation promotes tumorigenesis by activating angiogenesis downstream of vascular endothelial growth factor, while other studies suggest that elevated HIF activity may produce an antitumor phenotype. To evaluate the potential carcinogenicity of vadadustat in mice and rats, we dosed CByB6F1/Tg.rasH2 hemizygous (transgenic) mice orally by gavage with 5 to 50 mg/kg/d of vadadustat for 6 months and dosed Sprague-Dawley rats orally by gavage with 2 to 20 mg/kg/d for approximately 85 weeks...
May 9, 2023: Toxicologic Pathology
Takeshi Izawa, Gregory S Travlos, Ricardo A Cortes, Natasha P Clayton, Robert C Sills, Arun R Pandiri
Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease and its influence on drug-induced liver injury (DILI) is not fully understood. We investigated whether NAFLD can influence acetaminophen (APAP [N-acetyl-p-aminophenol])-induced hepatotoxicity in a diet-induced obese (DIO) mouse model of NAFLD. The male C57BL/6NTac DIO mice, fed a high-fat diet for more than 12 weeks, developed obesity, hyperinsulinemia, impaired glucose tolerance, and hepatomegaly with hepatic steatosis, similar to human NAFLD...
May 9, 2023: Toxicologic Pathology
Renee R Hukkanen, Michelle Trapani, Tana Derringer, Victoria Laast, Zbigniew W Wojcinski, Rosa Anna Manno, Matthias Rinke, Eric van Esch, Alys E Bradley, Patrizia Cristofori, Roger Alison, Barb Munch
Toxicologic/veterinary pathologists are working remotely from Good Laboratory Practice (GLP) test facilities (TFs) in increasing numbers, most commonly in home-office settings. A study pathologist (SP) generating data on GLP-compliant nonclinical studies must be keenly aware of applicable national GLP regulations and comply with TF and protocol requirements. This Toxicological Pathology Forum Opinion Piece will summarize primary areas of emphasis for the SP generating GLP data using glass slides. Peer review and digital review of whole slide images are out of scope for this opinion piece...
April 26, 2023: Toxicologic Pathology
Kerstin Wäse, Thomas Bartels, Uwe Schwahn, Mostafa Kabiri
Fibroblast growth factor 21 (FGF21) and FGF15/FGF19 belong to the same subgroup of FGFs and are believed to have therapeutic potential in the treatment of type 2 diabetes and associated metabolic dysfunctionalities and pathological conditions. FGF19 has been proposed to induce hyperplasia and liver tumors in FVB mice (named after its susceptibility to Friend leukemia virus B), mediated by the FGF receptor 4 (FGFR4). The goal of this work was to investigate whether FGF21 might also have a potential proliferative effect mediated via FGFR4 using liver-specific Fgfr4 knockout (KO) mice...
April 26, 2023: Toxicologic Pathology
Rani S Sellers
Nonclinical toxicity testing (GLP) of prophylactic vaccines to support human clinical trials is outlined in the World Health Organization nonclinical vaccine-development guidelines, which are followed by most regulatory agencies globally. Vaccine GLP toxicity studies include at least two groups: a buffer control (often phosphate-buffered saline) group and a highest anticipated clinical dose formulation group. However, studies may include additional groups, including lower-dose formulation groups and adjuvant-containing formulation control groups...
April 21, 2023: Toxicologic Pathology
Yi-Zhong Gu, Katerina Vlasakova, Glen Miller, Nicholas T Gatto, Paul J Ciaccio, Sabu Kuruvilla, Elizabeth G Besteman, Roger Smith, Spencer J Reynolds, Rupesh P Amin, Warren E Glaab, Gordon Wollenberg, Jose Lebron, Frank D Sistare
Activating mutations of the leucine-rich repeat kinase 2 ( LRRK2 ) gene are associated with Parkinson disease (PD), prompting development of LRRK2 inhibitors as potential treatment for PD. However, kidney safety concerns have surfaced from LRRK2 knockout (KO) mice and rats and from repeat-dose studies in rodents administered LRRK2 inhibitors. To support drug development of this therapeutic target, we conducted a study of 26 weeks' duration in 2-month-old wild-type and LRRK2 KO Long-Evans Hooded rats to systematically examine the performance of urinary safety biomarkers and to characterize the nature of the morphological changes in the kidneys by light microscopy and by ultrastructural evaluation...
April 20, 2023: Toxicologic Pathology
Brad Bolon
Gliosis, defined as a nonneoplastic reaction (hypertrophy and/or proliferation) of astrocytes and/or microglial cells, is a frequent finding in the central nervous system (CNS [brain and/or spinal cord]) in nonclinical safety studies. Gliosis in rodents and nonrodents occurs at low incidence as a spontaneous finding and is induced by various test articles (e.g., biomolecules, cell and gene therapies, small molecules) delivered centrally (i.e., by injection or infusion into cerebrospinal fluid or neural tissue) or systemically...
April 14, 2023: Toxicologic Pathology
Thai-Vu T Ton, Hue-Hua L Hong, Ramesh C Kovi, Keith R Shockley, Shyamal D Peddada, Kevin E Gerrish, Kyathanahalli S Janardhan, Gordon Flake, Mathew D Stout, Robert C Sills, Arun R Pandiri
Antimony trioxide (AT) is used as a flame retardant in fabrics and plastics. Occupational exposure in miners and smelters is mainly through inhalation and dermal contact. Chronic inhalation exposure to AT particulates in B6C3F1/N mice and Wistar Han rats resulted in increased incidences and tumor multiplicities of alveolar/bronchiolar carcinomas (ABCs). In this study, we demonstrated Kras (43%) and Egfr (46%) hotspot mutations in mouse lung tumors (n = 80) and only Egfr (50%) mutations in rat lung tumors (n = 26)...
April 3, 2023: Toxicologic Pathology
Kenneth A Schafer
No abstract text is available yet for this article.
March 29, 2023: Toxicologic Pathology
Chad M Thompson, Melissa M Heintz, Jeffrey C Wolf, Roza Cheru, Laurie C Haws, John M Cullen
Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate (HFPO-DA) is a short chain member of per- and polyfluoroalkyl substances (PFAS). To better understand the relevance of histopathological effects seen in livers of mice exposed to HFPO-DA for human health risk assessment, histopathological effects were summarized from hematoxylin and eosin (H&E)-stained sections in several repeat-dose toxicity studies in mice. Findings across studies revealed histopathological changes consistent with peroxisomal proliferation, whereas two reports of steatosis could not be confirmed in the published figures...
March 29, 2023: Toxicologic Pathology
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