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Toxicologic Pathology

Brad Bolon, Georg Krinke, Mark T Butt, Deepa B Rao, Ingrid D Pardo, Bernard S Jortner, Robert H Garman, Karl Jensen, Lydia Andrews-Jones, James P Morrison, Alok K Sharma, Michael S Thibodeau
Peripheral nervous system (PNS) toxicity is surveyed inconsistently in nonclinical general toxicity studies. These Society of Toxicologic Pathology "best practice" recommendations are designed to ensure consistent, efficient, and effective sampling, processing, and evaluation of PNS tissues for four different situations encountered during nonclinical general toxicity (screening) and dedicated neurotoxicity studies. For toxicity studies where neurotoxicity is unknown or not anticipated (situation 1), PNS evaluation may be limited to one sensorimotor spinal nerve...
June 2018: Toxicologic Pathology
Kathryn E Gropp, Cathy S Carlson, Mark G Evans, Cedo M Bagi, William J Reagan, Susan I Hurst, David L Shelton, Mark A Zorbas
Tanezumab, an anti-nerve growth factor (NGF) antibody, is in development for management of chronic pain. During clinical trials of anti-NGF antibodies, some patients reported unexpected adverse events requiring total joint replacements, resulting in a partial clinical hold on all NGF inhibitors. Three nonclinical toxicology studies were conducted to evaluate the effects of tanezumab or the murine precursor muMab911 on selected bone and joint endpoints and biomarkers in cynomolgus monkeys, Sprague-Dawley rats, and C57BL/6 mice...
June 2018: Toxicologic Pathology
Javiera Bahamonde, Bonnie Brenseke, Matthew Y Chan, Ronald D Kent, Peter J Vikesland, M Renee Prater
Nanotoxicity studies are greatly needed to advance nanomedical technologies into clinical practice. We assessed the toxic effects of a single intravenous exposure to commercially available gold nanoparticles (GNPs) in mice and rats. Fifteen-nm GNPs were purchased and independently characterized. Animals were exposed to either 1,000 mg GNPs/kg body weight (GNP group) or phosphate-buffered saline. Subsets of animals were euthanized and samples collected at 1, 7, 14, 21, and 28 days postexposure. Independent characterization demonstrated that the physicochemical properties of the purchased GNPs were in good agreement with the information provided by the supplier...
June 2018: Toxicologic Pathology
Daven N Jackson-Humbles, John Curtis Seely, Ronald A Herbert, David E Malarkey, Barry S McIntyre, Paul M Foster, Darlene Dixon
Congenital uterine wall cysts arising from paramesonephric (Müllerian) and mesonephric (Wolffian) ducts are typically incidental findings in most species. We used immunohistochemistry to characterize and determine the origin of uterine cysts in Sprague-Dawley (SD) rats from multigeneration studies conducted by the National Toxicology Program. Subserosal uterine cysts were observed in 20 of the 2,400 SD rats evaluated in five studies, and 10 cysts were characterized for this study. Single cysts were unilocular, fluid-filled, and occurred throughout the uterus...
June 2018: Toxicologic Pathology
Manoj Bhaskaran, Paul D Cornwell, Steven D Sorden, Michael R Elwell, Natalie R Russell, Michael L Pritt, John L Vahle
Inhibitors of Bruton's tyrosine kinase (BTK) are under development as potential therapies for various autoimmune diseases. In repeat-dose toxicity studies, small-molecule BTK inhibitors (BTKi) have been reported to cause a constellation of histologic effects at the pancreatic endocrine-exocrine interface in male rats; however, similar findings were not reported in other species. Since the BTKi-induced pancreatic effect is morphologically similar to well-documented spontaneous changes (predominantly characterized by insular/peri-insular hemorrhage, pigment deposition, chronic inflammation, and fibrosis) that are known to vary by rat strain, we investigated potential strain-dependent differences in the pancreatic effects of a small-molecule BTKi, LY3337641...
June 2018: Toxicologic Pathology
Molly H Boyle, Madhav G Paranjpe, Dianne M Creasy
The Tg.rasH2 model was accepted by regulatory agencies worldwide for 26-week carcinogenicity assays as an alternative to the standard 2-year assays in conventional mice in 2003. Several references documenting spontaneous nonneoplastic findings and incidences of spontaneous tumors in the Tg.rasH2 mice have been published. The purpose of this publication is to add adrenal gland subcapsular hyperplasia to the database pertaining to spontaneous lesions noted in Tg.rasH2 mice, review physiology related to this finding, and discuss its significance...
June 2018: Toxicologic Pathology
Stephanie M Shrader, William F Greentree
Since their development in the 1960s, Göttingen minipigs have become a popular nonrodent animal model in biomedical research, especially for ocular studies, because of their ease of handling, size, well-monitored genetics, and ocular anatomy that is similar to humans. The purpose of this mini-review is to introduce the reader to the various ways in which this animal model is currently being utilized in ocular research and to provide an overview of the diagnostic modalities that aid in this research. To date, the Göttingen minipig has been used for a variety of ocular research endeavors, including studies evaluating the safety and efficacy of ocular therapeutics, glaucoma etiopathogenesis and treatment, novel biomaterials, surgical procedures, and implantable materials/devices...
June 2018: Toxicologic Pathology
Robert J Ellis, David M Small, Keng Lim Ng, David A Vesey, Luis Vitetta, Ross S Francis, Glenda C Gobe, Christudas Morais
Indoxyl sulfate (IS) is a protein-bound uremic toxin that accumulates in patients with declining kidney function. Although generally thought of as a consequence of declining kidney function, emerging evidence demonstrates direct cytotoxic role of IS on endothelial cells and cardiomyocytes, largely through the expression of pro-inflammatory and pro-fibrotic factors. The direct toxicity of IS on human kidney proximal tubular epithelial cells (PTECs) remains a matter of debate. The current study explored the effect of IS on primary cultures of human PTECs and HK-2, an immortalized human PTEC line...
June 2018: Toxicologic Pathology
Shayne C Gad, JoAnn C L Schuh
Safety ("biocompatibility") assessment of medical devices has evolved along a different path than that of drugs, being historically governed more by the considerations and needs of engineers rather than chemists and biologists. As a result, the involvement of veterinary pathologists has been much more limited-almost entirely to evaluating tissue responses in tissues in direct contact with implanted devices. As devices have become more complex in composition, structure, placement, and use, concerns as to adverse systemic responses in patients have called for more comprehensive and thoughtful evaluations of effects throughout the body...
June 2018: Toxicologic Pathology
Cleopatra Kozlowski, Aaron Fullerton, Gary Cain, Paula Katavolos, Joseph Bravo, Jacqueline M Tarrant
The bone marrow is an important site for assessment of the hematopoietic toxicity of new drug candidates. Here, we extended our previous work, where we developed a computer algorithm to automatically quantitate overall bone marrow cell density by analyzing digitized images of standard hematoxylin and eosin (H&E) slides of rat bone marrow and further evaluated the capability to quantify myeloid: erythroid + lymphoid (M:EL) ratio and megakaryocyte cell density. We tested the algorithm in a toxicity study, where rats were dosed with two molecules known to affect bone marrow composition, monomethyl auristatin E, and a Bcl-xL inhibitor...
April 2018: Toxicologic Pathology
Cleopatra Kozlowski, Jochen Brumm, Gary Cain
Bone marrow toxicity is a common finding when assessing safety of drug candidate molecules. Standard hematoxylin and eosin (H&E) marrow tissue sections are typically manually evaluated to provide a semiquantitative assessment of overall cellularity. Here, we developed an automated image analysis method that allows quantitative assessment of changes in bone marrow cell population in sternal bone. In order to test whether the method was repeatable and sensitive, we compared the automated method with manual subjective histopathology scoring of total cellularity in rat sternal bone marrow samples across 17 independently run studies...
April 2018: Toxicologic Pathology
Rodrigo Portes Ureshino, Angelica Jardim Costa, Adolfo Garcia Erustes, Gustavo José da Silva Pereira, Rita Sinigaglia-Coimbra, Soraya Soubhi Smaili
Aging is a multifactorial process associated with functional deficits, and the brain is more prone to developing chronic degenerative diseases such as Parkinson's disease. Several groups have tried to correlate the age-related ultrastructural alterations to the neurodegeneration process using in vivo pharmacological models, but due to the limitations of the animal models, particularly in aged animals, the results are difficult to interpret. In this work, we investigated neurodegeneration induced by rotenone, as a pharmacological model of Parkinson's disease, in both young and aged Wistar rats...
April 2018: Toxicologic Pathology
Kyohei Yasuno, Kazuyoshi Kumagai, Takuma Iguchi, Yoshimi Tsuchiya, Kiyonori Kai, Kazuhiko Mori
Diacylglycerol acyltransferase 1 (DGAT1) catalyzes the final step in triglyceride synthesis. Since Dgat1-/- mice fed a high-fat diet (HFD) are resistant to hepatic steatosis, DGAT1 inhibitors are expected to have antifatty liver effects. To evaluate the hepatic effects of DS-7250, a selective DGAT1 inhibitor, vehicle or 10 mg/kg of DS-7250 was administered orally to male Fisher 344 (F344) and Zucker fatty (ZF) rats fed a standard diet or HFD for 14 or 28 days. ZF rats showed slight hepatic steatosis regardless of feeding conditions...
April 2018: Toxicologic Pathology
Naofumi Takahashi, Toshinori Yoshida, Sayuri Kojima, Satoru Yamaguchi, Ryoichi Ohtsuka, Makio Takeda, Tadashi Kosaka, Takanori Harada
Chromated copper arsenate (CCA) is used as a wood preservative worldwide. Exposure to it may adversely affect human health. Some events have increased human exposure to CCA, including the Great East Japan Earthquake, which generated a large amount of lumber debris from CCA-treated woods. We elucidated the toxicity due to daily exposure to CCA over a 4-week period at doses of 0, 8, 40, and 80 mg/kg/day in Wistar Hannover rats. Chromium (Cr) and arsenic (As), but not copper, were detected in the plasma samples of rats treated with various doses of CCA...
April 2018: Toxicologic Pathology
Yoshikazu Taketa, Kanta Horie, Tetsuya Goto, Etsuko Ohta, Kyoko Nakano-Ito, Kazuhiro Hayakawa, Yuki Seki, Aya Goto, Satoru Hosokawa
Mifepristone, which is an orally active synthetic steroid with antiprogesterone activity, is known as an ovarian toxicant. Because the available data regarding the histopathologic characteristics of ovarian toxicity in nonhuman primates are limited, the present study was undertaken in order to investigate detailed histopathologic changes accompanying mifepristone-induced ovarian toxicity and its relationship to changes in menstrual cycle and circulating sex steroid hormone. Twenty mg/kg of mifepristone was orally administered daily to 4 cynomolgus monkeys for 2 months...
April 2018: Toxicologic Pathology
Kenneth A Schafer, John Eighmy, James D Fikes, Wendy G Halpern, Renee R Hukkanen, Gerald G Long, Emily K Meseck, Daniel J Patrick, Michael S Thibodeau, Charles E Wood, Sabine Francke
The severity grade is an important component of a histopathologic diagnosis in a nonclinical toxicity study that helps distinguish treatment-related effects from background findings and aids in determining adverse dose levels during hazard characterization. Severity grades should be assigned based only on the extent (i.e., amount and complexity) of the morphologic change in the examined tissue section(s) and be clearly defined in the pathology report for critical lesions impacting study interpretation. However, the level of detail provided and criteria by which severity grades are assigned can vary, which can lead to inappropriate comparisons and confusion when evaluating pathology results...
April 2018: Toxicologic Pathology
Michael Creane, Mary McElroy, Aoife Duffy, Chaansha Shaik Dawood, Timothy O'Brien
Critical limb ischemia (CLI) represents the severest manifestation of peripheral arterial disease and is a major unmet medical need. This disease occurs when the arterial blood supply within the limb fails to meet the metabolic demands of the resting muscle or tissue, resulting in chronic ischemic rest pain and/or tissue necrosis. Human mesenchymal stromal cells, termed hMSCs, represent an exciting therapeutic modality for the treatment of this disease due to their immunomodulatory and tissue reparative functions...
April 2018: Toxicologic Pathology
Nathália P Souza, Gordon C Hard, Lora L Arnold, Kirk W Foster, Karen L Pennington, Samuel M Cohen
Chronic progressive nephropathy (CPN) occurs commonly in rats, more frequently and severely in males than females. High-grade CPN is characterized by increased layers of the renal papilla lining, designated as urothelial hyperplasia in the International Harmonization of Nomenclature and Diagnostic Criteria classification. However, urothelium lining the pelvis is not equivalent to the epithelium lining the papilla. To evaluate whether the epithelium lining the renal papilla is actually urothelial in nature and whether CPN-associated multicellularity represents proliferation, kidney tissues from aged rats with CPN, from rats with multicellularity of the renal papilla epithelium of either low-grade or marked severity, and from young rats with normal kidneys were analyzed and compared...
April 2018: Toxicologic Pathology
Jochen Woicke, Solomon Haile, Jagannatha Mysore, W Michael Peden, Typhaine Lejeune, Thomas Sanderson, Thomas Brodie
Spontaneous findings noted in the eyes of Mauritian cynomolgus monkeys are described and descriptions are supplemented with illustrations. Findings observed after extensive histopathologic examinations (20 to 44 sections per eye) from 20 control, 17 treatment-naive stock monkeys, and 2 findings noted in drug-treated monkeys that were considered to be spontaneous are included. Also included are findings from 361 control monkeys of routine toxicity studies performed at our laboratories, for most of which a standard histopathological examination of 1 section per eye was conducted...
April 2018: Toxicologic Pathology
Susan A Elmore
No abstract text is available yet for this article.
April 2018: Toxicologic Pathology
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