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Toxicologic Pathology

Lyn M Wancket
Lymph nodes and associated lymphatics filter extracellular fluid and lymph to maintain tissue-fluid balance and detect distant tissue injury. Examination of regional draining lymph nodes (RDLs; lymph nodes that drain the route of article dosing) is an important step in detecting immunotoxicity and other associated changes during general toxicology studies. Similarly, evaluation of RDLs is often a key component of evaluating medical devices. Nonclinical medical device studies can present challenges for RDL evaluation, due to the wide variety of tissues and organs that are implanted with devices, the potential for wear debris/degradation products, and the likely disruption of normal lymphatic drainage by surgical procedures...
November 9, 2018: Toxicologic Pathology
Madhav G Paranjpe, Jessica L Belich, Peter C Mann, Marie E McKeon, Reem H Elbekai, Caren M Brown, Daniel J Patrick
This article presents the historical control data of spontaneous tumors in Tg.rasH2 published in 2013 (2004-2012) and compares and contrasts it to more recent data collected from 2013 to 2018, reporting differences in the average percentage incidences or incidence ranges as well as the incidence of new tumors. In 2013, we published a comprehensive review of spontaneous tumors in Tg.rasH2 mice used in 26-week carcinogenicity studies, which included data from control dose groups from 26 studies and a total of 710 mice per sex...
November 8, 2018: Toxicologic Pathology
Koichi Yabe, Yuka Yamamoto, Takami Suzuki, Sanae Takada, Kazuhiko Mori
We characterized pancreatic islet lesions induced by several quinolones using functional and morphological examinations of the pancreatic islets in male rats orally administered gatifloxacin, lomefloxacin, or levofloxacin at 300 mg/kg for 14 consecutive days. Consequently, in contrast to lomefloxacin or levofloxacin, gatifloxacin increased serum glucose and glycosylated albumin on day 14 and elevated serum glucose tended to decrease insulin in the intravenous glucose tolerance test. Microscopically, only gatifloxacin induced cytoplasmic vacuoles containing eosinophilic homogenous contents in islet cells...
November 8, 2018: Toxicologic Pathology
Daniel G Rudmann
Microphysiological systems (MPS), commonly known as organs-on-chips, are a rapidly advancing technology that promises to impact many areas of medical and toxicological pathology. In this minireview, the history of MPS and its potential utility in safety assessment are described with the toxicologic pathologist in mind. Several MPS development focus areas are defined, and recent progress in the area is highlighted. MPS will likely become an important tool for the toxicologic pathologist as part of our role in the safety assessment process within the pharmaceutical, biotechnology, medical device, and cosmetic and agrichemical industries...
November 8, 2018: Toxicologic Pathology
Yuval Ramot, Kamala Kannan, Sathish Reddy, H Krishnappa, John E Dillberger, Abraham Nyska
It is important to detect injection site reactions during the nonclinical phases of drug development. However, differentiating between normal changes following needle trauma and changes due to the toxicity of injected drugs can be challenging. Therefore, we used the Sprague-Dawley rat model to evaluate the pathological findings expected following a single subcutaneous injection of normal saline. Rats were subcutaneously administered with normal saline, and the injection sites were examined microscopically. Inflammation was evident in most of the injection sites, mostly in minimal severity...
November 8, 2018: Toxicologic Pathology
Sivan Yogev, Ayelet Shabtay-Orbach, Abraham Nyska, Boaz Mizrahi
Thermoresponsive materials have the ability to respond to a small change in temperature-a property that makes them useful in a wide range of applications and medical devices. Although very promising, there is only little conclusive data about the cytotoxicity and tissue toxicity of these materials. This work studied the biocompatibility of three Food and Drug Administration approved thermoresponsive polymers: poly( N-isopropyl acrylamide), poly(ethylene glycol)-poly(propylene glycol)-poly(ethylene glycol) tri-block copolymer, and poly(lactic acid-co-glycolic acid) and poly(ethylene glycol) tri-block copolymer...
November 8, 2018: Toxicologic Pathology
Shannon M Harlan, Kathleen M Heinz-Taheny, Jessica M Overstreet, Matthew D Breyer, Raymond C Harris, Josef G Heuer
The ReninAAV db/db uNx model of diabetic kidney disease (DKD) exhibits hallmarks of advanced human disease, including progressive elevations in albuminuria and serum creatinine, loss of glomerular filtration rate, and pathological changes. Microarray analysis of renal transcriptome changes were more similar to human DKD when compared to db/db eNOS-/- model. The model responds to treatment with arterial pressure lowering (lisinopril) or glycemic control (rosiglitazone) at early stages of disease. We hypothesized the ReninAAV db/db uNx model with advanced disease would have residual disease after treatment with lisinopril, rosiglitazone, or combination of both...
November 5, 2018: Toxicologic Pathology
James E McDuffie
The inability to unequivocally predict translatable drug-induced kidney injury in nonclinical studies during pharmacological development is evidenced by drug attrition in human clinical trials. Eight urinary proteins have been qualified as renal safety biomarkers for limited context of use in nonclinical drug development studies in rats. Formal qualification of human renal safety biomarkers is pending the submission of data from prospective clinical trials and analyses of biomarker performance to the Food and Drug Administration and European Medicines Agency by the Foundation for the National Institutes of Health and Predictive Safety Testing Consortium's Nephrotoxicity Working Group...
November 5, 2018: Toxicologic Pathology
JoAnn C L Schuh, Kathleen A Funk
The development of biomaterials, medical device components, finished medical products, and 3-D printed and regenerative medicine products is governed by a variety of international and country-specific standards and guidelines. Of greatest importance to planning, executing, and reporting biocompatibility, safety and efficacy studies for most biomaterials and medical components or products are the International Organization for Standardization guidelines, U.S. Pharmacopeial Convention, ASTM International, and Conformité Européenne (European Conformity) marking...
November 5, 2018: Toxicologic Pathology
Erin M Quist, Gary A Boorman, John M Cullen, Robert R Maronpot, Amera K Remick, James A Swenberg, Les Freshwater, Jerry F Hardisty
A 24-month oral carcinogenicity study of permethrin was conducted by feeding male and female CD-1 mice diets containing concentrations of 0, 20, 500, and 2,000 ppm of permethrin (males) or 0, 20, 2,500, and 5,000 ppm of permethrin (females). After approximately two years on study, surviving mice were sacrificed for the evaluation of chronic toxicity and/or carcinogenicity. An expert panel of pathologists was convened as a Pathology Working Group (PWG) to review coded liver histology sections from male and female mice and to classify all liver neoplasms according to current nomenclature and diagnostic criteria guidelines...
November 1, 2018: Toxicologic Pathology
Yoshinori Yamagiwa, Yoshihiro Takei, Haruko Koizumi, Shingo Nemoto, Masaaki Kurata, Hiroshi Satoh
Cationic amphiphilic drugs (CADs) can induce phospholipidosis (PLD) in organs/tissues. Several ophthalmic pharmaceuticals containing CADs are marketed and used in children. To investigate the effect of PLD on the developing cornea, chloroquine and amiodarone, which are representative CADs, were applied topically to the eyes of juvenile rabbits, and the effects in juvenile rabbits were compared with those in young adult rabbits. Diffuse corneal cloudiness was observed in chloroquine- and amiodarone-treated eyes...
October 29, 2018: Toxicologic Pathology
Vinicius Carreira, Gopinath Palanisamy, Erin Quist, Keith Nelson, Stacey Fossey, Bevin Zimmerman, Lila Ramaiah, Kenneth A Schafer
The toxicologic pathologist plays a vital role in the scientific community, using their unique blend of diagnostic and investigative skills to advance biomedical research, public health, drug discovery, or regulatory practices. But what exactly do toxicologic pathologists contribute? Where do these specialized professionals work? How can toxicologic pathologists maximize their efficiency and potential? To enlighten students and trainees, as well as early- or mid-career toxicologic pathologists, or even those approaching retirement, the Career Development and Outreach Committee of the Society of Toxicologic Pathology (STP) sponsored a career development workshop entitled "Practical Strategies for Navigating Toxicologic Pathology in One's Early Career…and Beyond!" in conjunction with the STP 37th annual symposium...
October 23, 2018: Toxicologic Pathology
Nicholas E Langevin, Kenneth A Schafer, Oliver C Turner, Brittany J McPherson, Robert E Rose
Information on background changes in the ocular tissues of rabbits ( Oryctolagus cuniculus), a common species employed in ophthalmic toxicology studies, is sparse. This complicates interpretation of changes in light of small sample sizes on any single study. The purpose of this publication is to document the interstudy incidence of spontaneous or iatrogenic changes occurring in eyes of control rabbits. Photomicrographs of select lesions are provided. The data set was derived from a total of 54 studies conducted over an eleven-year period at Alcon Research Ltd...
October 22, 2018: Toxicologic Pathology
Béatrice E Gauthier, Laure Penard, Nicole F Bordier, Jean-Paul J Briffaux, Bernard M Ruty
The Göttingen minipig is recognized by the scientific community and by health authorities as the animal model of choice to evaluate dermally applied drugs under development. Young adults of approximately 4 months of age are most generally chosen to participate in dermal pharmacology and toxicology studies, and recently, minipigs have been proved to be also suitable for juvenile studies. A complete anatomical cartography of the skin morphology of juvenile male and female minipigs from postnatal day 1 (PND1) to twelve weeks of age was performed measuring the thickness of skin layers for each anatomical location and time point...
October 22, 2018: Toxicologic Pathology
Jennifer M Rojas, Florian Bolze, Inger Thorup, Jette Nowak, Charlotte M Dalsgaard, Mikala Skydsgaard, Line O Berthelsen, Kevin A Keane, Henrik Søeborg, Ingrid Sjögren, Jes T Jensen, Johannes J Fels, Hanne K Offenberg, Lærke W Andersen, Majken Dalgaard
The obese rodent serves as an indispensable tool for proof-of-concept efficacy and mode-of-action pharmacology studies. Yet the utility of this disease model as an adjunct to the conventional healthy animal in the nonclinical safety evaluation of anti-obesity pharmacotherapies has not been elucidated. Regulatory authorities have recommended employing disease models in toxicology studies when necessary. Our study investigated standard and exploratory toxicology parameters in the high-fat diet (HFD)-induced obese, polygenic Sprague-Dawley rat model in comparison to chow diet (CD)-fed controls...
October 22, 2018: Toxicologic Pathology
Basel T Assaf, Laurence O Whiteley
Progress in understanding the molecular bases of human health and disease in recent decades has flourished making it possible for the field of gene therapy (GT) to offer new possibilities for treating, and even curing, a plethora of medical conditions such as monogenic disorders and metabolic diseases. GT is a therapeutic intervention to genetically alter or modify living cells by means of gene delivery achieved using either viral vectors or nonviral vectors, with adeno-associated virus (AAV) vectors constituting market-share majority...
October 7, 2018: Toxicologic Pathology
Ingrid D Pardo, Deepa B Rao, Mark T Butt, Bernard S Jortner, William M Valentine, Joseph Arezzo, Alok K Sharma, Brad Bolon
Peripheral nervous system (PNS) toxicity is a frequent adverse effect encountered in patients treated with certain therapeutics (e.g., antiretroviral drugs, cancer chemotherapeutics), in occupational workers exposed to industrial chemicals (e.g., solvents), or during accidental exposures to household chemicals and/or environmental agents (e.g., pesticides). However, the literature and expertise needed for the effective design, conduct, analysis, and reporting of safety studies to identify and define PNS toxicity are hard to find...
October 7, 2018: Toxicologic Pathology
Lars Mecklenburg
Antibody-drug conjugates (ADCs) are an emerging class of anticancer therapeutics, delivering highly cytotoxic molecules directly to cancer cells. ADCs are composed of an antibody, a small molecule drug, and a linker attaching one to another. Antibodies are directed to a large variety of antigens overexpressed on tumor cells, tumor vasculature, or tumor-supporting stroma. After internalization, the ADC is transferred to lysosomes where the cytotoxic component is released, finally killing the target cell. All ADCs are administered via intravenous injection...
October 7, 2018: Toxicologic Pathology
Shambhunath Choudhary, Audrey Walker, Kathleen Funk, Charlotte Keenan, Imran Khan, Kimberly Maratea
The Standard for the Exchange of Nonclinical Data (SEND) is an implementation of the Study Data Tabulation Model for nonclinical studies that enables the U.S. Food and Drug Administration (FDA) to modernize and streamline the review process. As a result, patients may benefit from speedier approval of new drugs. However, SEND implementation and compliance can be challenging and require effective cooperation between pharmaceutical companies and contract research organizations. In order to improve Society of Toxicologic Pathology (STP) members' awareness about SEND, including the steps, obstacles, and mistakes to avoid in its implementation while applying for FDA approval, the Career Development and Outreach Committee of the STP sponsored a career development lunchtime series panel discussion entitled "The Standard for the Exchange of Nonclinical Data (SEND): Challenges and Promise" in conjunction with the STP 37th Annual Symposium...
October 7, 2018: Toxicologic Pathology
Susan A Elmore, Vinicius Carreira, Caralyn S Labriola, Debabrata Mahapatra, Sean R McKeag, Matthias Rinke, Cynthia Shackelford, Bhanu Singh, Ashley Talley, Shannon M Wallace, Lyn M Wancket, Cynthia J Willson
The 2018 annual National Toxicology Program Satellite Symposium, entitled "Pathology Potpourri," was held in Indianapolis, Indiana, at the Society of Toxicologic Pathology's 37th 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 other topics covered during the symposium included seminiferous tubule dysgenesis in rats, ameloblast and odontoblast degeneration/necrosis in a Sprague Dawley rat, intestinal leiomyositis in a beagle dog, gallbladder mucinous hyperplasia, focus of hepatocellular alteration and bile duct alteration in otters, renal tubule cytoplasmic vacuolation with basophilic granules in mice treated swith antisense oligonucleotide therapy, a uterine choriocarcinoma in a rhesus macaque, and rete ovarii proliferative ovarian lesions in various aged rat strains...
October 3, 2018: Toxicologic Pathology
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