Subjects -> ENVIRONMENTAL STUDIES (Total: 913 journals)
    - ENVIRONMENTAL STUDIES (810 journals)
    - POLLUTION (31 journals)
    - TOXICOLOGY AND ENVIRONMENTAL SAFETY (54 journals)
    - WASTE MANAGEMENT (18 journals)

ENVIRONMENTAL STUDIES (810 journals)            First | 1 2 3 4 5     

Showing 601 - 378 of 378 Journals sorted alphabetically
Multequina     Open Access  
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis     Hybrid Journal   (Followers: 5)
Mutation Research/Genetic Toxicology and Environmental Mutagenesis     Hybrid Journal   (Followers: 8)
Nano Select     Open Access  
Nanotechnology for Environmental Engineering     Hybrid Journal  
Nativa     Open Access  
Natur und Recht     Hybrid Journal   (Followers: 6)
Natural Areas Journal     Full-text available via subscription   (Followers: 10)
Natural Hazards     Hybrid Journal   (Followers: 53)
Natural Resources     Open Access  
Natural Resources & Engineering     Hybrid Journal  
Natural Resources and Environmental Issues     Open Access   (Followers: 2)
Nature and Culture     Full-text available via subscription   (Followers: 11)
Nature-Based Solutions     Open Access  
Nepal Journal of Environmental Science     Open Access   (Followers: 4)
NeuroToxicology     Hybrid Journal   (Followers: 1)
Neurotoxicology and Teratology     Hybrid Journal   (Followers: 3)
NEW SOLUTIONS: A Journal of Environmental and Occupational Health Policy     Full-text available via subscription   (Followers: 2)
New Zealand Journal of Environmental Law     Full-text available via subscription   (Followers: 4)
NJAS : Wageningen Journal of Life Sciences     Hybrid Journal  
Novos Cadernos NAEA     Open Access  
npj Urban Sustainability     Open Access  
Observatorio Medioambiental     Open Access  
Occupational and Environmental Medicine     Hybrid Journal   (Followers: 18)
Ochrona Srodowiska i Zasobów Naturalnych : Environmental Protection and Natural Resources     Open Access  
Oecologia     Hybrid Journal   (Followers: 54)
Oikos     Hybrid Journal   (Followers: 55)
One Earth     Hybrid Journal   (Followers: 2)
One Ecosystem     Open Access  
Open Environmental Research Journal     Open Access   (Followers: 1)
Open Journal of Marine Science     Open Access   (Followers: 6)
Open Journal of Modern Hydrology     Open Access   (Followers: 5)
Our Nature     Open Access   (Followers: 1)
Pace Environmental Law Review     Open Access   (Followers: 4)
Packaging, Transport, Storage & Security of Radioactive Material     Hybrid Journal   (Followers: 2)
Palaeobiodiversity and Palaeoenvironments     Hybrid Journal   (Followers: 3)
Particle and Fibre Toxicology     Open Access   (Followers: 2)
Pastos y Forrajes     Open Access  
Peer Community Journal     Open Access   (Followers: 8)
Perspectives in Ecology and Conservation     Full-text available via subscription   (Followers: 5)
Pharmacology & Therapeutics     Hybrid Journal   (Followers: 3)
Pharmacology Biochemistry and Behavior     Hybrid Journal   (Followers: 2)
Physio-Géo     Open Access   (Followers: 1)
Pittsburgh Journal of Environmental and Public Health Law     Open Access  
Planet     Open Access   (Followers: 4)
Planeta Amazônia : Revista Internacional de Direito Ambiental e Políticas Públicas     Open Access  
Planning & Environmental Law: Issues and decisions that impact the built and natural environments     Hybrid Journal   (Followers: 6)
Plant Ecology & Diversity     Partially Free   (Followers: 13)
Plant Knowledge Journal     Open Access   (Followers: 1)
Plant, Cell & Environment     Hybrid Journal   (Followers: 8)
Plant-Environment Interactions     Open Access  
Plants, People, Planet     Open Access   (Followers: 1)
Polar Journal     Hybrid Journal   (Followers: 2)
Political Studies     Hybrid Journal   (Followers: 42)
Political Studies Review     Hybrid Journal   (Followers: 18)
Population and Environment     Hybrid Journal   (Followers: 6)
Population Ecology     Hybrid Journal   (Followers: 12)
Practice Periodical of Hazardous, Toxic, and Radioactive Waste Management     Full-text available via subscription  
Presence: Virtual and Augmented Reality     Hybrid Journal   (Followers: 2)
Proceedings of the Institution of Civil Engineers - Waste and Resource Management     Hybrid Journal   (Followers: 1)
Proceedings of the Institution of Mechanical Engineers Part M: Journal of Engineering for the Maritime Environment     Hybrid Journal   (Followers: 3)
Proceedings of the International Academy of Ecology and Environmental Sciences     Open Access   (Followers: 1)
Proceedings of the Vertebrate Pest Conference     Open Access  
Process Integration and Optimization for Sustainability     Hybrid Journal  
Process Safety and Environmental Protection     Hybrid Journal   (Followers: 4)
Producción + Limpia     Open Access  
Progress in Disaster Science     Open Access   (Followers: 1)
Progress in Industrial Ecology, An International Journal     Hybrid Journal   (Followers: 2)
Projets de Paysage     Open Access  
Psychological Assessment     Full-text available via subscription   (Followers: 12)
Public Money & Management     Hybrid Journal   (Followers: 7)
Quaternary     Open Access  
Recursos Rurais     Open Access  
REDER : Revista de Estudios Latinoamericanos sobre Reducción del Riesgo de Desastres     Open Access  
Regional Environmental Change     Open Access   (Followers: 2)
Regional Sustainability     Open Access   (Followers: 1)
Rekayasa     Open Access  
Remediation Journal     Hybrid Journal   (Followers: 8)
Remote Sensing Applications : Society and Environment     Full-text available via subscription   (Followers: 9)
Remote Sensing Letters     Hybrid Journal   (Followers: 46)
Rendiconti Lincei     Hybrid Journal  
Renewable Energy and Environmental Sustainability     Open Access   (Followers: 1)
Renewable Energy Focus     Full-text available via subscription   (Followers: 7)
Research & Reviews : Journal of Ecology     Full-text available via subscription   (Followers: 3)
Research and Practice for Persons with Severe Disabilities     Full-text available via subscription   (Followers: 3)
Research Journal of Environmental Sciences     Open Access   (Followers: 2)
Research Journal of Environmental Toxicology     Open Access   (Followers: 2)
Resources     Open Access  
Resources and Environment     Open Access  
Resources, Conservation & Recycling     Hybrid Journal   (Followers: 20)
Resources, Conservation & Recycling : X     Open Access   (Followers: 1)
Resources, Conservation & Recycling Advances     Open Access   (Followers: 1)
Rethinking Ecology     Open Access  
Reuse/Recycle Newsletter     Hybrid Journal  
Review of Agricultural, Food and Environmental Studies     Hybrid Journal  
Review of Environmental Economics and Policy     Hybrid Journal   (Followers: 11)
Revista AIDIS de Ingeniería y Ciencias Ambientales. Investigación, desarrollo y práctica     Open Access  
Revista Ambivalências     Open Access  
Revista Brasileira de Ciências Ambientais     Open Access   (Followers: 1)
Revista Brasileira de Meio Ambiente     Open Access  
Revista Chapingo. Serie Ciencias Forestales y del Ambiente     Open Access  
Revista Ciência, Tecnologia & Ambiente     Open Access  
Revista de Ciencias Ambientales     Open Access  
Revista de Direito Ambiental e Socioambientalismo     Open Access  
Revista de Direito e Sustentabilidade     Open Access  
Revista de Gestão Ambiental e Sustentabilidade - GeAS     Open Access  
Revista de Investigación en Agroproducción Sustentable     Open Access  
Revista de Salud Ambiental     Open Access  
Revista ECOVIDA     Open Access   (Followers: 4)
Revista Eletrônica de Gestão e Tecnologias Ambientais     Open Access  
Revista Geama     Open Access  
Revista Hábitat Sustenable     Open Access  
Revista Iberoamericana Ambiente & Sustentabilidad     Open Access  
Revista Kawsaypacha: Sociedad y Medio Ambiente     Open Access  
Revista Laborativa     Open Access  
Revista Meio Ambiente e Sustentabilidade     Open Access  
Revista Mundi Meio Ambiente e Agrárias     Open Access  
Revista Verde de Agroecologia e Desenvolvimento Sustentável     Open Access   (Followers: 2)
Rivista di Studi sulla Sostenibilità     Full-text available via subscription   (Followers: 1)
RUDN Journal of Ecology and Life Safety     Open Access  
Russian Journal of Ecology     Hybrid Journal   (Followers: 1)
Safety Science     Hybrid Journal   (Followers: 28)
San Francisco Estuary and Watershed Science     Open Access  
SAR and QSAR in Environmental Research     Hybrid Journal   (Followers: 1)
Saúde e Meio Ambiente : Revista Interdisciplinar     Open Access  
Scandinavian Journal of Work, Environment & Health     Partially Free   (Followers: 13)
Science of The Total Environment     Hybrid Journal   (Followers: 37)
Sciences Eaux & Territoires : la Revue du Cemagref     Open Access  
Social and Environmental Accountability Journal     Hybrid Journal   (Followers: 3)
Sociedad y Ambiente     Open Access  
Soil and Sediment Contamination: An International Journal     Hybrid Journal   (Followers: 3)
Soil and Tillage Research     Hybrid Journal   (Followers: 9)
South Australian Geographical Journal     Open Access  
South Pacific Journal of Natural and Applied Sciences     Hybrid Journal  
Southern African Journal of Environmental Education     Open Access  
Southern Forests : a Journal of Forest Science     Hybrid Journal   (Followers: 3)
Sriwijaya Journal of Environment     Open Access  
Stochastic Environmental Research and Risk Assessment     Hybrid Journal   (Followers: 4)
Strategic Planning for Energy and the Environment     Hybrid Journal   (Followers: 4)
Studies in Conservation     Hybrid Journal   (Followers: 16)
Sustainability     Open Access   (Followers: 21)
Sustainability Agri Food and Environmental Research     Open Access   (Followers: 4)
Sustainability in Environment     Open Access   (Followers: 2)
Sustainable and Resilient Infrastructure     Hybrid Journal  
Sustainable Cities and Society     Hybrid Journal   (Followers: 22)
Sustainable Development     Hybrid Journal   (Followers: 14)
Sustainable Development Law & Policy     Open Access   (Followers: 12)
Sustainable Development Strategy and Practise     Open Access   (Followers: 4)
Sustainable Horizons     Full-text available via subscription   (Followers: 6)
Sustainable Technology and Entrepreneurship     Full-text available via subscription   (Followers: 8)
Sustinere : Journal of Environment and Sustainability     Open Access  
TECHNE - Journal of Technology for Architecture and Environment     Open Access   (Followers: 11)
Tecnogestión     Open Access  
Territorio della Ricerca su Insediamenti e Ambiente. Rivista internazionale di cultura urbanistica     Open Access  
The Historic Environment : Policy & Practice     Hybrid Journal   (Followers: 4)
The International Journal on Media Management     Hybrid Journal   (Followers: 7)
The Ring     Open Access  
Theoretical Ecology     Hybrid Journal   (Followers: 15)
Toxicologic Pathology     Hybrid Journal   (Followers: 18)
Toxicological & Environmental Chemistry     Hybrid Journal   (Followers: 2)
Toxicological Sciences     Hybrid Journal   (Followers: 11)
Toxicology     Hybrid Journal   (Followers: 18)
Toxicology and Applied Pharmacology     Hybrid Journal   (Followers: 24)
Toxicology and Industrial Health     Hybrid Journal   (Followers: 6)
Toxicology in Vitro     Hybrid Journal   (Followers: 11)
Toxicology Letters     Hybrid Journal   (Followers: 15)
Toxicology Mechanisms and Methods     Hybrid Journal   (Followers: 7)
Toxicon     Hybrid Journal   (Followers: 5)
Toxicon : X     Open Access  
Toxin Reviews     Hybrid Journal  
Transactions on Environment and Electrical Engineering     Open Access  
Transportation Research Part D: Transport and Environment     Hybrid Journal   (Followers: 28)
Transportation Safety and Environment     Open Access   (Followers: 1)
Transylvanian Review of Systematical and Ecological Research     Open Access  
Trends in Ecology & Evolution     Full-text available via subscription   (Followers: 242)
Trends in Environmental Analytical Chemistry     Hybrid Journal   (Followers: 3)
Trends in Pharmacological Sciences     Full-text available via subscription   (Followers: 19)
Tropicultura     Open Access  
Turkish Journal of Engineering and Environmental Sciences     Open Access   (Followers: 1)
UCLA Journal of Environmental Law and Policy     Open Access   (Followers: 1)
UD y la Geomática     Open Access  
Universidad y Ciencia     Open Access  
Universidad y Ciencia     Open Access  
UNM Environmental Journals     Open Access  
Urban Studies     Hybrid Journal   (Followers: 69)
Urban Transformations     Open Access  
Veredas do Direito : Direito Ambiental e Desenvolvimento Sustentável     Open Access  
VertigO - la revue électronique en sciences de l’environnement     Open Access   (Followers: 1)
Villanova Environmental Law Journal     Open Access  
Waste Management & Research     Hybrid Journal   (Followers: 6)
Water Conservation Science and Engineering     Hybrid Journal   (Followers: 1)
Water Environment Research     Full-text available via subscription   (Followers: 43)
Water International     Hybrid Journal   (Followers: 19)
Water Security     Hybrid Journal   (Followers: 6)
Water, Air, & Soil Pollution : Focus     Hybrid Journal   (Followers: 7)
Water, Air, & Soil Pollution     Open Access   (Followers: 21)
Weather and Forecasting     Hybrid Journal   (Followers: 43)
Weather, Climate, and Society     Hybrid Journal   (Followers: 16)
Web Ecology     Open Access   (Followers: 3)
Wetlands     Hybrid Journal   (Followers: 25)

  First | 1 2 3 4 5     

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Toxicologic Pathology
Journal Prestige (SJR): 0.807
Citation Impact (citeScore): 2
Number of Followers: 18  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0192-6233 - ISSN (Online) 1533-1601
Published by Sage Publications Homepage  [1174 journals]
  • A Technical Guide to Sampling the Beagle Dog Nervous System for General
           Toxicity and Neurotoxicity Studies

    • Free pre-print version: Loading...

      Authors: Xavier Palazzi, Ingrid D. Pardo, Hayley Ritenour, Deepa B. Rao, Brad Bolon, Robert H. Garman
      Abstract: Toxicologic Pathology, Ahead of Print.
      Beagle dogs are a key nonrodent species in nonclinical safety evaluation of new biomedical products. The Society of Toxicologic Pathology (STP) has published “best practices” recommendations for nervous system sampling in nonrodents during general toxicity studies (Toxicol Pathol 41[7]: 1028-1048, 2013), but their adaptation to the Beagle dog has not been defined specifically. Here we provide 2 trimming schemes suitable for evaluating the unique neuroanatomic features of the dog brain in nonclinical toxicity studies. The first scheme is intended for general toxicity studies (Tier 1) to screen test articles with unknown or no anticipated neurotoxic potential; this plan using at least 7 coronal hemisections matches the STP “best practices” recommendations. The second trimming scheme for neurotoxicity studies (Tier 2) uses up to 14 coronal levels to investigate test articles where the brain is a suspected or known target organ. Collection of spinal cord, ganglia (somatic and autonomic), and nerves for dogs during nonclinical studies should follow published STP “best practices” recommendations for sampling the central (Toxicol Pathol 41[7]: 1028-1048, 2013) and peripheral (Toxicol Pathol 46[4]: 372-402, 2018) nervous systems. This technical guide also demonstrates the locations and approaches to collecting uncommonly sampled peripheral nervous system sites.
      Citation: Toxicologic Pathology
      PubDate: 2022-06-22T10:46:26Z
      DOI: 10.1177/01926233221099300
       
  • A Critical Assessment of the Requirement for a Single Time Point Vaginal
           Cytology on the Day of Necropsy in Rats

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      Authors: Eveline de Rijk, Manon Beekhuijzen, Ankie Lambregts, Melissa Czajkowski, Hetty van den Brink-Knol
      Abstract: Toxicologic Pathology, Ahead of Print.
      For toxicology testing of (agro)chemicals, different study types are being performed with general and/or reproductive toxicity endpoints (see Organisation for Economic Co-operation and Development guidelines). In most of these rat studies, vaginal cytology is performed on serial samples (collected by lavage) for evaluation of cycle regularity and evidence of mating, and/or on a single sample collected on the day of necropsy for information on the estrous cycle stage and allowing correlation with histopathology. In the latter case, the utility of vaginal cytology can be argued. In this article, estrous cycle stages based on vaginal cytology of samples taken on the day of necropsy and histopathology of ovaries, uterus, and vagina (gold standard for estrous cycle stage assessment) were compared. The agreement was generally low. Disagreement between the two methods could be explained by time differences between lavage and necropsy, by manipulation of vaginal epithelium during lavage which may impact epithelial morphology on histology, and by misinterpretation of vaginal cytology during or shortly after lactation. Based on the results of estrous staging within different study types, we strongly discourage vaginal cytology from samples collected on the day of necropsy since there is no added value, vaginal manipulation can be stressful and may complicate the histologic diagnosis.
      Citation: Toxicologic Pathology
      PubDate: 2022-06-22T07:19:40Z
      DOI: 10.1177/01926233221103273
       
  • A Comparison of Historical Control Data From Cynomolgus Macaques (Macaca
           Fascicularis) of Chinese, Cambodian, and Vietnamese Origin

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      Authors: Molly Liepnieks, Caitlyn Carter, Michael J. Caruso, Zac Lloyd, Michael Muzyka, Daniel Patrick
      Abstract: Toxicologic Pathology, Ahead of Print.
      Cynomolgus macaques, the most commonly utilized nonhuman primate in nonclinical toxicology studies, are acquired from purpose-bred colonies across various geographic locations, including China, Cambodia, and Vietnam. Importation challenges and limited availability have restricted animals suitable for inclusion in nonclinical studies. The coronavirus disease 2019 (COVID-19) outbreak further stressed supply chains, reducing the ability to source animals from a singular location to complete a drug development program. These challenges raised concerns of increased variability in study endpoints due to heterogeneity of animals and that this could subsequently impact historical control data and toxicology study interpretation. To investigate the impact of Chinese, Vietnamese, or Cambodian geographic origin on standard nonclinical toxicology study endpoints, historical control data from studies conducted at a single facility from 2005 to 2020 were compiled and evaluated for the following: clinical observations, body weight, ophthalmoscopic examinations, and clinical and anatomic pathology data. Study populations consisted of 2- to 5-year-old cynomolgus macaques sourced from China (n = 750 males/741 females), Cambodia (n = 282 males/271 females), and Vietnam (n = 122 males/120 females). Interpretation of the various data demonstrated no notable differences in standard toxicology study endpoints or background findings among cynomolgus macaques originating from China, Cambodia, or Vietnam.
      Citation: Toxicologic Pathology
      PubDate: 2022-06-22T07:18:20Z
      DOI: 10.1177/01926233221103181
       
  • Immunosuppression Profile of CFZ533 (Iscalimab), a Non-Depleting Anti-CD40
           Antibody, and the Presence of Opportunistic Infections in a Rhesus Monkey
           Toxicology Study

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      Authors: Thierry D. Flandre, Keith G. Mansfield, Pascal J. Espié, Tina Rubic-Schneider, Peter Ulrich
      Abstract: Toxicologic Pathology, Ahead of Print.
      CFZ533 (iscalimab) is a nondepleting anti-CD40 antibody intended for inhibition of transplant organ rejection and treatment of autoimmune diseases. In a safety assessment in rhesus monkeys, CFZ533 was administered for 13 weeks up to 150 mg/kg/week subcutaneously. CFZ533 was shown previously to completely inhibit primary and secondary T-cell-dependent antibody responses. CD40 is expressed on B cells, antigen-presenting cells, and endothelial and epithelial cells, but is not expressed on T cells. Here, we demonstrate the complete suppression of germinal center formation in lymphoid organs. CFZ533 was well tolerated and did not cause any dose-limiting toxicity. However, the histological evaluation revealed increased numbers of CD4+ and CD8+ T cells in the T-cell-rich areas of lymph nodes enlarged in response to observed adenovirus and Cryptosporidium infections which suggest that T-cell immune function was unaffected. Background infections appear as the condition leading to unraveling the differential immunosuppressive effects by CFZ533. The presence of T cells at lymph nodes draining sites of infections corroborates the immunosuppressive mechanism, which is different from calcineurin-inhibiting drugs. Furthermore, CFZ533 did not show any hematological or microscopic evidence of thromboembolic events in rhesus monkeys, which were previously shown to respond with thromboembolism to treatment with anti-CD154 antibodies.
      Citation: Toxicologic Pathology
      PubDate: 2022-06-22T07:16:20Z
      DOI: 10.1177/01926233221100168
       
  • Preclinical In Vivo Safety of Poly-Phosphorylated Superlubrication Vectors
           for the Treatment of Osteoarthritis

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      Authors: Yuval Ramot, Oleg Dolkart, Michal Steiner, Sabrina Jahn, Ronit Goldberg, Orna Cacical, Yossi Lavie, Nati Ezov, Gabi Agar, Abraham Nyska
      Abstract: Toxicologic Pathology, Ahead of Print.
      Osteoarthritis (OA) can lead to a significant functional disability. Poly[2-(methacryloyloxy)ethyl phosphorylcholine] (pMPC) liposomes are a novel treatment modality for OA, intended to restore the natural lubrication properties of articular cartilage. Here, we report on two studies aimed to assess the local and systemic safety and toxicity of pMPCylated liposomes in comparison with physiological saline, in Sprague-Dawley (SD) rats and in sheep after a single intra-articular (IA) injection. The animals were sacrificed after 1 and 6 weeks (rats) and 3 and 6 weeks (sheep). No signs of toxicity or abnormal clinical findings were observed. Histopathological evaluation revealed no signs of reactivity or abnormal findings in the injected joints or in any other organs. In conclusion, a single IA injection of the pMPCylated liposomes demonstrated an excellent safety profile and did not result in local reactivity or systemic toxicity, thus supporting its further development for use in humans.
      Citation: Toxicologic Pathology
      PubDate: 2022-06-21T09:02:14Z
      DOI: 10.1177/01926233221105393
       
  • Society of Toxicologic Pathology Neuropathology Interest Group Article:
           Neuropathologic Findings in Nonhuman Primates Associated With
           Administration of Biomolecule-Based Test Articles

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      Authors: Dinesh S. Bangari, Lisa G. Lanigan, Felix Goulet, Silvia Siso, Brad Bolon
      Abstract: Toxicologic Pathology, Ahead of Print.
      The increasing specificity of novel druggable targets coupled with the complexity of emerging therapeutic modalities for treating human diseases has created a growing need for nonhuman primates (NHPs) as models for translational drug discovery and nonclinical safety assessment. In particular, NHPs are critical for investigating potential unexpected/undesired on-target and off-target liabilities associated with administration of candidate biotherapeutics (nucleic acids, proteins, viral gene therapy vectors, etc.) to treat nervous system disorders. Nervous system findings unique to or overrepresented in NHPs administered biomolecule-based (“biologic”) test articles include mononuclear cell infiltration in most neural tissues for all biomolecule classes as well as neuronal necrosis with glial cell proliferation in sensory ganglia for certain viral vectors. Such test article-related findings in NHPs often must be differentiated from procedural effects (e.g., local parenchymal or meningeal reactions associated with an injection site or implanted catheter to administer a test article directly into the central nervous system) or spontaneous background findings (e.g., neuronal autophagy in sensory ganglia).
      Citation: Toxicologic Pathology
      PubDate: 2022-06-13T12:10:23Z
      DOI: 10.1177/01926233221101314
       
  • Intrathecal sc-AAV9-CB-GFP: Systemic Distribution Predominates Following
           Single-Dose Administration in Cynomolgus Macaques

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      Authors: Emily K. Meseck, Ghiabe Guibinga, Stephen Wang, Cameron McElroy, Eloise Hudry, Keith Mansfield
      Abstract: Toxicologic Pathology, Ahead of Print.
      Biodistribution of self-complementary adeno-associated virus-9 (scAAV9)–chicken β-actin promoter–green fluorescent protein (GFP) was assessed in juvenile cynomolgus macaques infused intrathecally via lumbar puncture or the intracisterna magna (1.0×1013 or 3.0×1013 vg/animal), with necropsy 28 days later. Our results characterized central nervous system biodistribution compared with systemic organs/tissues by droplet digital polymerase chain reaction for DNA and in situ hybridization. Green fluorescent protein expression was characterized by Meso Scale Discovery electrochemiluminescence immunosorbent assay and immunohistochemistry (IHC). Biodistribution was widespread but variable, with vector DNA and GFP expression greatest in the spinal cord, dorsal root ganglia (DRG), and certain systemic tissues (e.g., liver), with low concentrations in many brain regions despite direct cerebrospinal fluid administration. Transduction and expression were observed primarily in perivascular astrocytes in the brain, with a paucity in neurons. Greater GFP expression was observed in hepatocytes, striated myocytes, cardiomyocytes, spinal cord lower motor neurons, and DRG sensory neurons by IHC. These results should be considered when evaluating scAAV9-based intrathecal delivery with the current expression cassette as a modality for neurologic diseases that require widespread brain neuronal expression. This capsid/expression cassette combination may be better suited for diseases that express a secreted protein and/or do not require widespread brain neuronal transduction.
      Citation: Toxicologic Pathology
      PubDate: 2022-06-04T06:53:57Z
      DOI: 10.1177/01926233221101309
       
  • Scientific and Regulatory Policy Committee Points to Consider: Primary
           Digital Histopathology Evaluation and Peer Review for Good Laboratory
           Practice (GLP) Nonclinical Toxicology Studies

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      Authors: Thomas Forest, Famke Aeffner, Dinesh S. Bangari, Bhupinder Bawa, Jonathan Carter, James Fikes, Wanda High, Shim-mo Hayashi, Matthew Jacobsen, LuAnn McKinney, Daniel Rudmann, Thomas Steinbach, Vanessa Schumacher, Oliver Turner, Jerrold M. Ward, Cynthia J. Willson
      Abstract: Toxicologic Pathology, Ahead of Print.
      The Society of Toxicologic Pathology’s Scientific and Regulatory Policy Committee formed a working group to consider the present and future use of digital pathology in toxicologic pathology in general and specifically its use in primary evaluation and peer review in Good Laboratory Practice (GLP) environments. Digital histopathology systems can save costs by reducing travel, enhancing organizational flexibility, decreasing slide handling, improving collaboration, increasing access to historical images, and improving quality and efficiency through integration with laboratory information management systems. However, the resources to implement and operate a digital pathology system can be significant. Given the magnitude and risks involved in the decision to adopt digital histopathology, this working group used pertinent previously published survey results and its members’ expertise to create a Points-to-Consider article to assist organizations with building and implementing digital pathology workflows. With the aim of providing a comprehensive perspective, the current publication summarizes aspects of digital whole-slide imaging relevant to nonclinical histopathology evaluations, and then presents points to consider applicable to both primary digital histopathology evaluation and digital peer review in GLP toxicology studies. The Supplemental Appendices provide additional tabulated resources.
      Citation: Toxicologic Pathology
      PubDate: 2022-06-03T10:53:31Z
      DOI: 10.1177/01926233221099273
       
  • Kidney Effects by Alternative Classes of Medicines in Patients and
           Relationship to Effects in Nonclinical Toxicity Studies

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      Authors: Kendall S. Frazier
      Abstract: Toxicologic Pathology, Ahead of Print.
      Drug-induced kidney injury has historically been associated with renal tubule injury related to small molecule pharmaceuticals such as nonsteroidal anti-inflammatory drugs, antineoplastic agents, or antibiotics, but as a greater number of alternative classes of medicines such as biotherapeutics, molecular-targeted antineoplastic drugs, chimeric antigen receptor T-cell therapies, antibody-drug conjugates, oligonucleotide therapies, or other immunomodulatory drugs come to market, the presentation of drug-induced nephrotoxicity is changing. This review article describes the potential rare clinical events in drug-induced kidney injury that might be noted with these new therapies and their potential impact on patients. Potential pathogenic mechanisms related to immunogenicity, immune complex formation, and stimulation of downstream proinflammatory pathways with some of these alternative medicine classes have resulted in the potential for glomerulonephritis, acute interstitial nephritis, renal vasculitis, and other immune-mediated renal disorders in humans. This contrasts with nonclinical toxicity studies, where biologic therapies more often result in vasculitis and glomerulonephritis associated with antidrug antibodies and immunomodulatory pharmacology, and which are not always predictive of clinical effects. While nonclinical antidrug antibody-related renal disease is generally not clinically relevant, other immune-mediated nephrotoxicities associated with immunomodulatory drugs may be predictive of clinical adverse events. Fortunately, these conditions are still rare and account for a small percentage of serious adverse events in kidneys of patients.
      Citation: Toxicologic Pathology
      PubDate: 2022-05-24T09:20:05Z
      DOI: 10.1177/01926233221100414
       
  • Comparison of ANP and BNP Granular Density in Atria of Rats After
           Physiological and Pathological Hypertrophy

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      Authors: Kevin Agostinucci, Thomas G. Manfredi, Arthur C. Cosmas, Frederick J. Vetter, Steven K. Engle
      Abstract: Toxicologic Pathology, Ahead of Print.
      Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones located in atria granules. Both peptides respond to cardiac pressure and volume dynamics and accordingly serve as translation biomarkers for the clinical treatment of heart failure. Serum ANP and BNP play central secretary roles in blood pressure and cardiac output regulation and have proven utility as differential biomarkers of cardiovascular proficiency and drug-induced maladaptation, yet both peptides are impervious to exercise-induced hypertrophy. We employed immunoelectron microscopy to examine the effects of 28 days of chronic swim exercise or administration of a PPARγ agonist on atrial granules and their stored natriuretic peptides in Sprague Dawley rats. Chronic swimming and drug treatment both resulted in a 15% increase in heart weight compared with controls, with no treatment effects on perinuclear granule area in the left atria (LAs). Drug treatment resulted in larger size granules with greater BNP density in the right atria. Comparing swimming and PPARγ agonist treatment effects on ANP:BNP granule density ratios between atrial chambers revealed a shift toward a greater proportion of ANP than BNP in LAs of swim-trained rats. These data suggest a distinction in the population of ANP and BNP after chronic swim or PPARγ that makes it a novel metric for the differentiation of pathological and physiological hypertrophy.
      Citation: Toxicologic Pathology
      PubDate: 2022-05-24T09:15:41Z
      DOI: 10.1177/01926233221097970
       
  • Does Geographical Origin of Long-Tailed Macaques (Macaca fascicularis)
           Matter in Drug Safety Assessment': A Literature Review and Proposed
           Conclusion

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      Authors: Gerhard Weinbauer, Lars Mecklenburg
      Abstract: Toxicologic Pathology, Ahead of Print.
      Long-tailed macaques are the predominant nonhuman primate species for the nonclinical safety testing of biopharmaceuticals. This species comprises 9 subspecies with Macaca fascicularis fascicularis naturally occurring in Southeast Asia. Since the 17th century, M. f. fascicularis also occurs on Mauritius. Cynomolgus macaques do not naturally occur in China, but are bred in many farms across the country. The current shortage in animal supply raises the question whether geographical animal origin matters and if animals from different geographical regions can be combined on a drug development program or even a single experiment. This article reviews geographical animal origin in relation to selected endpoints that are relevant in nonclinical drug safety testing. Animals from different countries within Asia mainland do not appear to show any meaningful difference. Very little data are available for animals from Asia island. Mauritian animals show consistent differences from Asian animals in several clinical and anatomical pathology parameters. For developmental parameters, animals from Mauritius and Asia are comparable with the exception that Mauritian animals mature faster. In the authors’ view, differences between the geographical clusters can be accounted for as long as baseline and reference data are available.
      Citation: Toxicologic Pathology
      PubDate: 2022-05-24T09:11:02Z
      DOI: 10.1177/01926233221095443
       
  • The MNU Plus Testosterone Rat Model of Prostate Carcinogenesis

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      Authors: Maarten C. Bosland, Michael J. Schlicht, Lori Horton, David L. McCormick
      Abstract: Toxicologic Pathology, Ahead of Print.
      Animal models of prostate cancer are essential to identify chemopreventive treatments against this major male malignancy. The N-methyl-N-nitrosourea (MNU) plus testosterone rat model of prostate carcinogenesis is a reliable animal model that recapitulates human prostate cancer in many respects and has been used extensively in chemoprevention studies with good predictive value for the results of human clinical trials. The objective of this article is to describe the induction protocol of this model, demonstrate its robustness and reproducibility over time and across rat strains, provide diagnostic criteria for the identification of prostate lesions, and present the current tumor induction protocol so that others can use this model in a reliable manner. The majority of accessory sex gland tumors in this model are adenocarcinomas originating in the anterior and dorsolateral prostate that metastasize to lungs and abdominal structures. The rat strain used is of critical importance, with the commercially available Wistar WU and Fischer F344 strains yielding the highest tumor incidences. Low dose, long-term testosterone treatment is essential for a high tumor incidence, but in advanced stage, large adenocarcinomas do not appear to be androgen dependent. This rat model is a robust and reproducible prostate cancer animal model of human prostate cancer.
      Citation: Toxicologic Pathology
      PubDate: 2022-05-19T12:28:03Z
      DOI: 10.1177/01926233221096345
       
  • The Influence of Geographical Origin, Age, Sex, and Animal Husbandry on
           the Spontaneous Histopathology of Laboratory Cynomolgus Macaques (Macaca
           Fascicularis): A Contemporary Global and Multisite Review of Historical
           Control Data

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      Authors: Ronnie Chamanza, Stuart W. Naylor, Michela Gregori, Molly Boyle, Marcia E. Pereira Bacares, Elodie Drevon-Gaillot, Annette Romeike, Cynthia Courtney, Kelsey Johnson, Julie Turner, Nadine Swierzawski, Alok K. Sharma
      Abstract: Toxicologic Pathology, Ahead of Print.
      To investigate the influence of geographical origin, age, and sex on toxicologically relevant spontaneous histopathology findings in cynomolgus macaques (Macaca fascicularis), we performed a comparative analysis of historical control data (HCD) from 13 test sites that included 3351 animals (1645 females and 1706 males) sourced from Mauritius, China, Vietnam, and Cambodia, aged from 2 to 9.5 years, and from 446 toxicology studies evaluated between 2016 and 2021. The most common findings were mononuclear infiltrates in the kidney, liver, brain, and lung, which showed highest incidences in Mauritian macaques, and heart, salivary glands, and gastrointestinal tract (GIT), which showed highest incidences of mononuclear infiltrates in mainland Asian macaques. Developmental and degenerative findings were more common in Mauritian macaques, while lymphoid hyperplasia and lung pigment showed higher incidences in Asian macaques. Various sex and age-related differences were also present. Despite origin-related differences, the similarities in the nature and distribution of background lesions indicate that macaques from all geographical regions are suitable for toxicity testing and show comparable lesion spectrum. However, in a toxicity study, it is strongly recommended to use animals from a single geographical origin and to follow published guidelines when using HCD to evaluate and interpretate commonly diagnosed spontaneous lesions.
      Citation: Toxicologic Pathology
      PubDate: 2022-05-10T10:34:20Z
      DOI: 10.1177/01926233221096424
       
  • The Common Marmoset—Biomedical Research Animal Model Applications and
           Common Spontaneous Diseases

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      Authors: Hyo-Jeong Han, Sarah J. Powers, Kathleen L. Gabrielson
      Abstract: Toxicologic Pathology, Ahead of Print.
      Marmosets are becoming more utilized in biomedical research due to multiple advantages including (1) a nonhuman primate of a smaller size with less cost for housing, (2) physiologic similarities to humans, (3) translatable hepatic metabolism, (4) higher numbers of litters per year, (5) genome is sequenced, molecular reagents are available, (6) immunologically similar to humans, (7) transgenic marmosets with germline transmission have been produced, and (8) are naturally occurring hematopoietic chimeras. With more use of marmosets, disease surveillance over a wide range of ages of marmosets has been performed. This has led to a better understanding of the disease management of spontaneous diseases that can occur in colonies. Knowledge of clinical signs and histologic lesions can assist in maximizing the colony’s health, allowing for improved outcomes in translational studies within biomedical research. Here, we describe some basic husbandry, biology, common spontaneous diseases, and animal model applications for the common marmoset in biomedical research.
      Citation: Toxicologic Pathology
      PubDate: 2022-05-10T10:27:13Z
      DOI: 10.1177/01926233221095449
       
  • Gastric Neuroendocrine Tumors With Parietal Cell Atrophy in a Long-term
           Carcinogenicity Study in Rats

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      Authors: Norimitsu Shirai, Shambhunath Choudhary, Christopher Houle
      Abstract: Toxicologic Pathology, Ahead of Print.
      Malignant neuroendocrine tumors were diagnosed in the stomach of two out of sixty female Sprague-Dawley rats treated for 89 weeks with a high dose of a novel, small molecule, cannabinoid-1 antagonist. The tumors were associated with parietal cell atrophy accompanied by foveolar hyperplasia of the glandular stomach mucosa. Parietal cell atrophy/foveolar hyperplasia was considered test article related at the high dose, given the higher incidence and severity relative to untreated controls, although the precise mechanism of the parietal cell atrophy was undetermined. Spontaneous gastric neuroendocrine tumors are very rare in rats, and the current cases were considered secondary to parietal cell atrophy causing reduced gastric acid secretion and subsequent overstimulation of gastrin release through a feedback loop.
      Citation: Toxicologic Pathology
      PubDate: 2022-05-05T01:50:26Z
      DOI: 10.1177/01926233221095445
       
  • Selected Resources for Pathology Evaluation of Nonhuman Primates in
           Nonclinical Safety Assessment

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      Authors: Brad Bolon, Jeffrey I. Everitt
      Abstract: Toxicologic Pathology, Ahead of Print.
      Humans and nonhuman primates (NHPs) share numerous anatomical and physiological characteristics, thereby explaining the importance of NHPs as essential animal models for translational medicine and nonclinical toxicity testing. Researchers, toxicologic pathologists, toxicologists, and regulatory reviewers must be familiar with normal and abnormal NHP biological traits when designing, performing, and interpreting data sets from NHP studies. The current compilation presents a list of essential books, journal articles, and websites that provide context to safety assessment and research scientists working with NHP models. The resources used most frequently by the authors have been briefly annotated to permit readers to rapidly ascertain their applicability to particular research endeavors. The references are aimed primarily for toxicologic pathologists working with cynomolgus and rhesus macaques and common marmosets in efficacy and safety assessment studies.
      Citation: Toxicologic Pathology
      PubDate: 2022-04-28T12:31:03Z
      DOI: 10.1177/01926233221091763
       
  • Comparison of Routine Hematology, Coagulation, and Clinical Chemistry
           Parameters of Cynomolgus Macaques of Mauritius Origin With Cynomolgus
           Macaques of Cambodia, China, and Vietnam Origin

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      Authors: Tara Arndt, Mandy Meindel, Joseph Clarke, Amanda Shaw, Michela Gregori
      Abstract: Toxicologic Pathology, Ahead of Print.
      Cynomolgus macaques (Macaca fascicularis) are commonly used in safety assessment and as translational models for drug development. Recent supply chain pressures, exportation bans, and increased demand for drug safety assessment studies exacerbated by the COVID-19 pandemic have prompted the investigation of utilizing macaques of different geographic origin in preclinical toxicity studies. This study compares routine hematology, coagulation, and clinical chemistry endpoints of 3 distinct subpopulations of mainland Asia origin (Cambodia, China, and Vietnam) with Mauritius origin macaques compiling results of 3,225 animals from 123 regulatory toxicology studies conducted at North American and European Union contract research organization facilities between 2016 and 2019. Results were generally similar amongst the subpopulations compared in this study. Few notable differences in hematology test results and several minor differences in serum biochemistry and coagulation test results were identified when 3 distinct subpopulations of mainland Asia origin macaques were compared with Mauritius origin macaques. Our findings support the use of different origin macaques in drug development programs; however, emphasizes the importance of maintaining consistency in geographic origin of animals within a study.
      Citation: Toxicologic Pathology
      PubDate: 2022-04-25T01:31:19Z
      DOI: 10.1177/01926233221089843
       
  • Organ Weights in Relation to Age and Sex in Cynomolgus Monkeys (Macaca
           fascicularis)

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      Authors: Rachel Amato, Jean F. Gardin, Janet A. Tooze, J. Mark Cline
      Abstract: Toxicologic Pathology, Ahead of Print.
      Laboratory animal research is an important contributor to both human and animal medicine. Currently, there is extensive use of cynomolgus monkeys (Macaca fascicularis) in pathology and toxicology research. The purpose of this study was to define reference values for absolute and percentage organ weights in M fascicularis of different ages and sex. Organ weights were obtained from necropsies of 1022 cynomolgus monkeys at the Wake Forest School of Medicine from 1997 to 2018. Distributions of absolute and percentage weights for each organ were described; sex and age groups were compared using analysis of variance. Age effects on percentage of body weights for each organ were analyzed within each sex. Diet effects were also analyzed. This evaluation showed that male body weights and absolute organ weights were greater for all age groups; however, female organ to body weight percentages were greater for most organs. Percentage of organ weight to body weight declined for the adrenals, brain, lung, thyroid and thymus during maturation, whereas percentage weight of pancreas, prostate, testes, and uterus increased. Animals consuming a high-fat, Western-type diet had a lower body weight than animals consuming a carbohydrate-rich chow diet. This information will be useful for further toxicology and pathology studies concerning cynomolgus monkeys.
      Citation: Toxicologic Pathology
      PubDate: 2022-04-06T11:17:26Z
      DOI: 10.1177/01926233221088283
       
  • Common and Not-So-Common Pathologic Findings of the Gastrointestinal Tract
           of Rhesus and Cynomolgus Macaques

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      Authors: Amanda L. Johnson, Rebekah I. Keesler, Anne D. Lewis, J. Rachel Reader, Steven T. Laing
      Abstract: Toxicologic Pathology, Ahead of Print.
      Rhesus and cynomolgus macaques are the most frequently used nonhuman primate (NHP) species for biomedical research and toxicology studies of novel therapeutics. In recent years, there has been a shortage of laboratory macaques due to a variety of competing factors. This was most recently exacerbated by the surge in NHP research required to address the severe acute respiratory syndrome (SARS)-coronavirus 2 pandemic. Continued support of these important studies has required the use of more varied cohorts of macaques, including animals with different origins, increased exposure to naturally occurring pathogens, and a wider age range. Diarrhea and diseases of the gastrointestinal tract are the most frequently occurring spontaneous findings in macaques of all origins and ages. The purpose of this review is to alert pathologists and scientists involved in NHP research to these findings and their impact on animal health and study endpoints, which may otherwise confound the interpretation of data generated using macaques.
      Citation: Toxicologic Pathology
      PubDate: 2022-04-01T12:51:25Z
      DOI: 10.1177/01926233221084634
       
  • Pseudoreticulocytosis by the ADVIA 2120 Hematology Analyzer and Other
           Hematologic Changes in a Cynomolgus Macaque (Macaca fascicularis) With
           Malaria

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      Authors: Diya Sharma, Heather Priest, Angela Wilcox
      Abstract: Toxicologic Pathology, Ahead of Print.
      Important hematologic changes can be observed in nonhuman primates with malaria, including inaccurate reticulocyte counts by the ADVIA 2120 hematology analyzer. A 5-year-old male purpose-bred cynomolgus macaque (Macaca fascicularis) imported from a commercial source in Cambodia was enrolled in a nonclinical toxicity study investigating the effects of an immunomodulatory pharmaceutical agent. On study day 22, an increase in large unstained cells (LUCs), due to increased monocytes (2.20 × 103/µl, reference interval: 0.17-0.76 × 103/µl), was reported by the analyzer during a scheduled hematologic evaluation, which prompted blood smear review and revealed that the macaque had a high burden of Plasmodium spp.. The macaque did not have clinical signs for the infection at this time point. Progressively higher parasite burdens and persistently increased monocytes (markedly increased by study day 56, 10.38 × 103/µl) were observed at subsequent hematologic evaluations. New Methylene Blue stain manual reticulocyte counts were performed on study day 43 and at later time points, and showed that the analyzer reported erroneous higher reticulocyte counts (study day 43: +6.7%, +266.2 × 109/L; study day 50: +18.9%, +409.8 × 109/L) compared with the manual reticulocyte counts (pseudoreticulocytosis). The magnitude of regenerative response was considered inadequate for the severity of anemia at these time points. Atypical reticulocyte scatter plot distributions from the analyzer were also observed at time points with high parasite burdens, and combined with increased LUCs, may suggest high burden parasitemia. Verification of automated reticulocyte counts is important in cases with high malarial parasite burdens and the recognition of pseudoreticulocytosis is prudent in assessing appropriateness of the regenerative response. Increases in monocytes correlated with higher parasite burdens and marked increases may be an indicator of advanced disease.
      Citation: Toxicologic Pathology
      PubDate: 2022-03-14T10:49:23Z
      DOI: 10.1177/01926233221083217
       
  • Spontaneous Findings in the Reproductive System of Sexually Mature Male
           Cynomolgus Macaques

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      Authors: Justin D. Vidal, Manoj Bhaskaran, Mary Carsillo, Steve Denham, Olivia Dubay, Steven Laing, Bala subramanian Manickam, Stephanie Phillips, Jonathan Werner, Armando R. Irizarry Rovira
      Abstract: Toxicologic Pathology, Ahead of Print.
      Sexually mature nonhuman primates are often used in nonclinical safety testing when evaluating biopharmaceuticals; however, there is limited information in historical control databases or in the published literature on the spontaneous findings in the male reproductive system. This review evaluated digital slides from the male reproductive tract (testes, epididymides, prostate, and seminal vesicles) in sexually mature cynomolgus macaques (Macaca fascicularis; n = 255) from vehicle control groups in nonclinical toxicology studies and compared the observations with body weight, organ weight, and geographical origin. The most common microscopic findings were hypospermatogenesis and tubular dilatation in the testes; inflammatory cell infiltrate, cellular debris, and decreased sperm in the epididymides; inflammatory cell infiltrate and acinar dilatation in the prostate; and corpora amylacea and atrophy in the seminal vesicles. There were a few correlative observations in animals when grouped by weight or geographical origin: animals with lower terminal body weights (
      Citation: Toxicologic Pathology
      PubDate: 2022-03-14T10:35:59Z
      DOI: 10.1177/01926233221082302
       
  • Society of Toxicologic Pathology Nonhuman Primate Special Interest Group:
           Idiopathic Femoral Head Chondrolysis in Nonclinical Research Macaques

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      Authors: Michelle A. Magagna, Shelley L. Beazley, Jesse W. Veenstra, Michelle A. Newell, Daniel J. Patrick
      Abstract: Toxicologic Pathology, Ahead of Print.
      Idiopathic femoral head chondrolysis is a recognized condition in human adolescents and has previously been reported in two macaques at a biomedical research facility. A cluster of coxofemoral joint abnormalities consistent with this condition affecting seven cynomolgus macaques over a four-month period in 2016 and 2017 was observed at a single, nonclinical contract research facility, prompting enhanced physical examination screening efforts during animal receipt and pre-study evaluation to identify additional affected animals. This article summarizes the results of this investigation from November 2016 to March 2021, yielding 97 total cases for an overall incidence of 0.54% (97/17,898 macaques). Affected animals were presented with one or more of the following unilateral or bilateral findings on physical examination and/or diagnostic imaging: lameness, palpable coxofemoral joint abnormalities, femoral head atrophy with variable loss of articular cartilage and irregularity of the femoral head surface, enlarged joint space with effusion, and increased radiographic density of the femoral head. This condition prevented use of affected animals on study for 54% of the cases (52/97 animals). Recognition of this idiopathic condition is important in drug safety evaluation studies to distinguish it from test article–related effects.
      Citation: Toxicologic Pathology
      PubDate: 2022-03-14T01:17:39Z
      DOI: 10.1177/01926233221082306
       
  • Modeling SARS-CoV-2: Comparative Pathology in Rhesus Macaque and Golden
           Syrian Hamster Models

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      Authors: Shambhunath Choudhary, Isis Kanevsky, Soner Yildiz, Rani S. Sellers, Kena A. Swanson, Tania Franks, Raveen Rathnasinghe, Raquel Munoz-Moreno, Sonia Jangra, Olga Gonzalez, Philip Meade, Timothy Coskran, Jessie Qian, Thomas A. Lanz, Jillian G. Johnson, Cassandra A Tierney, Justin D. Smith, Kristin Tompkins, Arthur Illenberger, Paula Corts, Tara Ciolino, Philip R. Dormitzer, Edward J. Dick, Vinay Shivanna, Shannan Hall-Ursone, Journey Cole, Deepak Kaushal, Jane A. Fontenot, Carles Martinez-Romero, Meagan McMahon, Florian Krammer, Michael Schotsaert, Adolfo García-Sastre
      First page: 280
      Abstract: Toxicologic Pathology, Ahead of Print.
      Coronavirus disease 2019 (COVID-19) in humans has a wide range of presentations, ranging from asymptomatic or mild symptoms to severe illness. Suitable animal models mimicking varying degrees of clinical disease manifestations could expedite development of therapeutics and vaccines for COVID-19. Here we demonstrate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection resulted in subclinical disease in rhesus macaques with mild pneumonia and clinical disease in Syrian hamsters with severe pneumonia. SARS-CoV-2 infection was confirmed by formalin-fixed, paraffin-embedded (FFPE) polymerase chain reaction (PCR), immunohistochemistry, or in situ hybridization. Replicating virus in the lungs was identified using in situ hybridization or virus plaque forming assays. Viral encephalitis, reported in some COVID-19 patients, was identified in one macaque and was confirmed with immunohistochemistry. There was no evidence of encephalitis in hamsters. Severity and distribution of lung inflammation were substantially more in hamsters compared with macaques and exhibited vascular changes and virus-induced cytopathic changes as seen in COVID-19 patients. Neither the hamster nor macaque models demonstrated evidence for multisystemic inflammatory syndrome (MIS). Data presented here demonstrate that macaques may be appropriate for mechanistic studies of mild asymptomatic COVID-19 pneumonia and COVID-19-associated encephalitis, whereas Syrian hamsters may be more suited to study severe COVID-19 pneumonia.
      Citation: Toxicologic Pathology
      PubDate: 2022-02-05T10:04:12Z
      DOI: 10.1177/01926233211072767
       
  • Toxicity and Local Tolerance of a Novel Spike Protein RBD Vaccine Against
           SARS-CoV-2, Produced Using the C1 Thermothelomyces Heterothallica Protein
           Expression Platform

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      Authors: Yuval Ramot, Noam Kronfeld, Yakir Ophir, Nati Ezov, Sheli Friedman, Markku Saloheimo, Marika Vitikainen, Hanna Ben-Artzi, Avi Avigdor, Ronen Tchelet, Noelia Valbuena Crespo, Mark Emalfarb, Abraham Nyska
      First page: 294
      Abstract: Toxicologic Pathology, Ahead of Print.
      Coronavirus disease 2019 (COVID-19) has caused the ongoing COVID-19 pandemic and there is a growing demand for safe and effective vaccines. The thermophilic Thermothelomyces heterothallica filamentous fungal host, C1-cell, can be utilized as an expression platform for the rapid production of large quantities of antigens for developing vaccines. The aim of this study was to evaluate the local tolerance and the systemic toxicity of a C1-cell expressed receptor-binding domain (C1-RBD) vaccine, following repeated weekly intramuscular injections (total of 4 administrations), in New Zealand White rabbits. The animals were sacrificed either 3 days or 3 weeks following the last dose. No signs of toxicity were observed, including no injection site reactions. ELISA studies revealed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunoglobulin G antibodies in the sera of C1-RBD-treated animals starting from day 13 post injection, that were further elevated. Histopathology evaluation and immunohistochemical staining revealed follicular hyperplasia, consisting of B-cell type, in the spleen and inguinal lymph nodes of the treated animals that were sustained throughout the recovery phase. No local or systemic toxicity was observed. In conclusion, the SARS-CoV-2 C1-RBD vaccine candidate demonstrated an excellent safety profile and a lasting immunogenic response against receptor-binding domain, thus supporting its further development for use in humans.
      Citation: Toxicologic Pathology
      PubDate: 2022-05-06T06:07:08Z
      DOI: 10.1177/01926233221090518
       
  • Immunohistochemical Characterization of Proliferative Lesions in the
           Thymus of Aging CD-1 Mice From Two Studies on the RITA Database, With
           Special Reference to the Perivascular Space

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      Authors: Juergen Funk, Christine Ruehl-Fehlert, Catherine Leonard, Rupert Kellner, Susanne Rittinghausen
      First page: 308
      Abstract: Toxicologic Pathology, Ahead of Print.
      Thymic lymphoid hyperplasia is a common age-related finding, which occurs particularly in female CD-1 mice. The main differential diagnoses are malignant lymphoma and thymoma. A systematic investigation of control groups from two carcinogenicity studies was performed including measurements of thymic size, and the immunohistochemistry (IHC) markers pan-Cytokeratin (pan-CK) for thymic epithelial cells; CD3 and CD45R/B220 for T and B lymphocytes, respectively; CD31 for endothelial cells; and F4/80 for macrophages. Thymoma can be differentiated by increased numbers of proliferating epithelial cells demonstrated by pan-CK IHC staining. Differentiation between lymphoid hyperplasia and lymphoma is more challenging as a mixture of B and T lymphocytes can be present in both findings. The present investigation showed that the thymic perivascular space is the compartment where the increased numbers of lymphocytes in hyperplasia are localized and not the medulla, as previously thought. The lymphoepithelial compartment is atrophic to the same extent in thymi diagnosed with age-related involution or lymphoid hyperplasia. Both diagnoses are thus related to variations in lymphoid cellularity of the nonepithelial perivascular space, which is continuous with the perithymic tissue. Likewise, lymphomas have a predilection to colonize the perivascular space and to spare the lymphoepithelial compartment.
      Citation: Toxicologic Pathology
      PubDate: 2022-03-24T06:45:12Z
      DOI: 10.1177/01926233221082972
       
  • Developing a Solution for Nasal and Olfactory Transport of Nanomaterials

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      Authors: Ryan C. O’Connell, Tiana M. Dodd, Sidney M. Clingerman, Kara L. Fluharty, Jayme Coyle, Todd A. Stueckle, Dale W. Porter, Lauren Bowers, Aleksandr B. Stefaniak, Alycia K. Knepp, Raymond Derk, Michael Wolfarth, Robert R. Mercer, Theresa E. Boots, Krishnan Sriram, Ann F. Hubbs
      First page: 329
      Abstract: Toxicologic Pathology, Ahead of Print.
      With advances in nanotechnology, engineered nanomaterial applications are a rapidly growing sector of the economy. Some nanomaterials can reach the brain through nose-to-brain transport. This transport creates concern for potential neurotoxicity of insoluble nanomaterials and a need for toxicity screening tests that detect nose-to-brain transport. Such tests can involve intranasal instillation of aqueous suspensions of nanomaterials in dispersion media that limit particle agglomeration. Unfortunately, protein and some elements in existing dispersion media are suboptimal for potential nose-to-brain transport of nanomaterials because olfactory transport has size- and ion-composition requirements. Therefore, we designed a protein-free dispersion media containing phospholipids and amino acids in an isotonic balanced electrolyte solution, a solution for nasal and olfactory transport (SNOT). SNOT disperses hexagonal boron nitride nanomaterials with a peak particle diameter below 100 nm. In addition, multiwalled carbon nanotubes (MWCNTs) in an established dispersion medium, when diluted with SNOT, maintain dispersion with reduced albumin concentration. Using stereomicroscopy and microscopic examination of plastic sections, dextran dyes dispersed in SNOT are demonstrated in the neuroepithelium of the nose and olfactory bulb of B6;129P2-Omptm3Mom/MomJ mice after intranasal instillation in SNOT. These findings support the potential for SNOT to disperse nanomaterials in a manner permitting nose-to-brain transport for neurotoxicity studies.
      Citation: Toxicologic Pathology
      PubDate: 2022-04-13T09:10:03Z
      DOI: 10.1177/01926233221089209
       
  • Quantification of Hepatocellular Mitoses in a Toxicological Study in Rats
           Using a Convolutional Neural Network

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      Authors: Fabian Heinemann, Charlotte Lempp, Florian Colbatzky, Ulrich Deschl, Thomas Nolte
      First page: 344
      Abstract: Toxicologic Pathology, Ahead of Print.
      Convolutional neural networks (CNNs) have been recognized as valuable tools for rapid quantitative analysis of morphological changes in toxicologic histopathology. We have assessed the performance of CNN-based (Halo-AI) mitotic figure detection in hepatocytes in comparison with detection by pathologists. In addition, we compared with Ki-67 and 5-bromodesoxyuridin (BrdU) immunohistochemistry labeling indices (LIs) obtained by image analysis. Tissues were from an exploratory toxicity study with a glycogen synthase kinase-3 (GSK-3) inhibitor. Our investigations revealed that (1) the CNN achieved similarly accurate but faster results than pathologists, (2) results of mitotic figure detection were comparable to Ki-67 and BrdU LIs, and (3) data from different methods were only moderately correlated. The latter is likely related to differences in the cell cycle component captured by each method. This highlights the importance of considering the differences of the available methods upon selection. Also, the pharmacology of our test item acting as a GSK-3 inhibitor potentially reduced the correlation. We conclude that hepatocyte cell proliferation assessment by CNNs can have several advantages when compared with the current gold standard: it relieves the pathologist of tedious routine tasks and contributes to standardization of results; the CNN algorithm can be shared and iteratively improved; it can be performed on routine histological slides; it does not require an additional animal experiment and in this way can contribute to animal welfare according to the 3R principles.
      Citation: Toxicologic Pathology
      PubDate: 2022-03-24T06:46:50Z
      DOI: 10.1177/01926233221083500
       
  • Possible Cytoprotection of Low Dose Lipopolysaccharide in Rat
           Thioacetamide-Induced Liver Lesions, Focusing on the Analyses of Hepatic
           Macrophages and Autophagy

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      Authors: Munmun Pervin, Mohammad Rabiul Karim, Mizuki Kuramochi, Takeshi Izawa, Mitsuru Kuwamura, Jyoji Yamate
      First page: 353
      Abstract: Toxicologic Pathology, Ahead of Print.
      Lipopolysaccharide (LPS) may influence hepatic macrophages and autophagy. We evaluated the potential participation of macrophages and autophagosomes in thioacetamide (TAA)-induced rat liver injury under pretreatment of a low dose LPS (0.1 mg/kg BW, intraperitoneally; nonhepatotoxic dose). F344 rats were pretreated with LPS (LPS + TAA) or saline (TAA alone) at 24 hours before TAA injection (100 mg/kg BW, intraperitoneally); rats were examined on Days 0 (controls), 1, 2, and 3 after TAA injection. Data were compared between TAA alone and LPS + TAA rats. LPS pretreatment significantly reduced TAA-induced hepatic lesion (centrilobular necrosis with inflammation) on Days 1 and 2, being reflected by declined hepatic enzyme values and decreased number of apoptotic cells. LC3B-immunoreacting autophagosomes (as cytoplasmic fine granules) were significantly increased on Days 1 and 2 in hepatocytes of LPS + TAA rats. In LPS + TAA rats, hepatic macrophages reacting to CD68, CD163, and MHC class II mainly on Day 2 and mRNA levels of macrophage-related factors (MCP-1, IL-1β, and IL-4) on Day 1 were significantly decreased. Collectively, the low-dose LPS pretreatment might act as cytoprotection against TAA-induced hepatotoxicity through increased autophagosomes and decreased hepatic macrophages, although the dose/time-dependent cytoprotection of LPS should be further investigated at molecular levels.
      Citation: Toxicologic Pathology
      PubDate: 2022-02-10T10:48:50Z
      DOI: 10.1177/01926233221076758
       
  • In Utero Exposure to 3,3′,4,4′, 5-Pentachlorobiphenyl Dose-Dependently
           Induces N-butyl-4-(hydroxybutyl) Nitrosamine in Rats With Urinary Bladder
           Carcinoma

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      Authors: Shin Wakui, Hiroyuki Takahashi, Tomoko Muto
      First page: 366
      Abstract: Toxicologic Pathology, Ahead of Print.
      Polychlorinated biphenyls (PCBs) are fat-soluble environmental pollutants that can accumulate in adipose tissue or be secreted in milk. N-butyl-4-(hydroxy butyl) (BBN), a rat bladder carcinogen, recruits the host metabolism to yield its ultimate carcinogenic form via CYP1s. Since estrogen receptors (ERs) mediate biological responses important for the growth of bladder carcinoma, we investigated PCNA, Cyclin D1, ERs, CYP1s, and AhR expression in BBN rat bladder carcinomas with prenatal PCB exposure. Female SD rats were treated with 7.5 μg, 250 ng, and 2.5 ng of 3,3′,4,4′,5-pentachlorobiphenyl (PCB126)/kg or vehicle on days 13 to 19 post-pregnancy. Six-week-old male offspring were treated with 0.05% BBN for 10 weeks before being anesthetized and the urinary bladder wall incised to expose the bladder carcinomas. N-butyl-4-(hydroxybutyl) bladder carcinoma incidence increased with prenatal PCB exposure dose-dependently. In bladder carcinoma, PCB126 exposure significantly increased PCNA, D1, ERα, CYPIA1, CYP1B1, and AhR expression dose-dependently, and increased ERα expression was particularly prominent. However, the expression of ERβ was low, independent of the volume of PCB126 given, indicating similarity to the Vehicle group. We conclude that prenatal PCB126 exposure in rats can induce PCB126 to dose-dependently metabolize BBN via CYP1A1, and contribute to bladder carcinogenesis with upregulation of ERα expression.
      Citation: Toxicologic Pathology
      PubDate: 2022-01-20T09:21:02Z
      DOI: 10.1177/01926233211064180
       
  • Bortezomib-Induced Ovarian Toxicity in Mice

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      Authors: Duygu Mutluay, Gözde Yücel Tenekeci, Yanad Abou Monsef
      First page: 381
      Abstract: Toxicologic Pathology, Ahead of Print.
      Cancer survivors may experience long-term adverse effects of cancer treatments such as premature ovarian failure and infertility. We aimed to investigate the potential effects and toxicity of bortezomib (BTZ) as an effective anticancer drug on ovaries, raise awareness to the negative consequences of the treatment, and help increase the quality of life after treatment. Mice were distributed into bortezomib (BTZ1, BTZ2) and saline-injected control groups (C1, C2) at a dose of 1 mg/kg twice per week for 6 weeks. We sacrificed C1, BTZ1 groups at day 1 and C2, BTZ2 groups at 4 weeks after the last injection. Ovary samples were examined using histopathological and immunohistochemical methods. Ovarian follicle impairment was detected on BTZ-treated mice and was associated with a statistically significant decreased population of primordial and antral follicles compared with control groups. In experimental groups, Caspase-3 and Ki67 expressions were increased, whereas estrogen receptor alpha (ERα) and progesterone receptor (PR) expressions were decreased in various developmental stages of follicles. BTZ specifically targets granulosa cells by inducing granulosa cell apoptosis and may have long-term effects on follicles. Bortezomib treatment may adversely affect ovarian function by accelerating ovarian reserve depletion and changing ERα and PR hormone levels that can cause fertility problems in the long term.
      Citation: Toxicologic Pathology
      PubDate: 2022-03-30T12:00:52Z
      DOI: 10.1177/01926233221083527
       
  • Degenerative Myelopathy and Neuropathy in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ
           (NSG) Mice Caused by Lactate Dehydrogenase–Elevating Virus (LDV)

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      Authors: P. Yang, Z. T. Freeman, R. C. Dysko, M. J. Hoenerhoff
      First page: 390
      Abstract: Toxicologic Pathology, Ahead of Print.
      Following implantation of patient-derived xenograft (PDX) breast carcinomas from three separate individuals, 33/51 female NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice presented with progressive, unilateral to bilateral, ascending hindlimb paresis to paralysis. Mice were mildly dehydrated, in thin to poor body condition, with reduced to absent hindlimb withdrawal reflex and deep pain sensation. Microscopically, there was variable axonal swelling, vacuolation, and dilation of myelin sheaths within the ventral spinal cord and spinal nerve roots of the thoracolumbar and sacral spinal cord, as well as within corresponding sciatic nerves. Results of PCR screening of PDX samples obtained at necropsy and pooled environmental swabs from the racks housing affected animals were positive for lactate dehydrogenase–elevating virus (LDV). LDV is transmitted through animal-animal contact or commonly as a contaminant of biologic materials of mouse origin. Infection is associated with progressive degenerative myelopathy and neuropathy in strains of mice harboring endogenous retrovirus (AKR, C58), or in immunosuppressed strains (NOD-SCID, Foxn1nu), and can interfere with normal immune responses and alter engraftment and growth of xenograft tumors in immunosuppressed mice. This is the first reported series of LDV-induced poliomyelitis in NSG mice and should be recognized as a potentially significant confounder to biomedical studies utilizing immunodeficient xenograft models.
      Citation: Toxicologic Pathology
      PubDate: 2022-04-22T05:41:09Z
      DOI: 10.1177/01926233221091747
       
  • Scientific and Regulatory Policy Committee Brief Communication: 2019
           Survey on Use of Digital Histopathology Systems in Nonclinical Toxicology
           Studies

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      Authors: Thomas Forest, Famke Aeffner, Dinesh S. Bangari, Bhupinder Bawa, Jonathan Carter, James Fikes, Wanda B. High, Shim-mo Hayashi, Matthew Jacobsen, LuAnn McKinney, Daniel Rudmann, Thomas Steinbach, Vanessa Schumacher, Oliver C. Turner, Jerrold M. Ward, Cynthia J. Willson
      First page: 397
      Abstract: Toxicologic Pathology, Ahead of Print.
      Histopathologic evaluation and peer review using digital whole-slide images (WSIs) is a relatively new medium for assessing nonclinical toxicology studies in Good Laboratory Practice (GLP) environments. To better understand the present and future use of digital pathology in nonclinical toxicology studies, the Society of Toxicologic Pathology (STP) formed a working group to survey STP members with the goal of creating recommendations for implementation. The survey was administered in December 2019, immediately before the COVID-19 pandemic, and the results suggested that the use of digital histopathology for routine GLP histopathology assessment was not widespread. Subsequently, in follow-up correspondence during the pandemic, many responding institutions either began investigating or adopting digital WSI systems to reduce employee exposure to COVID-19. Therefore, the working group presents the survey results as a pre-pandemic baseline data set. Recommendations for use of WSI systems in GLP environments will be the subject of a separate publication.
      Citation: Toxicologic Pathology
      PubDate: 2022-03-24T06:48:10Z
      DOI: 10.1177/01926233221084621
       
 
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