Toxicologic Pathology最新文献

Carcinogenicity Risk Assessment of Targeted Protein Degraders. 靶向蛋白降解物的致癌性风险评估。

IF 1.8 4区医学

Toxicologic Pathology Pub Date : 2026-04-29 DOI: 10.1177/01926233261439117

James Sidaway, Emily E Meseck

{"title":"Carcinogenicity Risk Assessment of Targeted Protein Degraders.","authors":"James Sidaway, Emily E Meseck","doi":"10.1177/01926233261439117","DOIUrl":"https://doi.org/10.1177/01926233261439117","url":null,"abstract":"Targeted protein degraders (TPDs) have recently emerged as a novel drug class. Targeted protein degraders engage E3 ubiquitin ligase complexes to degrade therapeutic proteins of interest via cereblon and other adapter proteins, acting as either molecular glue degraders (MGDs) or proteolysis-targeting chimeras (PROTACs). Several cereblon-based MGDs and PROTACs are in late-stage clinical development for oncology indications. However, as TPD drug discovery includes non-life-threatening indications, carcinogenicity risk assessment will be required. Although there is no regulatory requirement to treat TPDs differently from conventional small molecules in carcinogenesis risk assessment, several properties of TPDs could influence weight of evidence (WoE) assessments and carcinogenicity study design. A series of case studies is presented to provide examples for evolved, modified WoE approaches for carcinogenicity assessment that may be acceptable to health authorities and regulatory agencies. These examples also highlight that the biological assessment of E3 ligase is as critically important to the carcinogenicity and toxicology assessment as is the assessment of the primary target. Finally, drug developers must contend with limitations for early-generation cereblon MGDs related to the translatability of findings that may challenge traditional interpretation paradigms.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233261439117"},"PeriodicalIF":1.8,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147782023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Carcinogenicity in the 21st Century: Data Interpretation-Session 4. 21世纪的致癌性：数据解释-第4部分。

IF 1.8 4区医学

Toxicologic Pathology Pub Date : 2026-04-08 DOI: 10.1177/01926233261435939

Sandra De Jonghe, Matthew Jacobsen, Jim Saul, Alys Bradley, John R Foster, Zuhal Dincer, Ute Bach, Tanasa Osborne

引用次数: 0

Thymic Epithelial Hyperplasia and Thymoma in Control rasH2 Transgenic Mice From 26-Week Carcinogenicity Assays. 对照rasH2转基因小鼠胸腺上皮增生和胸腺瘤的26周致癌性研究

IF 1.8 4区医学

Toxicologic Pathology Pub Date : 2026-04-05 DOI: 10.1177/01926233261429439

Sasmita Mishra, Vimala Vemireddi, Marcia E Pereira Bacares, Molly H Boyle, Mark Mense, Alok K Sharma

{"title":"Thymic Epithelial Hyperplasia and Thymoma in Control rasH2 Transgenic Mice From 26-Week Carcinogenicity Assays.","authors":"Sasmita Mishra, Vimala Vemireddi, Marcia E Pereira Bacares, Molly H Boyle, Mark Mense, Alok K Sharma","doi":"10.1177/01926233261429439","DOIUrl":"https://doi.org/10.1177/01926233261429439","url":null,"abstract":"Since the FDA's approval in 2003, transgenic rasH2 (Tg.rasH2) mice have been used as alternative models to assess the carcinogenic potential of new drug candidates. While several articles documenting spontaneous non-neoplastic and neoplastic findings in Tg.rasH2 mice have been published, the incidence and morphologic criteria of proliferative thymic epithelial lesions have not been discussed in detail. Here we report the incidence and diagnostic morphologic criteria of non-neoplastic (epithelial hyperplasia) and neoplastic (benign and malignant thymoma) proliferative findings in the thymus. Incidences were derived through a review of pathology data from 3948 male and female control Tg.rasH2 mice from sixty-three 26-week carcinogenicity studies conducted at Labcorp, Madison, WI, between 2012 and 2024. Compared with published literature, an increased incidence of epithelial hyperplasia was noted in both sexes, with a higher incidence noted in females (7.4%) versus males (3.4%). Benign thymomas occurred at a higher-than-published incidence in both sexes, being more frequent in females (1.8% in females vs 0.7% in males), and our data also documented the first occurrence of malignant thymoma in this mouse strain, which was also more common in females (1% in females vs 0.7% in males). The epithelial features of selected proliferative findings were confirmed by immunohistochemistry using pan-cytokeratin.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233261429439"},"PeriodicalIF":1.8,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147623741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

No Clear Evidence of Histopathological Effects Linked to NSAIDs in the Kidney or Liver of Fish Exposed to Treated Municipal Wastewaters. 没有明确的证据表明非甾体抗炎药对暴露于处理过的城市废水的鱼的肾脏或肝脏有组织病理学影响。

IF 1.8 4区医学

Toxicologic Pathology Pub Date : 2026-04-05 DOI: 10.1177/01926233261423895

Johanna Näslund, Leif Norrgren, D G Joakim Larsson

{"title":"No Clear Evidence of Histopathological Effects Linked to NSAIDs in the Kidney or Liver of Fish Exposed to Treated Municipal Wastewaters.","authors":"Johanna Näslund, Leif Norrgren, D G Joakim Larsson","doi":"10.1177/01926233261423895","DOIUrl":"https://doi.org/10.1177/01926233261423895","url":null,"abstract":"Non-steroidal anti-inflammatory drugs (NSAIDs) can cause histopathological changes in the kidney and liver of fish. Still, it is unclear whether exposure to treated municipal wastewater that contains NSAID residues causes similar effects. We therefore conducted a comprehensive, critical review on claimed histopathological changes in fish exposed either to NSAIDs or to treated municipal wastewater in the laboratory or downstream from treatment plants. A detailed scrutinization questioned the basis for several findings. Hepatocellular necrosis, hepatocellular vacuolation, and an increase of developing nephrons/basophilic clusters (DNs/BCs) were overlapping findings, but the lowest observed effect concentrations (LOEC) for the hepatic endpoints were well above concentrations frequently encountered in treated effluents. An increase of DNs/BCs were reported at lower NSAID concentrations, but with some concerns regarding reliability. Hence, there is no clear documentation that histopathological effects caused by NSAIDs are present in fish exposed to municipal effluents. Study design, including the species studied, exposure regimes, endpoints analyzed, and applied methodology varied widely between studies, all of which could make overlapping effects difficult to detect. In addition, limitations in both experimental design and reporting standards in fish histopathology studies prevent any firm conclusions. More comparable study designs in future studies would facilitate comparisons.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233261423895"},"PeriodicalIF":1.8,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147623710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Carcinogenicity Risk Assessment of Agrochemicals and Pharmaceuticals. 农用化学品和药品致癌性风险评估。

IF 1.8 4区医学

Toxicologic Pathology Pub Date : 2026-04-05 DOI: 10.1177/01926233261435923

Xavier Palazzi, Samuel M Cohen, Stephanie Melching-Kollmuss, Thomas Nolte, Frederic Schorsch, Kris Siezen, Douglas Wolf, Lindsay Wright

引用次数: 0

Deep Learning-Based Image Analysis Model for Classification and Quantification of Multiple Histopathological Findings in Rat Testis and Epididymis. 基于深度学习的图像分析模型对大鼠睾丸和附睾多种组织病理学结果的分类和量化。

IF 1.8 4区医学

Toxicologic Pathology Pub Date : 2026-04-05 DOI: 10.1177/01926233261429448

Taishi Shimazaki, Rohit Garg, Pranab Samanta, Amogh Mohanty, Tijo Thomas, Kyotaka Muta, Naohito Yamada, Yuzo Yasui, Toshiyuki Shoda

{"title":"Deep Learning-Based Image Analysis Model for Classification and Quantification of Multiple Histopathological Findings in Rat Testis and Epididymis.","authors":"Taishi Shimazaki, Rohit Garg, Pranab Samanta, Amogh Mohanty, Tijo Thomas, Kyotaka Muta, Naohito Yamada, Yuzo Yasui, Toshiyuki Shoda","doi":"10.1177/01926233261429448","DOIUrl":"https://doi.org/10.1177/01926233261429448","url":null,"abstract":"Supervised deep learning-based image analysis models using whole slide images (WSIs) have been reported to be effective for detecting simple histopathological findings in laboratory animals. However, there are no models that simultaneously detect multiple types of abnormal testicular findings on hematoxylin and eosin (H&E)-stained specimens in rats. In this study, we developed a model that can detect, classify, and quantify major 7 testicular toxicity findings in rats (degeneration of germ cell, tubular atrophy, tubular dilatation, vacuolation of Sertoli cell, multinucleated giant cell in the testis, and decreased sperm and cell debris in the epididymis) in addition to classify spermatogenic stages on H&E-stained WSIs. For training the model, we used WSIs of the testis and epididymis of rats that were administered various compounds in toxicity studies, and we developed it using supervised deep learning algorithms and WSI data sets. Detection accuracy of the spermatogenic stage classification and the 7 findings generated by the model was compared with histopathological diagnoses made by board-certified pathologists and confirmed to be high performance. Therefore, this model is a useful tool to support histopathological evaluation, especially in initial screening in rat toxicity studies and is expected to improve work efficiency and prevent errors due to oversights.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233261429448"},"PeriodicalIF":1.8,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147623685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Scientific and Regulatory Policy Committee Points to Consider*: Sample Selection, Assay Design, Data Generation and Interpretation, and Reporting Practices for Chromogenic Immunohistochemical (IHC) Assays in Nonclinical Drug Development. 科学和监管政策委员会考虑的要点*：非临床药物开发中显色免疫组化（IHC）分析的样本选择、分析设计、数据生成和解释以及报告实践。

IF 1.8 4区医学

Toxicologic Pathology Pub Date : 2026-04-01 Epub Date: 2025-12-30 DOI: 10.1177/01926233251393154

Famke Aeffner, Brad Bolon, Molly H Boyle, Bernard S Buetow, Thomas Forest, Kyathanahalli Janardhan, Keith Mansfield, David K Meyerholz, Shari Price, Marlon C Rebelatto

{"title":"Scientific and Regulatory Policy Committee Points to Consider*: Sample Selection, Assay Design, Data Generation and Interpretation, and Reporting Practices for Chromogenic Immunohistochemical (IHC) Assays in Nonclinical Drug Development.","authors":"Famke Aeffner, Brad Bolon, Molly H Boyle, Bernard S Buetow, Thomas Forest, Kyathanahalli Janardhan, Keith Mansfield, David K Meyerholz, Shari Price, Marlon C Rebelatto","doi":"10.1177/01926233251393154","DOIUrl":"10.1177/01926233251393154","url":null,"abstract":"Chromogenic immunohistochemistry (IHC) is an important molecular localization assay in biomedical research and nonclinical drug development, enabling the visualization of specific epitopes within tissues. The methodology is widely used in drug target selection, risk assessment, understanding disease biology, and characterizing histopathological findings in nonclinical studies. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology formed a working group to compile essential information on chromogenic IHC assays not performed in compliance with Good Laboratory Practice (GLP) from nonclinical studies, using relevant literature and the Working Group members' collective expertise. In this \"Points to Consider\" article, emphasis is placed on factors influencing IHC data quality, including sample selection, general assay considerations, data generation and interpretation, and effective reporting. The Working Group members deliberated extensively on pertinent topics, aiming to provide specific and practical guidance for pathologists, histologists, and allied scientists engaged in chromogenic IHC assays. While refraining from an exhaustive exploration of the intricate technical details associated with chromogenic IHC, this article offers insights to enhance the accuracy, credibility, and reproducibility of chromogenic IHC, thereby facilitating informed decision-making in the nonclinical development of biomedical products.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"233-266"},"PeriodicalIF":1.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145864883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Streptozotocin-Induced Mouse Model of Renal Tumors: Histopathological and Immunohistochemical Comparisons With Human Chromophobe Renal Cell Carcinoma. 链脲佐菌素诱导的小鼠肾肿瘤模型：与人憎色性肾细胞癌的组织病理学和免疫组化比较。

IF 1.8 4区医学

Toxicologic Pathology Pub Date : 2026-04-01 Epub Date: 2025-12-28 DOI: 10.1177/01926233251400265

Yutaro Fukuma, Hideki Mori, Takuji Tanaka, Yoshinobu Hirose

{"title":"A Streptozotocin-Induced Mouse Model of Renal Tumors: Histopathological and Immunohistochemical Comparisons With Human Chromophobe Renal Cell Carcinoma.","authors":"Yutaro Fukuma, Hideki Mori, Takuji Tanaka, Yoshinobu Hirose","doi":"10.1177/01926233251400265","DOIUrl":"10.1177/01926233251400265","url":null,"abstract":"Streptozotocin (STZ) is known to induce renal tumors in rodents, but their similarity to human tumors remains poorly defined. We characterized and comparatively validated a mouse model of STZ-induced renal tumorigenesis by administering a single intraperitoneal dose of STZ (250 mg/kg) to female CBA/NSlc mice and maintaining them for 182 days. Renal tumors developed in 25 of 28 surviving mice (89%), with mean and median numbers of 3.4 and 2.5 tumors per animal, respectively. Histopathologically, the tumors were diagnosed as adenomas or adenocarcinomas and exhibited clear, eosinophilic, or mixed cytoplasm. Immunohistochemical analysis of four representative adenocarcinomas revealed positivity for CK AE1/AE3, CK7, PAX8, CD10, CD82, E-cadherin, CD117, and S100A1, and negativity for CK20 and vimentin. These morphological and immunohistochemical features resembled those of human chromophobe renal cell carcinoma (chRCC). Furthermore, the tumors expressed collecting duct markers (uromodulin, CD15, MUC1, and GLUT-1) but lacked proximal convoluted tubule markers (AQP1 and megalin), suggesting a collecting duct origin. Taken together, STZ-induced mouse renal tumors closely resemble human chRCC, providing a reproducible model for investigating the biology and potential therapeutic approaches for this tumor type.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"200-213"},"PeriodicalIF":1.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145851117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Spontaneous Abdominal Hemangiosarcoma With Metastases to the Lungs in a Control Sprague-Dawley Rat. Sprague-Dawley大鼠自发性腹腔血管肉瘤伴肺转移。

IF 1.8 4区医学

Toxicologic Pathology Pub Date : 2026-04-01 Epub Date: 2026-02-25 DOI: 10.1177/01926233261419482

Gayle Hennig, Jean-Guy Bienvenu, Muthafar Al-Haddawi

{"title":"Spontaneous Abdominal Hemangiosarcoma With Metastases to the Lungs in a Control Sprague-Dawley Rat.","authors":"Gayle Hennig, Jean-Guy Bienvenu, Muthafar Al-Haddawi","doi":"10.1177/01926233261419482","DOIUrl":"10.1177/01926233261419482","url":null,"abstract":"This short communication describes a spontaneous hemangiosarcoma within the abdomen, which appeared to have originated from the prostate gland area with infiltration, and that metastasized to the lungs in a 46-week-old male Sprague-Dawley rat. At necropsy, a 90 mm × 60 mm × 50 mm dark cystic neoplastic mass was present in the abdomen and the lung lobes had multiple dark cystic neoplastic structures. The abdominal mass was necrotic with a few peripheral areas of plump oval cells and frond-like structures lined by spindle-shaped cells. The lung neoplastic cysts were filled with blood and there were foci of plump oval cells within and peripheral to the cysts, as well as multiple small clusters throughout the lung parenchyma. Neoplastic cells of the abdominal mass and lung cysts stained positively for von Willebrand Factor by immunohistochemistry, indicating a vascular endothelial cell origin and consistent with a diagnosis of hemangiosarcoma. The lung hemangiosarcomas were considered metastases from the abdominal hemangiosarcoma based on their similar cellular morphology and multiple foci throughout the lung lobes.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"267-271"},"PeriodicalIF":1.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147285182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Toxicologic Pathology Forum*: Summary of the 2024 Society of Toxicologic Pathology Town Hall and 2025 STP Member Survey on Determining and Communicating Adversity. 毒物病理学论坛*:2024年毒物病理学学会市政厅和2025年STP成员关于确定和沟通逆境的调查总结。

IF 1.8 4区医学

Toxicologic Pathology Pub Date : 2026-04-01 Epub Date: 2025-12-09 DOI: 10.1177/01926233251395000

Kathleen A Funk, Lyn M Wancket, Brad Bolon, Sabine Francke, Renee R Hukkanen, Lila Ramaiah

{"title":"Toxicologic Pathology Forum*: Summary of the 2024 Society of Toxicologic Pathology Town Hall and 2025 STP Member Survey on Determining and Communicating Adversity.","authors":"Kathleen A Funk, Lyn M Wancket, Brad Bolon, Sabine Francke, Renee R Hukkanen, Lila Ramaiah","doi":"10.1177/01926233251395000","DOIUrl":"10.1177/01926233251395000","url":null,"abstract":"In 2016, the publication of the Society of Toxicologic Pathology's (STP) \"best practice\" recommendations on determining and communicating adversity and the European Society of Toxicologic Pathology's (ESTP) expert working group report on adversity were key milestones in addressing adversity determinations for nonclinical studies as translational tools for assessing human risk. Since then, many publications attest to the ongoing difficulty in adversity decision-making posed by unique context-specific challenges. The STP gathered input on current adversity practices from Society members via an open discussion at the 2024 STP Town Hall session (held at the STP 43rd Annual Symposium) and by a subsequent online survey. Most STP pathologists make adversity determinations by applying the STP and/or ESTP recommendations at their discretion. Adversity decisions are generally made for pivotal toxicity studies but occasionally may be assigned for other study types. Adversity determinations are difficult for certain organ systems (immune, reproductive, and endocrine) and product classes (eg, cell and gene therapies, proteins, and small molecules). Most pathologists assign adversity based on direct effects of the test article, but other factors (eg, secondary pharmacology, species relevance, adaptive responses) are also considered. Procedural adversity (eg, effects of administration/implantation) is a key factor in some circumstances.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"214-223"},"PeriodicalIF":1.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145709358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0