Toxicologic Pathology最新文献_第8页

Toxicologic Pathology Forum: Opinion on Approaches for Reporting Toxic and Adverse Dose Levels in Nonclinical Toxicology Studies Supporting the Development of Anticancer Pharmaceuticals. 毒理病理学论坛：关于在支持抗癌药物开发的非临床毒理学研究中报告毒性和不良剂量水平的方法的意见。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2023-01-01 Epub Date: 2023-01-25 DOI: 10.1177/01926233221146937

Renee R Hukkanen, Tomoyuki Moriyama, Daniel J Patrick, Jonathan Werner

{"title":"Toxicologic Pathology Forum: Opinion on Approaches for Reporting Toxic and Adverse Dose Levels in Nonclinical Toxicology Studies Supporting the Development of Anticancer Pharmaceuticals.","authors":"Renee R Hukkanen, Tomoyuki Moriyama, Daniel J Patrick, Jonathan Werner","doi":"10.1177/01926233221146937","DOIUrl":"10.1177/01926233221146937","url":null,"abstract":"The advancement of an investigational new drug in humans is a significant developmental milestone. In first-in-human (FIH)-enabling toxicology studies, the highest dose without a test article-related adverse effect (no-observed-adverse-effect-level [NOAEL]) serves as the basis for deriving a safe FIH starting dose. For anticancer pharmaceuticals, the FIH dose may be calculated using the highest non-severely toxic dose (HNSTD) in nonrodent models or the dose severely toxic to 10% (STD10) in rodents. Given the practice of reporting the NOAEL, but the lack of regulatory requirements to do so for anticancer pharmaceuticals, we conducted an informal survey of 20 companies to answer the question \"How is our industry reporting toxic/adverse dose levels in FIH-enabling toxicology studies for anticancer indications?\" The data indicated 4 reporting approaches, each providing a path to regulatory acceptance. Within the integrated toxicology study report, 45% of respondents report the HNSTD/STD10, 25% report the NOAEL, 20% report both the HNSTD/STD10 and NOAEL, and 10% do not define either, reserving definitions for regulatory submissions. One reporting approach may be preferred over another for reasons including consistency across indications, repurposing pharmaceuticals, regulatory feedback, or simplicity. The reporting approach should be defined in advance of study initiation, and the pathologist should provide context to support the chosen approach.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9647526","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

Pharmacobezoar Formation From HPMC-AS-Containing Spray-Dried Formulations in Nonclinical Safety Studies in Rats. 含hmc - as的喷雾干燥制剂在大鼠体内的非临床安全性研究。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2022-12-01 DOI: 10.1177/01926233221145112

Hannes Gierke, Teresa Pfrommer, Kerstin Schäfer, Werner Weitschies, Thomas Nolte

{"title":"Pharmacobezoar Formation From HPMC-AS-Containing Spray-Dried Formulations in Nonclinical Safety Studies in Rats.","authors":"Hannes Gierke, Teresa Pfrommer, Kerstin Schäfer, Werner Weitschies, Thomas Nolte","doi":"10.1177/01926233221145112","DOIUrl":"https://doi.org/10.1177/01926233221145112","url":null,"abstract":"Changing the physical state from crystalline to amorphous is an elegant method to increase the bioavailability of poorly soluble new chemical entity (NCE) drug candidates. Subsequently, we report findings from repeat-dose toxicity studies of an NCE formulated as a spray-dried amorphous solid dispersion (SD-ASD) based on hydroxypropyl methylcellulose acetate succinate (HPMC-AS) in rats. At necropsy, agglomerates of SD-ASD were found in the stomach and small intestine, which in reference to literature were termed pharmacobezoars. We interpreted the pH-dependent insolubility of HPMC-AS in the acidic gastric environment to be a precondition for pharmacobezoar formation. Gastric pharmacobezoars were not associated with clinical signs or alterations of clinical pathology parameters. Pharmacobezoar-correlated histopathological findings were limited to the stomach and consisted of atrophy, erosion, ulcer, and inflammation, predominantly of the nonglandular mucosa. Pharmacobezoars in the small intestines induced obstructive ileus with overt clinical signs which required unscheduled euthanasia, prominent alterations of clinical pathology parameters indicative of hypotonic dehydration, degenerative and inflammatory processes in the gastrointestinal tract, and secondary renal findings. The incidence of pharmacobezoars increased with dose and duration of dosing. Besides the relevance of pharmacobezoars to animal welfare, they limit the non-observed adverse effect level in nonclinical testing programs and conclusively their informative value.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10542011","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: 2

Toxicologic Pathology Forum: Opinion on Not Euthanizing Control Animals in the Recovery Phase of Non-Rodent Toxicology Studies. 毒理学病理论坛:关于在非啮齿动物毒理学研究的恢复阶段不对对照动物实施安乐死的意见。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2022-12-01 DOI: 10.1177/01926233221129214

Kyathanahalli S Janardhan, Radhakrishna Sura, Smita Salian-Mehta, Thierry Flandre, Xavier Palazzi, Doris Zane, Bhanu Singh, Binod Jacob, Renee Rosemary Hukkanen, Muthafar Al-Haddawi, Bindu Bennet, Victoria Laast, Donna Lee, Richard Peterson, Annette Romeike, Frederic Schorsch, Magali Guffroy

{"title":"Toxicologic Pathology Forum: Opinion on Not Euthanizing Control Animals in the Recovery Phase of Non-Rodent Toxicology Studies.","authors":"Kyathanahalli S Janardhan, Radhakrishna Sura, Smita Salian-Mehta, Thierry Flandre, Xavier Palazzi, Doris Zane, Bhanu Singh, Binod Jacob, Renee Rosemary Hukkanen, Muthafar Al-Haddawi, Bindu Bennet, Victoria Laast, Donna Lee, Richard Peterson, Annette Romeike, Frederic Schorsch, Magali Guffroy","doi":"10.1177/01926233221129214","DOIUrl":"https://doi.org/10.1177/01926233221129214","url":null,"abstract":"Nonclinical toxicology studies that are required to support human clinical trials of new drug candidates are generally conducted in a rodent and a non-rodent species. These studies typically contain a vehicle control group and low, intermediate, and high dose test article groups. In addition, a dosing-free recovery phase is sometimes included to determine reversibility of potential toxicities observed during the dosing phase and may include additional animals in the vehicle control and one or more dose groups. Typically, reversibility is determined by comparing the test article-related changes in the dosing phase animals to concurrent recovery phase animals at the same dose level. Therefore, for interpretation of reversibility, it is not always essential to euthanize the recovery vehicle control animals. In the absence of recovery vehicle control tissues, the pathologist's experience, historical control database, digital or glass slide repositories, or literature can be used to interpret the findings in the context of background pathology of the species/strain/age. Therefore, in most studies, the default approach could be not to euthanize recovery vehicle control animals. This article provides opinions on scenarios that may or may not necessitate euthanasia of recovery phase vehicle control animals in nonclinical toxicology studies involving dogs and nonhuman primates.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10540407","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: 1

Toxicologic Pathology Forum: A Roadmap for Building State-of-the-Art Digital Image Data Resources for Toxicologic Pathology in the Pharmaceutical Industry. 毒物病理学论坛:为制药行业的毒物病理学建立最先进的数字图像数据资源的路线图。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2022-12-01 DOI: 10.1177/01926233221132747

Xing-Yue Ge, Juergen Funk, Tom Albrecht, Merima Birkhimer, Moritz Gilsdorf, Matthew Hayes, Fangyao Hu, Pierre Maliver, Mark McCreary, Trung Nguyen, Fernando Romero-Palomo, Shanon Seger, Reina N Fuji, Vanessa Schumacher, Ruth Sullivan

{"title":"Toxicologic Pathology Forum: A Roadmap for Building State-of-the-Art Digital Image Data Resources for Toxicologic Pathology in the Pharmaceutical Industry.","authors":"Xing-Yue Ge, Juergen Funk, Tom Albrecht, Merima Birkhimer, Moritz Gilsdorf, Matthew Hayes, Fangyao Hu, Pierre Maliver, Mark McCreary, Trung Nguyen, Fernando Romero-Palomo, Shanon Seger, Reina N Fuji, Vanessa Schumacher, Ruth Sullivan","doi":"10.1177/01926233221132747","DOIUrl":"https://doi.org/10.1177/01926233221132747","url":null,"abstract":"Digitization of histologic slides brings with it the promise of enhanced toxicologic pathology practice through the increased application of computational methods. However, the development of these advanced methods requires access to substrate image data, that is, whole slide images (WSIs). Deep learning methods, in particular, rely on extensive training data to develop robust algorithms. As a result, pharmaceutical companies interested in leveraging computational methods in their digital pathology workflows must first invest in data infrastructure to enable data access for both data scientists and pathologists. The process of building robust image data resources is challenging and includes considerations of generation, curation, and storage of WSI files, and WSI access including via linked metadata. This opinion piece describes the collective experience of building resources for WSI data in the Roche group. We elaborate on the challenges encountered and solutions developed with the goal of providing examples of how to build a data resource for digital pathology analytics in the pharmaceutical industry.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10543002","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

Extraintestinal Pathogenic Escherichia Coli Causes Necrohemorrhagic Pneumonia in Multiple Research Dogs. 肠外致病性大肠杆菌引起多只研究犬的坏死性出血性肺炎。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2022-12-01 DOI: 10.1177/01926233221129233

Sarah E Coe, Michelle A Magagna, Annie Zimmerman, April George, Caitlyn Carter, Charissa Dean, Keith Nelson

{"title":"Extraintestinal Pathogenic Escherichia Coli Causes Necrohemorrhagic Pneumonia in Multiple Research Dogs.","authors":"Sarah E Coe, Michelle A Magagna, Annie Zimmerman, April George, Caitlyn Carter, Charissa Dean, Keith Nelson","doi":"10.1177/01926233221129233","DOIUrl":"https://doi.org/10.1177/01926233221129233","url":null,"abstract":"Extraintestinal pathogenic Escherichia coli expressing cytotoxic necrotizing factor (CNF) 1 and 2 virulence factors is a rarely reported cause of acute, fatal necrohemorrhagic pneumonia in canines. A review of cases of necrohemorrhagic pneumonia in beagles at our facility between 2013 and 2021 revealed 21 dogs that died or were euthanized after acute onset lethargy, dyspnea, and hemorrhage. Some affected animals had recently been transported to the facility. In all dogs, lung lobes were discolored dark red and consolidated. Histologic lesions in 17 of these included alveolar necrosis, hemorrhage, edema, fibrin, acute inflammation, and intralesional colonies of bacilli. Lung was cultured for 10 dogs with E. coli isolated and CNF1 identified by virulence factor PCR in 7 of those. Based on these findings, extraintestinal E. coli should be considered an important cause of acute fatal necrohemorrhagic pneumonia in purpose-bred beagle research dogs and may be associated with a recent history of transport.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10546947","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: 1

Scientific and Regulatory Policy Committee Best Practices: Recommended ("Best") Practices for Informed (Non-blinded) Versus Masked (Blinded) Microscopic Evaluation in Animal Toxicity Studies. 科学和监管政策委员会最佳实践:动物毒性研究中知情(非盲法)与蒙面(盲法)显微评估的推荐(“最佳”)实践。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2022-12-01 DOI: 10.1177/01926233221135563

Brad Bolon, Sabine Francke, Jessica M Caverly Rae, Evelyne Polack, Karen S Regan, Elizabeth F McInnes, Jamie K Young, Kevin Keane, Rick Perry, Annette Romeike, Karyn Colman, Karl Jensen, Kyoko Nakano-Ito, Elizabeth J Galbreath

{"title":"Scientific and Regulatory Policy Committee Best Practices: Recommended (\"Best\") Practices for Informed (Non-blinded) Versus Masked (Blinded) Microscopic Evaluation in Animal Toxicity Studies.","authors":"Brad Bolon, Sabine Francke, Jessica M Caverly Rae, Evelyne Polack, Karen S Regan, Elizabeth F McInnes, Jamie K Young, Kevin Keane, Rick Perry, Annette Romeike, Karyn Colman, Karl Jensen, Kyoko Nakano-Ito, Elizabeth J Galbreath","doi":"10.1177/01926233221135563","DOIUrl":"https://doi.org/10.1177/01926233221135563","url":null,"abstract":"This article describes the Society of Toxicologic Pathology's (STP) five recommended (\"best\") practices for appropriate use of informed (non-blinded) versus masked (blinded) microscopic evaluation in animal toxicity studies intended for regulatory review. (1) Informed microscopic evaluation is the default approach for animal toxicity studies. (2) Masked microscopic evaluation has merit for confirming preliminary diagnoses for target organs and/or defining thresholds (\"no observed adverse effect level\" and similar values) identified during an initial informed evaluation, addressing focused hypotheses, or satisfying guidance or requests from regulatory agencies. (3) If used as the approach for an animal toxicity study to investigate a specific research question, masking of the initial microscopic evaluation should be limited to withholding only information about the group (control or test article-treated) and dose equivalents. (4) The decision regarding whether or not to perform a masked microscopic evaluation is best made by a toxicologic pathologist with relevant experience. (5) Pathology peer review, performed to verify the microscopic diagnoses and interpretations by the study pathologist, should use an informed evaluation approach. The STP maintains that implementing these five best practices has and will continue to consistently deliver robust microscopic data with high sensitivity for animal toxicity studies intended for regulatory review. Consequently, when conducting animal toxicity studies, the advantages of informed microscopic evaluation for maximizing sensitivity outweigh the perceived advantages of minimizing bias through masked microscopic examination.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9452241","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: 4

Neutropenia in Cynomolgus Monkeys With Anti-Drug Antibodies Associated With Administration of Afucosylated Humanized Monoclonal Antibodies. 含抗药物抗体的食蟹猴中性粒细胞减少症与集中人源单克隆抗体有关。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2022-12-01 DOI: 10.1177/01926233221131510

Adeyemi O Adedeji, Fiona Zhong, Jennifer A Getz, Zoe Zhong, Wendy Halpern

{"title":"Neutropenia in Cynomolgus Monkeys With Anti-Drug Antibodies Associated With Administration of Afucosylated Humanized Monoclonal Antibodies.","authors":"Adeyemi O Adedeji, Fiona Zhong, Jennifer A Getz, Zoe Zhong, Wendy Halpern","doi":"10.1177/01926233221131510","DOIUrl":"https://doi.org/10.1177/01926233221131510","url":null,"abstract":"Removal of the core fucose from the Fc region of humanized monoclonal antibodies (afucosylated antibodies) enhances their antibody-dependent cell cytotoxicity activities in killing cancer cells. Based on the authors’ experience and literature, administrations of afucosylated antibodies have been associated with neutropenia in cynomolgus monkeys. However, in a recent general toxicology study conducted with an afucosylated antibody in cynomolgus monkeys, transient neutropenia was observed and correlated with the emergence of anti-drug antibodies (ADAs) in the affected animals. To further explore the relationship between neutropenia, afucosylated antibodies, and ADAs in cynomolgus monkeys, we performed an investigational retrospective meta-analysis of data from general toxicology studies conducted with Genentech’s therapeutic antibodies administered to cynomolgus monkeys between 2005 and 2021. In this analysis, transient neutropenia strongly correlated with ADA-induced inflammation in cynomolgus monkeys administered afucosylated antibodies. This may reflect the simultaneous occurrence of two distinct processes of neutrophil elimination and utilization, thus overwhelming bone marrow reserve capacity leading to transient neutropenia. The integrated analysis of immunogenicity, and anatomic and clinical pathology results from these studies highlights the correlation of transient neutropenia in cynomolgus monkeys with ADA-related inflammation, potentially exacerbated by enhanced effector function of afucosylated antibodies.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4c/e5/10.1177_01926233221131510.PMC9806483.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10597173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

To Clot or Not to Clot: Deepening Our Understanding of Alterations in the Hemostatic System. 凝血还是不凝血:加深我们对止血系统改变的认识。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2022-10-01 DOI: 10.1177/01926233221125172

William J Reagan, Marjory B Brooks, Renata Grozovsky, Debra Pittman, Allison Vitsky, Karrie Brenneman

{"title":"To Clot or Not to Clot: Deepening Our Understanding of Alterations in the Hemostatic System.","authors":"William J Reagan, Marjory B Brooks, Renata Grozovsky, Debra Pittman, Allison Vitsky, Karrie Brenneman","doi":"10.1177/01926233221125172","DOIUrl":"https://doi.org/10.1177/01926233221125172","url":null,"abstract":"The session on the hemostatic system focused on new developments in coagulation and platelet biology as well as how therapeutic agents may affect hemostasis. The classic cascade model of coagulation was compared with the more recent models of cell-based and vascular-based coagulation, which may provide better insight on how the coagulation cascade works in vivo. A review of platelet biology highlighted that, as platelets age, desialylated platelets form and are recognized by Ashwell-Morell receptor (AMR), leading to hepatic uptake and subsequent increase in thrombopoietin (TPO) production. Administration of therapeutics that induce thrombocytopenia was also discussed, including Mylotarg, which is an antibody-drug conjugate that was shown to decrease human megakaryocyte development but had no effect on platelet aggregation. An acetyl co-A carboxylase inhibitor was shown to cause thrombocytopenia by inhibiting de novo lipogenesis, which is critical for the formation of the megakaryocyte demarcation membrane system responsible for platelet production. It was also illustrated how preclinical translation models have been very helpful in the development of adeno-associated virus (AAV) hemophilia B gene therapy and what old and new preclinical tools we have that can predict the risk of a prothrombotic state in people.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10456523","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: 1

Identifying Erythrocyte Injury in Toxicology Studies. 在毒理学研究中识别红细胞损伤。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2022-10-01 DOI: 10.1177/01926233221127942

Erica Behling-Kelly

引用次数: 2

Black Cohosh Herbal Extract and Hematologic Alterations in B6C3F1/N Mice. 黑升麻草药提取物对B6C3F1/N小鼠血液学的影响。

IF 1.5 4区医学

Toxicologic Pathology Pub Date : 2022-10-01 DOI: 10.1177/01926233221133549

Michelle Cora

{"title":"Black Cohosh Herbal Extract and Hematologic Alterations in B6C3F1/N Mice.","authors":"Michelle Cora","doi":"10.1177/01926233221133549","DOIUrl":"https://doi.org/10.1177/01926233221133549","url":null,"abstract":"Black cohosh is a readily available dietary supplement currently marketed as a remedy for dysmenorrhea and menopausal symptoms and is one of the top-selling herbal supplements in the United States. Black cohosh extract (BCE) was nominated to the National Toxicology Program (NTP) by the National Cancer Institute and the National Institute of Environmental Health Sciences due to its widespread use and lack of animal toxicity studies. Results of the NTP BCE subchronic mouse toxicity study revealed a dose-dependent, non-regenerative decrease in the erythron with an increase in the mean corpuscular volume (macrocytosis). Howell-Jolly bodies, or micronuclei, were significantly increased. These particular changes indicated an ineffective erythropoiesis consistent with a condition known as megaloblastic anemia. Megaloblastic anemia is due to disruptions in DNA synthesis during hematopoiesis and can be a result of an inherited or drug-induced disorder or a consequence of folate or cobalamin deficiency. Subsequent mouse studies revealed hematological and biochemical changes that were consistent with a functional cobalamin deficiency. This article will review basic mechanisms and laboratory features of megaloblastic anemia. The results of our studies including morphological abnormalities of the erythron and biomarkers of folate and cobalamin deficiencies, as well as hepatic microarray gene changes, are also discussed.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10396382","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