International Journal of Toxicology最新文献_第3页

Mitochondrial Impact of Organophosphate Pesticide-Induced Cardiotoxicity: An In Silico and In Vitro Study. 有机磷农药诱发的心脏毒性对线粒体的影响：线粒体对有机磷农药诱发的心脏毒性的影响：一项硅学和体外研究。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2024-09-01 Epub Date: 2024-06-19 DOI: 10.1177/10915818241261624

Fuat Karakuş, Ege Arzuk, Ali Ergüç

{"title":"Mitochondrial Impact of Organophosphate Pesticide-Induced Cardiotoxicity: An In Silico and In Vitro Study.","authors":"Fuat Karakuş, Ege Arzuk, Ali Ergüç","doi":"10.1177/10915818241261624","DOIUrl":"10.1177/10915818241261624","url":null,"abstract":"Organophosphate pesticides are widely used; however, their use is limited due to neurotoxicity and, to a lesser extent, cardiotoxicity in humans. Given the high energy demands of cardiac muscle, which is characterized by a dense population of mitochondria, any damage to these organelles can exacerbate cardiotoxicity. This study aims to elucidate whether the cardiotoxic effects of organophosphate pesticides originate from mitochondrial dysfunction. To investigate this, in silico toxicogenomic analyses were performed using various tools, such as the Comparative Toxicogenomic Database, GeneMANIA, STRING, and Cytoscape. Results revealed that 11 out of the 13 WHO-recommended Class Ia organophosphate pesticides target genes associated with cardiotoxicity. Notably, three of these genes were mitochondrial, with catalase (CAT) being the common differentially expressed gene among parathion, methyl parathion, and phorate. Furthermore, protein-protein interaction analysis indicated a strong association between CAT and superoxide dismutase 2, mitochondrial (SOD2). Subsequently, isolated heart mitochondria were utilized to assess CAT and superoxide dismutase (SOD) activities in vitro. The findings demonstrated that at a concentration of 7.5 ng/µL, both methyl parathion and phorate significantly decreased CAT activity by approximately 35%. Moreover, phorate reduced total SOD and SOD2 activities by 17% and 19%, respectively, at the same concentration. In contrast, none of the three organophosphate pesticides induced the opening of the mitochondrial permeability transition pore. These results suggest that the reduction in CAT and SOD2 activities, critical antioxidant enzymes, leads to the accumulation of reactive oxygen species within mitochondria, ultimately resulting in mitochondrial damage. This mechanism likely underlies the observed cardiotoxicity induced by these organophosphate pesticides.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426876","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

Exploring Greater Flexibility for Chronic Toxicity Study Designs to Support Human Safety Assessment While Balancing 3Rs Considerations. 探索更灵活的慢性毒性研究设计，以支持人类安全评估，同时兼顾 3Rs 考虑因素。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2024-09-01 Epub Date: 2024-05-31 DOI: 10.1177/10915818241255885

Helen Prior, Paul Baldrick, David O Clarke, Elisa Passini, Fiona Sewell, Peter van Meer

{"title":"Exploring Greater Flexibility for Chronic Toxicity Study Designs to Support Human Safety Assessment While Balancing 3Rs Considerations.","authors":"Helen Prior, Paul Baldrick, David O Clarke, Elisa Passini, Fiona Sewell, Peter van Meer","doi":"10.1177/10915818241255885","DOIUrl":"10.1177/10915818241255885","url":null,"abstract":"Chronic repeated-dose toxicity studies are required to support long-term dosing in late-stage clinical trials, providing data to adequately characterize adverse effects of potential concern for human safety. Different regulatory guidances for the design and duration of chronic toxicity studies are available, with flexibility in approaches often adopted for specific drug modalities. These guidances may provide opportunities to reduce time, cost, compound requirement and animal use within drug development programs if applied more broadly and considered outside their current scopes of use. This article summarizes presentations from a workshop at the 43rd Annual Meeting of the American College of Toxicology (ACT) in November 2022, discussing different approaches for chronic toxicity studies. A recent industry collaboration between the Netherlands Medicines Evaluation Board (MEB) and UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) illustrated current practices and the value of chronic toxicity studies for monoclonal antibodies (mAbs) and evaluated a weight of evidence (WOE) model where a 3-month study rather than a 6-month study might be adequate. Other topics included potential opportunities for single-species chronic toxicity studies for small molecules, peptides and oligonucleotides and whether a 6-month duration non-rodent study can be used more routinely than a 9-month study (similar to ICH S6(R1) for biological products). Also addressed were opportunities to optimize recovery animal use if warranted and whether restriction to one study only (if at all) can be applied more widely within and outside ICH S6(R1).","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11408957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141185608","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

Preclinical Safety Evaluation of Etripamil Nasal Spray in Cynomolgus Macaques (Macaca fascicularis) to Assess for Safety in Patients With Paroxysmal Supraventricular Tachycardia. 对犬科猕猴（Macaca fascicularis）进行依曲帕米鼻腔喷雾剂的临床前安全性评价，以评估其对阵发性室上性心动过速患者的安全性。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2024-09-01 Epub Date: 2024-07-22 DOI: 10.1177/10915818241263068

Johanne Pion, Carlos Lopez Mendez, Jean-Pierre Moreau, Veronique Boulanger, Douglas Wight

{"title":"Preclinical Safety Evaluation of Etripamil Nasal Spray in Cynomolgus Macaques (Macaca fascicularis) to Assess for Safety in Patients With Paroxysmal Supraventricular Tachycardia.","authors":"Johanne Pion, Carlos Lopez Mendez, Jean-Pierre Moreau, Veronique Boulanger, Douglas Wight","doi":"10.1177/10915818241263068","DOIUrl":"10.1177/10915818241263068","url":null,"abstract":"Etripamil is a calcium channel blocker currently in Phase 3 trials for the treatment of paroxysmal supraventricular tachycardia (PSVT). Systemic and local toxicity following once-weekly intranasal administration of etripamil was evaluated in cynomolgus macaques to support clinical development. Groups of animals (N = 8, 4 males and 4 females) were administered etripamil into the left nostril weekly at dose levels of 0 (vehicle), 1.9, 3.8, or 5.7 mg/kg/dose for 26 doses. Persistence, reversibility, and progression of findings were examined following a 28-day recovery period. Clinical signs were transient and were related to the intranasal administration (e.g., nasal discharge, sneezing, etc.) of etripamil. There were no macroscopic or systemic microscopic findings at any dose. Etripamil-related adaptive and reactive local changes affecting the nasal cavity, larynx, and nasopharynx were observed at ≥1.9 mg/kg/dose. Minimal to severe dose-dependent nasal epithelial damage was observed, mainly affecting respiratory and transitional epithelium. Following the 28-day recovery period, microscopic changes were confined to the left nasal cavity and nasopharynx. These changes were significantly lower in incidence and severity, with noticeable reversal of the adaptive and reactive changes, indicating partial to complete recovery of the epithelial lining. Based on the lack of systemic toxicity and the minimal and transient nasal changes, the systemic, no observable adverse effect level (NOAEL) of etripamil in monkeys was the high dose, 5.7 mg/kg/dose. The NOAEL for local toxicity was 1.9 mg/kg/dose. Collectively, these data support further study of etripamil in human trials as a potential treatment for PSVT.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11402258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141734065","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

Safety Assessment of Polysilicone-11 as Used in Cosmetics. 化妆品中使用的聚硅氧烷-11 的安全性评估。

IF 2.2 4区医学

International Journal of Toxicology Pub Date : 2024-08-01 Epub Date: 2024-03-12 DOI: 10.1177/10915818241237789

Priya Cherian, Wilma F Bergfeld, Donald V Belsito, David E Cohen, Curtis D Klaassen, Daniel C Liebler, James G Marks, Lisa A Peterson, Ronald C Shank, Thomas J Slaga, Paul W Snyder, Monice Fiume, Bart Heldreth

引用次数: 0

Safety Assessment of Capryloyl Salicylic Acid as Used in Cosmetics. 化妆品中使用的辛酰水杨酸的安全性评估。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2024-08-01 Epub Date: 2024-03-11 DOI: 10.1177/10915818241237794

Wilbur Johnson, Wilma F Bergfeld, Donald V Belsito, Curtis D Klaassen, Daniel C Liebler, James G Marks, Lisa A Peterson, Ronald C Shank, Thomas J Slaga, Paul W Snyder, Monice Fiume, Bart Heldreth

引用次数: 0

Safety Assessment of Basic Red 76 as Used in Cosmetics. 化妆品中使用的碱性红 76 的安全性评估。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2024-08-01 Epub Date: 2024-03-12 DOI: 10.1177/10915818241237795

Priya Cherian, Wilma F Bergfeld, Donald V Belsito, Ronald A Hill, Curtis D Klaassen, Daniel C Liebler, James G Marks, Ronald C Shank, Thomas J Slaga, Paul W Snyder, Monice Fiume, Bart Heldreth

引用次数: 0

Safety Assessment of Hydroxyethyl Urea as Used in Cosmetics. 化妆品中使用的羟乙基尿素的安全性评估。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2024-08-01 Epub Date: 2024-03-11 DOI: 10.1177/10915818241237791

Alice Akinsulie, Wilma F Bergfeld, Donald V Belsito, Ronald A Hill, Curtis D Klaassen, Daniel C Liebler, James G Marks, Ronald C Shank, Thomas J Slaga, Paul W Snyder, Monice Fiume, Bart Heldreth

引用次数: 0

Safety Assessment of Hydrogen Peroxide as Used in Cosmetics. 化妆品中使用的过氧化氢的安全评估。

IF 2.2 4区医学

International Journal of Toxicology Pub Date : 2024-08-01 Epub Date: 2024-03-12 DOI: 10.1177/10915818241237790

Lillian C Becker, Priya A Cherian, Wilma F Bergfeld, Donald V Belsito, Ronald A Hill, Curtis D Klaassen, Daniel C Liebler, James G Marks, Ronald C Shank, Thomas J Slaga, Paul W Snyder, Monice Fiume, Bart Heldreth

引用次数: 0

Safety Assessment of Palm-Derived Ingredients as Used in Cosmetics. 化妆品中使用的棕榈提取物成分的安全评估。

IF 2.2 4区医学

International Journal of Toxicology Pub Date : 2024-08-01 Epub Date: 2024-03-14 DOI: 10.1177/10915818241237797

Wilbur Johnson, Wilma F Bergfeld, Donald V Belsito, Curtis D Klaassen, Daniel C Liebler, James G Marks, Lisa A Peterson, Ronald C Shank, Thomas J Slaga, Paul W Snyder, Monice Fiume, Bart Heldreth

引用次数: 0

Hepatitis A Virus Infection in Cynomolgus Monkeys Confounds the Safety Evaluation of a Drug Candidate. 绒猴感染甲型肝炎病毒影响候选药物的安全性评估

IF 2.2 4区医学

International Journal of Toxicology Pub Date : 2024-07-01 Epub Date: 2024-03-19 DOI: 10.1177/10915818241237992

Chris J Powell, John C Kapeghian, John C Bernal, John R Foster

{"title":"Hepatitis A Virus Infection in Cynomolgus Monkeys Confounds the Safety Evaluation of a Drug Candidate.","authors":"Chris J Powell, John C Kapeghian, John C Bernal, John R Foster","doi":"10.1177/10915818241237992","DOIUrl":"10.1177/10915818241237992","url":null,"abstract":"In a 3-month toxicity study in cynomolgus monkeys at a European contract laboratory, animals were infected with HAV, initially resulting in hepatic injury being incorrectly attributed to the test compound. Elevated serum ALT/AST/GLDH (5- to 10-fold) were noted in individual animals from all groups including controls, with no apparent dose, exposure, or time-related relationship. Liver histopathology revealed minimal to slight inflammatory cell accumulation in periportal zones of most animals, and minimal to slight hepatocyte degeneration/necrosis in 10/42 animals from all groups. As these findings were more pronounced in 6 drug-treated animals, including 2/6 in the low dose group, the draft report concluded: \"treatment-related hepatotoxicity at all dose levels precluded determination of a NOAEL.\" However, the unusual pattern of hepatotoxicity suggested a factor other than drug exposure might have caused the hepatic effects. Therefore, snap-frozen liver samples were tested for hepatitis viruses using a PCR method. Tests for hepatitis B, C, and E virus were negative; however, 20/42 samples were positive for hepatitis A virus (HAV). Infection was strongly associated with increased serum ALT/GLDH, and/or hepatocyte degeneration/necrosis. Re-evaluation of the study in light of these data concluded that the hepatic injury was not drug-related. A subsequent 6-month toxicology study in HAV-vaccinated cynomolgus monkeys confirmed the absence of hepatotoxicity. Identification of HAV infection supported progression of the drug candidate into later clinical trials. Although rarely investigated, subclinical HAV infection has occasionally been reported in laboratory primates, including those used for toxicology studies and it may be more prevalent than the literature indicates.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11155213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140158138","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