International Journal of Toxicology最新文献_第3页

Safety Assessment of Methylxanthines as Used in Cosmetics. 对化妆品中使用的甲基黄嘌呤进行安全评估。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2024-10-01 Epub Date: 2024-07-24 DOI: 10.1177/10915818241260282

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 Vinylpyrrolidone Polymers as Used in Cosmetics. 化妆品中使用的乙烯基吡咯烷酮聚合物的安全性评估。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2024-10-01 Epub Date: 2024-07-24 DOI: 10.1177/10915818241267203

Wilbur Johnson, 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

In Utero Exposure to Di-n-butyl Phthalate Causes Modulation in Neurotransmitter System of Wistar Rats: A Multigenerational Assessment. 子宫内暴露于邻苯二甲酸二正丁酯对 Wistar 大鼠神经递质系统的影响：多代评估。

IF 2.2 4区医学

International Journal of Toxicology Pub Date : 2024-09-12 DOI: 10.1177/10915818241278670

M J Radha,Mahaboob P Basha

{"title":"In Utero Exposure to Di-n-butyl Phthalate Causes Modulation in Neurotransmitter System of Wistar Rats: A Multigenerational Assessment.","authors":"M J Radha,Mahaboob P Basha","doi":"10.1177/10915818241278670","DOIUrl":"https://doi.org/10.1177/10915818241278670","url":null,"abstract":"Neuroendocrine regulation is disrupted by di-n-butyl phthalate (DBP) when exposure occurs during the critical periods of fetal development, which can lead to neurological disorders. To evaluate the toxic potential of DBP, it is necessary to conduct teratological studies, which could determine impacts on the development of the fetus. The present study was designed to understand the sequelae of neuroendocrine regulation in one-month-old pups when rats were exposed to DBP (F1-F3) in utero and during lactation. The rats received DBP (500 mg/kg BW/day) dissolved in olive oil through oral gavage from gestation day 6 to postnatal day 30, while the control group received the olive oil (vehicle) during the same timeline. Following the exposure, thyroid profile and estradiol, which were measured at GD-19, exhibited a significant decrease (P < 0.05) in dams (F0-F2). The exposure resulted in developmental outcomes, including underdeveloped fetuses, and a notable number of resorptions in experimental rats. The one-month-old pups were assessed for serum thyroid profile and testosterone and neurotransmitters in discrete brain regions, cerebral cortex, cerebellum, and hippocampus for up to three generations. The levels of dopamine and cortisol showed a significant increase (P < 0.05), but serotonin levels decreased when examined in distinct brain regions of the experimental group as compared to the control. DBP, which is considered an endocrine disruptor, had the most impact on the third generation in this study, leading to a significant decrease in testosterone levels. In summary, in utero exposure to DBP impaired the neuroendocrine system and had an antiandrogenic effect in the three successive generations.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":"6 1","pages":"10915818241278670"},"PeriodicalIF":2.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142205681","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

Weight of Evidence: Is an Animal Study Warranted? Assessments for Carcinogenicity, Drug Abuse Liability, and Pediatric Safety. 证据的重要性：是否需要进行动物实验？致癌性、药物滥用责任和儿童安全性评估。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2024-09-01 Epub Date: 2024-07-20 DOI: 10.1177/10915818241259794

Thulasi Ramani, Ronald L Wange, T Scott Manetz, Paul J Kruzich, Susan B Laffan, David R Compton

引用次数: 0

13-Week Repeated Oral Toxicity and Toxicokinetic Studies of Rabeprazole Sodium and Sodium Bicarbonate Combination in Dogs. 对狗进行为期 13 周的雷贝拉唑钠和碳酸氢钠复方制剂重复口服毒性和毒物动力学研究

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2024-09-01 Epub Date: 2024-06-19 DOI: 10.1177/10915818241261631

Jae Seok Roh, Kyu-Yeol Nam, Won Tae Jung, Young-Min Kim, Eui-Kyung Hwang, Tae-Won Jeon

{"title":"13-Week Repeated Oral Toxicity and Toxicokinetic Studies of Rabeprazole Sodium and Sodium Bicarbonate Combination in Dogs.","authors":"Jae Seok Roh, Kyu-Yeol Nam, Won Tae Jung, Young-Min Kim, Eui-Kyung Hwang, Tae-Won Jeon","doi":"10.1177/10915818241261631","DOIUrl":"10.1177/10915818241261631","url":null,"abstract":"The subchronic toxicity and toxicokinetics of a combination of rabeprazole sodium and sodium bicarbonate were investigated in dogs by daily oral administration for 13 consecutive weeks with a 4-week recovery period. The dose groups consisted of control (vehicles), (5 + 200), (10 + 400), and (20 + 800) mg/kg of rabeprazole sodium + sodium bicarbonate, 20 mg/kg of rabeprazole sodium only, and 800 mg/kg of sodium bicarbonate only. Esophageal ulceration accompanied by inflammation was observed in only one animal in the male (20 + 800) mg/kg rabeprazole sodium + sodium bicarbonate group. However, the severity of the ulceration was moderate, and the site of occurrence was focally extensive; thus, it was assumed to be a treatment-related effect of rabeprazole sodium + sodium bicarbonate. In the toxicokinetics component of this study, systemic exposure to rabeprazole sodium (AUClast and Cmax at Day 91) was greater in males than females, suggesting sex differences. AUClast and Cmax at Day 91 were increased compared to those on Day 1 in a dose-dependent manner. A delayed Tmax and no drug accumulation were observed after repeated dosage. In conclusion, we suggest under the conditions of this study that the no-observed-adverse-effect level (NOAEL) of the combination of rabeprazole sodium + sodium bicarbonate in male and female dogs is (10 + 400) and (20 + 800) mg/kg, respectively.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"472-490"},"PeriodicalIF":1.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426875","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

Safety Assessment of a Novel Intravenous Diclofenac Sodium Formulation Following 28-Day Repeated Administration in Wistar Rats. 新型静脉注射双氯芬酸钠制剂在 Wistar 大鼠体内 28 天重复给药后的安全性评估

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2024-09-01 Epub Date: 2024-06-20 DOI: 10.1177/10915818241261922

Laxit K Bhatt, Chitrang R Shah, Jitendra H Patel, Viral I Rajwadi, Pankaj Dwivedi, Rajesh J Patel, Ramchandra K Ranvir, Harilal Patel, Rajesh Sundar, Mukul R Jain

{"title":"Safety Assessment of a Novel Intravenous Diclofenac Sodium Formulation Following 28-Day Repeated Administration in Wistar Rats.","authors":"Laxit K Bhatt, Chitrang R Shah, Jitendra H Patel, Viral I Rajwadi, Pankaj Dwivedi, Rajesh J Patel, Ramchandra K Ranvir, Harilal Patel, Rajesh Sundar, Mukul R Jain","doi":"10.1177/10915818241261922","DOIUrl":"10.1177/10915818241261922","url":null,"abstract":"These toxicity studies aimed to assess the safety and tolerability of a novel intravenous diclofenac sodium (37.5 mg/mL) formulation containing povidone K12 (80 mg/mL) as the key excipient in Wistar rats. This formulation was tested at doses of 3, 7, and 15 mg/kg/day and was administered daily for 28 days by intravenous route. Toxicokinetic estimation revealed a dose-proportional increase in plasma exposure to diclofenac. The formulation was well tolerated in males; however, mortality was observed in females (2/15) at the highest dose (15 mg/kg/day). Adverse gastrointestinal events related to NSAIDS and a few other treatment-related effects on clinical and anatomic pathology were noted at the 15 mg/kg/day dose, which normalized at the end of the 2-week recovery period. In addition, the excipient povidone K12 was present in a higher amount than the approved Inactive Ingredient Database (IID) limit in the proposed novel formulation. It was qualified through a separate 28-day repeated dose toxicity study by intravenous route in Wistar rats. Povidone K12 was found to be well tolerated and safe up to a dose of 165 mg/kg/day. No treatment-related adverse effects were observed in this study. In conclusion, repeated administration of a novel intravenous formulation containing diclofenac sodium was found to be safe up to the dose of 7 mg/kg/day in female rats and 15 mg/kg/day in male rats.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"491-502"},"PeriodicalIF":1.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141431875","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

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":" ","pages":"464-471"},"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":" ","pages":"456-463"},"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":" ","pages":"503-510"},"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