Regulatory Toxicology and Pharmacology最新文献_第3页

Applicability of the in vitro skin irritation methods (EpiSkin™, EpiDerm™ SIT) to organosilicon-based substances

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-07 DOI: 10.1016/j.yrtph.2025.105778

Carole Forlini , Farah Koraichi-Emeriau , Barbara G. Schmitt , Wendy Koch , Shawn Seidel , Eckart Gura , Michael Haack , Dorothea Eigler

{"title":"Applicability of the in vitro skin irritation methods (EpiSkin™, EpiDerm™ SIT) to organosilicon-based substances","authors":"Carole Forlini , Farah Koraichi-Emeriau , Barbara G. Schmitt , Wendy Koch , Shawn Seidel , Eckart Gura , Michael Haack , Dorothea Eigler","doi":"10.1016/j.yrtph.2025.105778","DOIUrl":"10.1016/j.yrtph.2025.105778","url":null,"abstract":"<div><div>It is now widely accepted that the reconstructed human epidermis models (OECD TG 439) can be used as a standalone replacement of the <em>in vivo</em> rabbit assay (OECD TG 404) to accurately predict skin irritancy. Many legislations have now introduced the legal requirement to use <em>in vitro</em> methods as the first step. The applicability of these methods to organosilicon-based substances was not evaluated during the validation of this guideline. Therefore, the aim of the current work was to assess the applicability of EpiSkin™ and EpiDerm™ SIT <em>in vitro</em> methods for organosilicons. Ten substances were evaluated, and results were compared with existing rabbit data. The data showed that both test methods failed to accurately predict the <em>in vivo</em> skin irritation potential, with predictive capacities below the minimum test guideline requirements. The two models delivered consistent results in only 60% of the cases. Several hypotheses were explored to explain this high rate of discordance without success. As EpiDerm™ SIT showed 100% sensitivity, a new stepwise testing strategy is proposed for organosilicons consisting of starting with EpiDerm™ SIT, following by EpiSkin™ in case of positive outcome. While keeping protective, this adapted strategy avoids unnecessary animal testing.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"157 ","pages":"Article 105778"},"PeriodicalIF":3.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143383094","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

Establishment of a threshold of toxicological concern for pharmaceutical intermediates based on historical repeat-dose data and its application in setting health based exposure limits 基于历史重复剂量数据的药物中间体毒理学关注阈值的建立及其在设定健康暴露限值中的应用。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-01 DOI: 10.1016/j.yrtph.2024.105764

Zoe Dunn , Delorice Murudzwa , Kamila Blum

{"title":"Establishment of a threshold of toxicological concern for pharmaceutical intermediates based on historical repeat-dose data and its application in setting health based exposure limits","authors":"Zoe Dunn , Delorice Murudzwa , Kamila Blum","doi":"10.1016/j.yrtph.2024.105764","DOIUrl":"10.1016/j.yrtph.2024.105764","url":null,"abstract":"<div><div>Availability of toxicological data for pharmaceutical intermediates (IMs) used in the manufacture of small molecules is often limited. Scarcity of data – in particular, repeat-dose toxicity (RDT) – renders the calculation of health-based exposure limits (HBELs) problematic. Establishment of HBELs, including occupational exposure limits (OELs) and permitted daily exposures (PDEs) facilitating worker and patient safety respectively, is however essential. Historic 28-day oral rodent toxicity data was analysed for 103 GSK isolated IMs. No-observed (adverse) effect levels (NO(A)ELs) and critical effects were extracted. The 5th percentile (p05) of the NO(A)EL distribution was 15 mg/kg/day. Substance specific HBELs were calculated, selecting the NO(A)EL as the Point of Departure (PoD); 99% of IMs (n = 102) were assigned an oral PDE ≥1000 μg/day and OEL ≥100 μg/m<sup>3</sup>. A default oral PDE of 1000 μg/day and OEL of 100 μg/m<sup>3</sup> is thus proposed for IMs. Evaluation of an additional PoD – benchmark dose lower confidence limit (BMDL) – further supported the default HBELs. The default oral PDE can also serve as a threshold of toxicological concern (TTC) for IMs. Default limits can aid in setting HBELs for novel data-poor IMs, as well as supporting waiving of RDT in the future through read-across.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105764"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807901","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

Evaluating dermal absorption of perfluorooctanoic acid (PFOA) and implications for other per- and polyfluoroalkyl substances (PFAS) 评估全氟辛酸（PFOA）的皮肤吸收及其对其他全氟烷基和多氟烷基物质（PFAS）的影响。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-01 DOI: 10.1016/j.yrtph.2024.105766

Andrew Yeh , Robyn L. Prueitt , Laura E. Kerper , Barbara D. Beck

{"title":"Evaluating dermal absorption of perfluorooctanoic acid (PFOA) and implications for other per- and polyfluoroalkyl substances (PFAS)","authors":"Andrew Yeh , Robyn L. Prueitt , Laura E. Kerper , Barbara D. Beck","doi":"10.1016/j.yrtph.2024.105766","DOIUrl":"10.1016/j.yrtph.2024.105766","url":null,"abstract":"<div><div>To date, only four studies directly measured dermal absorption kinetics of perfluorooctanoic acid (PFOA) in human skin. Reported kinetic parameters spanned two to five orders of magnitude, demonstrating the need to determine the causes of variability and identify the most appropriate dermal absorption factors for use in exposure assessments. We evaluated the reliability and physiological relevance of studies that measured PFOA fractional absorption, steady-state flux (J<sub>ss</sub>), and dermal permeability coefficient (K<sub>p</sub>). We verified whether the reported kinetic parameters were measured under appropriate conditions (<em>i.e.</em>, fractional absorption under finite dose conditions, and J<sub>ss</sub> and K<sub>p</sub> under infinite dose conditions). We recommend the following values measured at the approximate pH of the skin, and in aqueous solvents or relevant consumer product matrices, for use as provisional values in PFOA exposure assessments: 1.6% fractional absorption under finite dose conditions, and 0.132 μg/cm<sup>2</sup>-hr and 0.000044 cm/h for J<sub>ss</sub> and K<sub>p</sub>, respectively, under infinite dose conditions. Using the recommended absorption factors, we estimated PFOA exposures in children from soil and water <em>via</em> dermal and ingestion routes. Our results indicate low dermal absorption of PFOA relative to ingestion, and low dermal absorption is expected for per- and polyfluoroalkyl substances (PFAS) with physicochemical properties similar to PFOA.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105766"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865335","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

Rodent estrous cycle pattern: Harmonizing the cycle evaluation and interpretation 啮齿动物发情周期模式：协调周期评价与解释。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-01 DOI: 10.1016/j.yrtph.2024.105768

Shivakumar Holalagoudar , Susan Kisielewski , Austin Martini , Kamin Johnson , Anne-Laure Leoni , Corinna Demminger , Sonja Brosel

{"title":"Rodent estrous cycle pattern: Harmonizing the cycle evaluation and interpretation","authors":"Shivakumar Holalagoudar , Susan Kisielewski , Austin Martini , Kamin Johnson , Anne-Laure Leoni , Corinna Demminger , Sonja Brosel","doi":"10.1016/j.yrtph.2024.105768","DOIUrl":"10.1016/j.yrtph.2024.105768","url":null,"abstract":"<div><div>The estrous cycle is a sensitive endpoint from an endocrine disruptor perspective and is included in rodent reproductive toxicity studies. In this paper, the methods for estrous cycle timing and different approaches followed by testing laboratories for evaluating the days of the estrous cycle were reviewed. No major differences are identified for counting 4-day estrous cycle. However, when extended episodes of estrus (E) stages occur, the cycle counting differs between testing laboratories potentially resulting in misinterpretation and inaccurate outcome. Appearance of extended episodes of two to three E in an estrous cycle need explanation. Therefore, the following are proposed, 1) follow OECD guidance document for normal 4/5 day cycles, 2) recommends an update of the OECD document as in the current one it is unclear for a 5-day cycle ending with Proestrus(P) followed by episode(s) of estrus(E), 3) two episodes of E after P in a 5-day cycle and three consecutive episodes of E should be considered abnormal, and 4) stages prior to first E of the first cycle or after last E (last P of a 5-day) of last cycle should not be assumed a complete cycle. Additionally, call for collaboration is made to harmonize the cycle counting approach.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105768"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882850","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 the link: DNA methylation and kidney injury markers in farmers exposed to glyphosate-surfactant herbicides 探索联系：暴露于草甘膦表面活性剂除草剂的农民的DNA甲基化和肾损伤标志物。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-01 DOI: 10.1016/j.yrtph.2024.105765

Supakit Khacha-ananda, Unchisa Intayoung, Kanyapak Kohsuwan, Klintean Wunnapuk

{"title":"Exploring the link: DNA methylation and kidney injury markers in farmers exposed to glyphosate-surfactant herbicides","authors":"Supakit Khacha-ananda, Unchisa Intayoung, Kanyapak Kohsuwan, Klintean Wunnapuk","doi":"10.1016/j.yrtph.2024.105765","DOIUrl":"10.1016/j.yrtph.2024.105765","url":null,"abstract":"<div><div>Glyphosate-surfactant herbicides (GSH), widely used herbicides, have raised concerns about their potential nephrotoxic effects. Despite extensive studies, the safety of GSH remains debatable. This study aimed to determine if occupational exposure to GSH causes detectable changes in renal injury biomarkers—specifically DNA methylation, KIM-1, TIMP2, and IGFBP7—in farmers regularly exposed to these chemicals. Two urine samples, pre-task (0-h) and post-task (24-h), were collected to analyze these biomarkers. No significant immediate changes were observed post-exposure, possibly due to personal protective equipment use. Moderate positive correlations were found between IGFBP7 and KIM-1, and IGFBP7 and TIMP2, suggesting early kidney injury. About 50% of subjects had a biomarker ratio greater than 1, indicating increased levels of IGFBP7, TIMP2, and KIM-1 after GSH exposure. This indicates that farmers who regularly spray GSH are at high risk of exposure, potentially leading to significant renal injury. Further long-term studies are needed to assess the chronic effects and validate these biomarkers for monitoring renal health in populations exposed to glyphosate.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105765"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865347","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

Control of N-nitrosamine impurities in drug products: Progressing the current CPCA framework and supporting the derivation of robust compound specific acceptable intakes 药品中n -亚硝胺杂质的控制：推进现行CPCA框架并支持衍生稳健的化合物特异性可接受摄入量。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-01 DOI: 10.1016/j.yrtph.2024.105762

David J. Ponting , Andreas Czich , Susan P. Felter , Susanne Glowienke , James S. Harvey , Raphael Nudelman , Joerg Schlingemann , Stephanie Simon , Graham F. Smith , Andrew Teasdale , Robert Thomas

{"title":"Control of N-nitrosamine impurities in drug products: Progressing the current CPCA framework and supporting the derivation of robust compound specific acceptable intakes","authors":"David J. Ponting , Andreas Czich , Susan P. Felter , Susanne Glowienke , James S. Harvey , Raphael Nudelman , Joerg Schlingemann , Stephanie Simon , Graham F. Smith , Andrew Teasdale , Robert Thomas","doi":"10.1016/j.yrtph.2024.105762","DOIUrl":"10.1016/j.yrtph.2024.105762","url":null,"abstract":"<div><div>The carcinogenic potency categorisation approach (CPCA) has recently been introduced by health authorities. In this model, structural features from recent literature, industry proposals, and analyses performed by health authorities, provide a rapid assessment of the potential acceptable intake (AI) for a nitrosamine impurity. As with other screening regulatory values (such as the ICH M7 Threshold of Toxicological Concern), the CPCA is conservative and can be considered a <em>de minimis</em> risk management framework. In cases where a nitrosamine drug substance-related impurity (NDSRI) is present below the CPCA limit, the framework provides resolution from a toxicological perspective (i.e., no further toxicology studies are required). Where an NDSRI is above the CPCA limit, the framework provides for the initiation of additional activities (i.e., the CPCA is not the only possible limit). Read-across approaches are described in both the CPCA and M7 guidance and can provide a limit with more specific applicability than the general model. The use of available experimental data (<em>in vitro</em> or <em>in vivo</em>), is valuable in order to provide an even more specific limit. The CPCA provides a framework; however, data should permit changing the AI from initial structural assessment, based on increasing data, to ultimately increase precision of the AI.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105762"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814074","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

Unraveling Caco-2 cells through functional and transcriptomic assessments 通过功能和转录组学评估揭示Caco-2细胞。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-01 DOI: 10.1016/j.yrtph.2025.105771

Ye Eun Jeong, Katherine Shea, Kevin A. Ford

{"title":"Unraveling Caco-2 cells through functional and transcriptomic assessments","authors":"Ye Eun Jeong, Katherine Shea, Kevin A. Ford","doi":"10.1016/j.yrtph.2025.105771","DOIUrl":"10.1016/j.yrtph.2025.105771","url":null,"abstract":"<div><div>The static Caco-2 monolayer is an extensively utilized model for predicting the permeability of small molecules during the drug development process. While these cells can differentiate and develop key functional and morphological features that emulate human enterocytes, they do not fully replicate the complexity of human intestinal physiology. In this study, we investigated functional and morphological aspects of Caco-2 cells, alongside their transcriptomic profiles, with a particular emphasis on genes encoding drug-metabolizing enzymes and drug transporters. We found that Caco-2 cells not only established a robust and bio-relevant permeable intestinal barrier but also demonstrated functional maturity and differentiation in the intestinal epithelium, substantiated by the activities of important enzymes and an efflux transporter. However, our targeted gene expression analyses revealed that substantial disparities were found in mRNA transcript levels among Caco-2 cells and human biopsy samples. These findings highlight that, although Caco-2 cells are valuable for assessing the passive transport of drugs, their accuracy for predicting active transport or small intestinal drug metabolism is constrained by their transcriptomic divergence from human intestinal tissues. This study highlights the importance of understanding the Caco-2 model's inherent limitations and provides insights that could inform its appropriate application in drug development and regulatory decision-making.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105771"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979724","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

Quantifying the effect of human interindividual kinetic differences on the relative potency value for riddelliine N-oxide at low dose levels by a new approach methodology 用一种新的方法量化人体个体间动力学差异对低剂量氧化罗德利林相对效价的影响。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-01 DOI: 10.1016/j.yrtph.2024.105767

F. Widjaja-van den Ende , M.A.J.S. van Boekel , C. Davis , S. Wesseling , I.M.C.M. Rietjens

{"title":"Quantifying the effect of human interindividual kinetic differences on the relative potency value for riddelliine N-oxide at low dose levels by a new approach methodology","authors":"F. Widjaja-van den Ende , M.A.J.S. van Boekel , C. Davis , S. Wesseling , I.M.C.M. Rietjens","doi":"10.1016/j.yrtph.2024.105767","DOIUrl":"10.1016/j.yrtph.2024.105767","url":null,"abstract":"<div><div>Pyrrolizidine alkaloid N-oxides (PA-N-oxides) are predominant in plants and herbal foods, and are converted to pyrrolizidine alkaloids (PAs) upon consumption, leading to toxicity. The effect of interindividual kinetic differences on the relative potency values of PA-N-oxides compared to their PAs (REP<sub>PANO to PA</sub>) was studied, with riddelliine N-oxide (RIDO) and riddelliine (RID) as model compounds. <em>In vitro</em> kinetic data measured in incubations with 30 fecal and 25 liver S9 donor samples showed high variation across individuals, where the interindividual variability was captured with Bayesian multilevel regression. The distributions of influential PBK model parameters were used as input for physiologically based kinetic (PBK) modeling combined with Monte Carlo (MC) simulations to calculate the probability distribution of REP<sub>RIDO to RID</sub> values. At low dose levels, interindividual differences were shown to be a factor that influences the REP<sub>RIDO to RID</sub> value while neither dose nor endpoint used plays a role. The distribution of the REP<sub>RIDO to RID</sub> value ranged from 0.71 to 0.97 (95th percentile) with a mean value of 0.87. The approach described enables determination of interindividual REP<sub>PANO to PA</sub> values at low dose levels, which are not accessible in <em>in vivo</em> experiments quantifying the REP<sub>PANO to PA</sub>value.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105767"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877848","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

Global regulatory considerations and practices for tumorigenicity evaluation of cell-based therapy 细胞治疗致瘤性评估的全球监管考虑和实践。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-01 DOI: 10.1016/j.yrtph.2024.105769

Dehu Dou , Jing Lu , Jinhui Dou , Yan Huo , Xinjiang Gong , Xuefeng Zhang , Xijing Chen

{"title":"Global regulatory considerations and practices for tumorigenicity evaluation of cell-based therapy","authors":"Dehu Dou , Jing Lu , Jinhui Dou , Yan Huo , Xinjiang Gong , Xuefeng Zhang , Xijing Chen","doi":"10.1016/j.yrtph.2024.105769","DOIUrl":"10.1016/j.yrtph.2024.105769","url":null,"abstract":"<div><div>Cell-based therapy, as a “living drug”, possesses inherent complexity and heterogeneity. Tumorigenicity evaluation is a crucial aspect of safety assessment for cell-based therapies. Stem cell-based therapies such as hESCs and hiPSCs, may contain residual undifferentiated cells in final product, which have a high potential for proliferation and differentiation, posing a risk of tumor formation in vivo. Additionally, the source, phenotype, differentiation status, proliferative capacity, ex vivo culture conditions, ex vivo processing methods, injection site, and route of administration also influence the tumorigenicity risk of the cells. Tumorigenicity evaluation needs to consider the complexity of design and multifactorial influences. Through the analysis and summary of partial existing marketed and under-development products, combined with practical experience, it is found that there are many differences in requirements and practices related to cell tumorigenicity globally. Regulatory requirements also vary, and guidance and support for applicants’ declaration requirements in different regions need to be considered in conjunction with product characteristics and regulatory considerations. This article comprehensively summarizes the requirements of tumorigenicity from main regulatory agencies. Currently, there is no unified global regulatory consensus on technical implementation guide, measures for quantitation or standardization have not been established for evaluation systems. However, based on regulatory requirements and industry practice summaries, through literature research and analysis of tumorigenicity strategy of representative marketed products, the basic focus, and evaluation strategies for tumorigenicity assessment have been preliminarily clarified, providing a reference for the tumorigenicity design of variety of cell-based therapy products.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105769"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915356","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

The dual endothelin A and angiotensin II type 1 receptor antagonist sparsentan (FILSPARI®) exhibits a safe nonclinical male fertility toxicity profile 双重内皮素A和血管紧张素II型1受体拮抗剂sparsentan （FILSPARI®）显示出安全的非临床男性生育毒性。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-01 DOI: 10.1016/j.yrtph.2024.105770

Patricia W. Bedard , Francesca Pretto , Sima Patel , Celia Jenkinson , Tacey White , Donald E. Kohan

{"title":"The dual endothelin A and angiotensin II type 1 receptor antagonist sparsentan (FILSPARI®) exhibits a safe nonclinical male fertility toxicity profile","authors":"Patricia W. Bedard , Francesca Pretto , Sima Patel , Celia Jenkinson , Tacey White , Donald E. Kohan","doi":"10.1016/j.yrtph.2024.105770","DOIUrl":"10.1016/j.yrtph.2024.105770","url":null,"abstract":"<div><div>Marketed endothelin receptor antagonists (ERAs) have been associated with testicular tubular atrophy and decreases in male animal fertility in chronic toxicity studies in rats and dogs. Consistent with these findings, reduced sperm count has been observed in the clinical setting and is considered a potential class risk with chronic administration of ERAs. In contrast, no such effects on male animal fertility are noted with angiotensin II type 1 receptor blocker (ARB) treatment. Sparsentan (FILSPARI®) is a novel single molecule dual antagonist that antagonizes both the endothelin type A and angiotensin II type 1 receptors. We explored whether the reproductive toxicology profile of this dual endothelin angiotensin antagonist is more like that of marketed ERAs or ARBs. A full package of repeat dose general toxicity, juvenile toxicity, carcinogenicity, and reproductive and developmental toxicity studies was completed with sparsentan. A thorough review of the results from these studies has shown no evidence of effects of sparsentan on spermatogenesis or testicular histopathology. The overall conclusion of this assessment is that sparsentan is not toxic to the testes or the spermatogenic process and is more like ARBs than ERAs in its male fertility toxicity profile.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105770"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915360","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