Altex-Alternatives To Animal Experimentation最新文献_第4页

Intestinal in vitro transport assay combined with physiologically based kinetic modeling as a tool to predict bile acid levels in vivo. 将肠道体外转运试验与基于生理学的动力学模型相结合，作为预测体内胆汁酸水平的工具。

IF 5.6 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2024-01-09 Epub Date: 2023-07-27 DOI: 10.14573/altex.2302011

Véronique M P De Bruijn, Willem Te Kronnie, Ivonne M C M Rietjens, Hans Bouwmeester

{"title":"Intestinal in vitro transport assay combined with physiologically based kinetic modeling as a tool to predict bile acid levels in vivo.","authors":"Véronique M P De Bruijn, Willem Te Kronnie, Ivonne M C M Rietjens, Hans Bouwmeester","doi":"10.14573/altex.2302011","DOIUrl":"10.14573/altex.2302011","url":null,"abstract":"Bile acid homeostasis is vital for numerous metabolic and immune functions in humans. The enterohepatic circulation of bile acids is extremely efficient, with ~95% of intestinal bile acids being reabsorbed. Disturbing intestinal bile acid uptake is expected to substantially affect intestinal and systemic bile acid levels. Here, we aimed to predict the effects of apical sodium-dependent bile acid transporter (ASBT)-inhibition on systemic plasma levels. For this, we combined in vitro Caco-2 cell transport assays with physiologically based (PBK) modeling. We used the selective ASBT-inhibitor odevixibat (ODE) as a model compound. Caco-2 cells grown on culture inserts were used to obtain transport kinetic parameters of glycocholic acid (GCA). The apparent Michaelis-Menten constant (Km,app), apparent maximal intestinal transport rate (Vmax,app), and ODE’s inhibitory constant (Ki) were determined for GCA. These kinetic parameters were incorporated into a PBK model and used to predict the ASBT inhibition effects on plasma bile acid levels. GCA is transported over Caco-2 cells in an active and sodium-dependent manner, indicating the presence of functional ASBT. ODE inhibited GCA transport dose-dependently. The PBK model predicted that oral doses of ODE reduced conjugated bile acid levels in plasma. Our simulations match in vivo data and provide a first proof-of-principle for the incorporation of active intestinal bile acid uptake in a bile acid PBK model. This approach could in future be of use to predict the effects of other ASBT-inhibitors on plasma and intestinal bile acid levels.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":" ","pages":"20-36"},"PeriodicalIF":5.6,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9911350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Why adverse outcome pathways need to be FAIR. 为什么不良结果路径需要 FAIR？

IF 5.6 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2024-01-09 Epub Date: 2023-08-01 DOI: 10.14573/altex.2307131

Clemens Wittwehr, Laure-Alix Clerbaux, Stephen Edwards, Michelle Angrish, Holly Mortensen, Annamaria Carusi, Maciej Gromelski, Eftychia Lekka, Vassilis Virvilis, Marvin Martens, Luiz Olavo Bonino da Silva Santos, Penny Nymark

引用次数: 0

The importance of variations in in vitro dosimetry to support risk assessment of inhaled toxicants. 体外剂量测定变化对支持吸入毒物风险评估的重要性。

IF 5.6 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2024-01-09 Epub Date: 2023-10-12 DOI: 10.14573/altex.2305311

Yvonne C M Staal, Liesbeth Geraets, Barbara Rothen-Rutishauser, Martin J D Clift, Hedwig Braakhuis, Anne S Kienhuis, Peter M J Bos

{"title":"The importance of variations in in vitro dosimetry to support risk assessment of inhaled toxicants.","authors":"Yvonne C M Staal, Liesbeth Geraets, Barbara Rothen-Rutishauser, Martin J D Clift, Hedwig Braakhuis, Anne S Kienhuis, Peter M J Bos","doi":"10.14573/altex.2305311","DOIUrl":"10.14573/altex.2305311","url":null,"abstract":"In vitro methods provide a key opportunity to model human-relevant exposure scenarios for hazard identification of inhaled toxicants. Compared to in vivo tests, in vitro methods have the advantage of assessing effects of inhaled toxicants caused by differences in dosimetry, e.g., variations in concentration (exposure intensity), exposure duration, and exposure frequency, in an easier way. Variations in dosimetry can be used to obtain information on adverse effects in human-relevant exposure scenarios that can be used for risk assessment. Based on the published literature of exposure approaches using air-liquid interface models of the respiratory tract, supplemented with additional experimental data from the EU H2020 project “PATROLS” and research funded by the Dutch Ministry of Agriculture, Nature and Food Quality, the advantages and disadvantages of different exposure methods and considerations to design an experimental setup are summarized and discussed. As the cell models used are models for the respiratory epithelium, our focus is on the local effects in the airways. In conclusion, in order to generate data from in vitro methods for risk assessment of inhaled toxicants it is recommended that (1) it is considered what information really is needed for hazard or risk assessment; (2) the exposure system that is most suitable for the chemical to be assessed is chosen; (3) a deposited dose that mimics deposition in the human respiratory tract is used, and (4) the post-exposure sampling methodology should be carefully considered and relevant to the testing strategy used.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":" ","pages":"91-103"},"PeriodicalIF":5.6,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41240755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

The probable future of toxicology - probabilistic risk assessment. 毒理学的可能未来--概率风险评估。

IF 5.6 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2024-01-01 Epub Date: 2024-01-12 DOI: 10.14573/altex.2310301

Alexandra Maertens, Eric Antignac, Emilio Benfenati, Denise Bloch, Ellen Fritsche, Sebastian Hoffmann, Joanna Jaworska, George Loizou, Kevin McNally, Przemyslaw Piechota, Erwin L Roggen, Marc Teunis, Thomas Hartung

{"title":"The probable future of toxicology - probabilistic risk assessment.","authors":"Alexandra Maertens, Eric Antignac, Emilio Benfenati, Denise Bloch, Ellen Fritsche, Sebastian Hoffmann, Joanna Jaworska, George Loizou, Kevin McNally, Przemyslaw Piechota, Erwin L Roggen, Marc Teunis, Thomas Hartung","doi":"10.14573/altex.2310301","DOIUrl":"10.14573/altex.2310301","url":null,"abstract":"Both because of the shortcomings of existing risk assessment methodologies, as well as newly available tools to predict hazard and risk with machine learning approaches, there has been an emerging emphasis on probabilistic risk assessment. Increasingly sophisticated AI models can be applied to a plethora of exposure and hazard data to obtain not only predictions for particular endpoints but also to estimate the uncertainty of the risk assessment outcome. This provides the basis for a shift from deterministic to more probabilistic approaches but comes at the cost of an increased complexity of the process as it requires more resources and human expertise. There are still challenges to overcome before a probabilistic paradigm is fully embraced by regulators. Based on an earlier white paper (Maertens et al., 2022), a workshop discussed the prospects, challenges and path forward for implementing such AI-based probabilistic hazard assessment. Moving forward, we will see the transition from categorized into probabilistic and dose-dependent hazard outcomes, the application of internal thresholds of toxicological concern for data-poor substances, the acknowledgement of user-friendly open-source software, a rise in the expertise of toxicologists required to understand and interpret artificial intelligence models, and the honest communication of uncertainty in risk assessment to the public.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":" ","pages":"273-281"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139433258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

In vitro evaluation of the carcinogenic potential of perfluorinated chemicals. 全氟化学品致癌潜力的体外评估。

IF 4.5 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2024-01-01 Epub Date: 2024-04-22 DOI: 10.14573/altex.2310281

Monica Vaccari, Stefania Serra, Andrea Ranzi, Federico Aldrovandi, Giangabriele Maffei, Maria G Mascolo, Ada Mescoli, Elisa Montanari, Gelsomina Pillo, Francesca Rotondo, Ivan Scaroni, Lorenzo Vaccari, Cristina Zanzi, Tony Fletcher, Martin Paparella, Annamaria Colacci

{"title":"In vitro evaluation of the carcinogenic potential of perfluorinated chemicals.","authors":"Monica Vaccari, Stefania Serra, Andrea Ranzi, Federico Aldrovandi, Giangabriele Maffei, Maria G Mascolo, Ada Mescoli, Elisa Montanari, Gelsomina Pillo, Francesca Rotondo, Ivan Scaroni, Lorenzo Vaccari, Cristina Zanzi, Tony Fletcher, Martin Paparella, Annamaria Colacci","doi":"10.14573/altex.2310281","DOIUrl":"10.14573/altex.2310281","url":null,"abstract":"Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are the major components of long-chain per- and polyfluorinated alkyl substances (PFAS), known for their chemical stability and environmental persistence. Even if PFOA and PFOS have been phased out or are limited in use, they still represent a concern for human and environmental health. Several studies have been performed to highlight the toxicological behavior of these chemicals and their mode of action (MoA). Data have suggested a causal association between PFOA or PFOS exposure and carcinogenicity in humans, but the outcomes of epidemiological studies showed some inconsistency. Moreover, the hypothesized MoA based on animal studies is considered not relevant for human cancer. To improve the knowledge on PFAS toxicology and contribute to the weight of evidence for the regulatory classification of PFAS, we used the BALB/c 3T3 cell transformation assay (CTA), an in vitro model under consideration to be included in an integrated approach to testing and assessment for non-genotoxic carcinogens (NGTxCs). PFOS and PFOA were tested at several concentrations using a validated experimental protocol. Our results demonstrate that PFOA does not induce cell transformation, whereas PFOS exposure induced a concentration-related increase of type III foci. Malignant foci formation was triggered at PFOS concentrations equal to or higher than 50 ppm and was not directly associated with cytotoxicity or proliferation induction. The divergent CTA outcomes suggest that different molecular events could be responsible for the toxicological profiles of PFOS and PFOA, which were not fully captured in our study.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":" ","pages":"439-456"},"PeriodicalIF":4.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140861360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Application of microphysiological systems for nonclinical evaluation of cell therapies 应用微观生理学系统对细胞疗法进行非临床评估。

IF 4.5 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2024-01-01 Epub Date: 2024-05-15 DOI: 10.14573/altex.2402201

Pelin L Candarlioglu, Louise Delsing, Lauren Gauthier, Lauren Lewis, George Papadopoulos, May Freag, Tom S Chan, Kimberly A Homan, Mick D Fellows, Amy Pointon, Kyle Kojala

{"title":"Application of microphysiological systems for nonclinical evaluation of cell therapies","authors":"Pelin L Candarlioglu, Louise Delsing, Lauren Gauthier, Lauren Lewis, George Papadopoulos, May Freag, Tom S Chan, Kimberly A Homan, Mick D Fellows, Amy Pointon, Kyle Kojala","doi":"10.14573/altex.2402201","DOIUrl":"10.14573/altex.2402201","url":null,"abstract":"Microphysiological systems (MPS) are gaining broader application in the pharmaceutical industry but have primarily been leveraged in early discovery toxicology and pharmacology studies with small molecules. The adoption of MPS offers a promising avenue to reduce animal use, improve in-vitro-to-in-vivo translation of pharmacokinetics/pharmacodynamics and toxicity correlation, and provide mechanistic understanding of model species suitability. While MPS have demonstrated utility in these areas with small molecules and biologics, MPS models in cell therapy development have not been fully explored, let alone validated. Distinguishing features of MPS, including long-term viability and physiologically relevant expression of functional enzymes, receptors, and pharmacological targets make them attractive tools for nonclinical characterization. However, there is currently limited published evidence of MPS being utilized to study the disposition, metabolism, pharmacology, and toxicity profiles of cell therapies. This review provides an industry perspective on the nonclinical application of MPS on cell therapies, first with a focus on oncology applications followed by examples in regenerative medicine.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":" ","pages":"469-484"},"PeriodicalIF":4.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

In vitro model of neurotrauma using the chick embryo to test regenerative bioimplantation. 神经创伤的体外模型使用鸡胚测试再生生物植入。

IF 4.5 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2024-01-01 Epub Date: 2023-11-02 DOI: 10.14573/altex.2304171

Aina Mogas Barcons, Divya M Chari, Christopher Adams

{"title":"In vitro model of neurotrauma using the chick embryo to test regenerative bioimplantation.","authors":"Aina Mogas Barcons, Divya M Chari, Christopher Adams","doi":"10.14573/altex.2304171","DOIUrl":"10.14573/altex.2304171","url":null,"abstract":"Effective repair of spinal cord injury sites remains a major clinical challenge. One promising strategy is the implantation of multifunctional bioscaffolds to enhance nerve fiber growth, guide regenerating tissue, and modulate scarring/inflammation processes. Given their multifunctional nature, such implants require testing in models which replicate the complex neuropathological responses of spinal injury sites. This is often achieved using live, adult animal models of spinal injury. However, these have substantial drawbacks for developmental testing, including the requirement for large numbers of animals, costly infrastructure, high levels of expertise, and complex ethical processes. As an alternative, we show that organotypic spinal cord slices can be derived from the E14 chick embryo and cultured with high viability for at least 24 days, with major neural cell types detected. A transecting injury could be reproducibly introduced into the slices and characteristic neuropathological responses similar to those in adult spinal cord injury observed at the lesion margin. This included aligned astrocyte morphologies and upregulation of glial fibrillary acidic protein in astrocytes, microglial infiltration into the injury cavity, and limited nerve fiber outgrowth. Bioimplantation of a clinical grade scaffold biomaterial was able to modulate these responses, disrupting the astrocyte barrier, enhancing nerve fiber growth, and supporting immune cell invasion. Chick embryos are inexpensive and simple, requiring facile methods to generate the neurotrauma model. Our data show the chick embryo spinal cord slice system could be a replacement spinal injury model for laboratories developing new tissue engineering solutions.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":" ","pages":"202-212"},"PeriodicalIF":4.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71428862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Leveraging biomarkers and translational medicine for preclinical safety - Lessons for advancing the validation of alternatives to animal testing. 利用生物标志物和转化医学促进临床前安全性--推动动物试验替代品验证的经验教训。

IF 4.5 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2024-01-01 DOI: 10.14573/altex.2410011

Thomas Hartung, Nicholas M P King, Nicole Kleinstreuer, Marcel Leist, Danilo A Tagle

{"title":"Leveraging biomarkers and translational medicine for preclinical safety - Lessons for advancing the validation of alternatives to animal testing.","authors":"Thomas Hartung, Nicholas M P King, Nicole Kleinstreuer, Marcel Leist, Danilo A Tagle","doi":"10.14573/altex.2410011","DOIUrl":"https://doi.org/10.14573/altex.2410011","url":null,"abstract":"This article explores the potential of principles established in translational medicine for the use of bio-markers to advance the validation of alternatives to animal testing in preclinical safety assessment. It examines especially how such principles can enhance the predictive power, mechanistic under-standing, and human relevance of new approach methodologies (NAMs). Key concepts from translational medicine, such as fit-for-purpose validation, evidence-based approaches, and inte-grated testing strategies, are already being applied to the development and validation of NAMs. The article discusses challenges in implementing biomarker-based approaches, including standardi-zation, demonstration of relevance, regulatory acceptance, and addressing biological complexity. It also highlights opportunities for advancement through collaborative efforts, technological inno-vations, and regulatory evolution. Case studies demonstrate successful applications of biomarkers in preclinical safety, while future perspectives explore emerging trends like multi-omics integration, microphysiological systems, and artificial intelligence. The article emphasizes the potential of bio-markers and translational science approaches in creating more predictive, efficient, and ethical preclinical safety assessment paradigms in the use of NAMs. Use of biomarkers can enable the mechanistic validation of human-relevant models and provide a means to relate changes in NAMs to animal or clinical study results. By leveraging these tools, the field can work towards reducing reliance on animal testing while improving the accuracy and human relevance of safety predictions.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"41 4","pages":"545-566"},"PeriodicalIF":4.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142512492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Characterization and optimization of variability in a human colonic epithelium culture model. 人类结肠上皮细胞培养模型的特征和变异性优化。

IF 4.5 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2024-01-01 Epub Date: 2024-04-18 DOI: 10.14573/altex.2309221

Colleen M Pike, Bailey Zwarycz, Bryan E McQueen, Mariana Castillo, Catherine Barron, Jeremy M Morowitz, James A Levi, Dhiral Phadke, Michele Balik-Meisner, Deepak Mav, Ruchir Shah, Danielle L Cunningham Glasspoole, Ron Laetham, William Thelin, Maureen K Bunger, Elizabeth M Boazak

{"title":"Characterization and optimization of variability in a human colonic epithelium culture model.","authors":"Colleen M Pike, Bailey Zwarycz, Bryan E McQueen, Mariana Castillo, Catherine Barron, Jeremy M Morowitz, James A Levi, Dhiral Phadke, Michele Balik-Meisner, Deepak Mav, Ruchir Shah, Danielle L Cunningham Glasspoole, Ron Laetham, William Thelin, Maureen K Bunger, Elizabeth M Boazak","doi":"10.14573/altex.2309221","DOIUrl":"10.14573/altex.2309221","url":null,"abstract":"Animal models have historically been poor preclinical predictors of gastrointestinal (GI) directed therapeutic efficacy and drug-induced GI toxicity. Human stem and primary cell-derived culture systems are a major focus of efforts to create biologically relevant models that enhance preclinical predictive value of intestinal efficacy and toxicity. The inherent variability in stem cell-based cultures makes development of useful models a challenge; the stochastic nature of stem cell differentiation interferes with the ability to build and validate reproducible assays that query drug responses and pharmacokinetics. In this study, we aimed to characterize and reduce sources of variability in a complex stem cell-derived intestinal epithelium model, termed RepliGut® Planar, across cells from multiple human donors, cell lots, and passage numbers. Assessment criteria included barrier formation and integrity, gene expression, and cytokine responses. Gene expression and culture metric analyses revealed that controlling cell passage number reduces variability and maximizes physiological relevance of the model. In a case study where passage number was optimized, distinct cytokine responses were observed among four human donors, indicating that biological variability can be detected in cell cultures originating from diverse human sources. These findings highlight key considerations for designing assays that can be applied to additional primary cell-derived systems, as well as establish utility of the RepliGut® Planar platform for robust development of human-predictive drug-response assays.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":" ","pages":"425-438"},"PeriodicalIF":4.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140861390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

National workshop on alternatives to higher animals in toxicology and biomedical science. 关于毒理学和生物医学科学中高等动物替代品的国家研讨会。

IF 4.5 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2024-01-01 DOI: 10.14573/altex.2403151

Yasir H Siddique, Tanveer Beg, Himanshi Varshney, Iqra Subhan, Kajal Gaur, Javeria Fatima, Mohammad A Akbarsha

引用次数: 0