Altex-Alternatives To Animal Experimentation最新文献

{"title":"A microfluidic thyroid-liver platform to assess chemical safety in humans.","authors":"Julia Kühnlenz,&nbsp;Diana Karwelat,&nbsp;Thomas Steger-Hartmann,&nbsp;Marian Raschke,&nbsp;Sophie Bauer,&nbsp;Özlem Vural,&nbsp;Uwe Marx,&nbsp;Helen Tinwell,&nbsp;Remi Bars","doi":"10.14573/altex.2108261","DOIUrl":"https://doi.org/10.14573/altex.2108261","url":null,"abstract":"<p><p>Thyroid hormones (THs) are crucial regulators of human metabolism and early development. During the safety assessment of plant protection products, the human relevance of chemically induced TH perturbations observed in test animals remains uncertain. European regulatory authorities request follow-up in vitro studies to elucidate human-relevant interferences on thyroid gland function or TH catabolism through hepatic enzyme induction. However, human in vitro assays based on single molecular initiating events poorly reflect the complex TH biology and related liver-thyroid axis. To address this complexity, we present human three-dimensional thyroid and liver organoids with key functions of TH metabolism. The thyroid model resembles in vivo-like follicular architecture and a TSH-dependent triiodothyronine synthesis over 21 days, which is inhibited by methimazole. The HepaRG-based liver model, secreting the critical TH-binding proteins albumin and thyroxine-binding globulin, emulates an active TH catabolism via the formation of glucuronidated and sulfated thyroxine (gT4/sT4). Activation of the nuclear receptors PXR and AHR was demonstrated via the induction of specific CYP isoenzymes by rifampicin, pregnenolone-16α-carbonitrile, and β-naphthoflavone. However, this nuclear receptor activation, assumed to regulate UDP-glucuronosyltransferases and sulfotransferases, appeared to have no effect on gT4 and sT4 formation in this human-derived hepatic cell line model. Finally, established single-tissue models were successfully co-cultured in a perfused two-organ chip for 21 days. In conclusion, this model presents a first step towards a complex multimodular human platform that will help to identify both direct and indirect thyroid disruptors that are relevant from a human safety perspective.</p>","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"40 1","pages":"61-82"},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10541617","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}

{"title":"A call for a Human Exposome Project.","authors":"Thomas Hartung","doi":"10.14573/altex.2301061","DOIUrl":"https://doi.org/10.14573/altex.2301061","url":null,"abstract":"<p><p>Four decades of the Human Genome Project and its consequences have shown how the entrepreneurial state, through significant investment into science, can drive scientific progress and advance biomedicine. A certain fraction of diseases can now be explained as caused by genetics, and a more significant fraction as impacted by genetics. Besides another fraction caused by pathogens, the third and probably largest impactor is exposure, i.e., the many physicochemical and lifestyle factors. This article makes the case that it is time to start a Human Exposome Project, which systematically explores and catalogs the exposure side of human health and disease. The envisioned Human Exposome Project needs to be more than a scaled exposomics approach, aiming to assess the totality of relevant exposures through ~omics of human body fluids and forming exposure hypotheses. Exposomics is increasingly complemented by exposure science and biomonitoring to measure exposure, mechanistic understanding, human-relevant microphysiological systems, big data, and artificial intelligence (AI) to mine these data and integrate pieces of evidence. The potential impact of AI on a possible Human Exposome Project is so substantial that we should speak of exposome intelligence (EI) because this allows us to expand our limited current knowledge to the big unknown unknowns of threats to human health.</p>","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"40 1","pages":"4-33"},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9614323","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}

{"title":"Novel prediction models for genotoxicity based on biomarker genes in human HepaRG™ cells.","authors":"Anouck Thienpont,&nbsp;Stefaan Verhulst,&nbsp;Leo A Van Grunsven,&nbsp;Vera Rogiers,&nbsp;Tamara Vanhaecke,&nbsp;Birgit Mertens","doi":"10.14573/altex.2206201","DOIUrl":"https://doi.org/10.14573/altex.2206201","url":null,"abstract":"<p><p>Transcriptomics-based biomarkers are promising new approach methodologies (NAMs) to identify molecular events underlying the genotoxic mode of action of chemicals. Previously, we developed the GENOMARK biomarker, consisting of 84 genes selected based on whole genomics DNA microarray profiles of 24 (non-)genotoxic reference chemicals covering different modes of action in metabolically competent human HepaRG™ cells. In the present study, new prediction models for genotoxicity were developed based on an extended reference dataset of 38 chemicals including existing as well as newly generated gene expression data. Both unsupervised and supervised machine learning algorithms were used, but as unsupervised machine learning did not clearly distinguish between groups, the performance of two supervised machine learning algorithms, i.e., support vector machine (SVM) and random forest (RF), was evaluated. More specifically, the predictive accuracy was compared, the sensitivity to outliers for one or more biomarker genes was assessed, and the prediction performance for 10 misleading positive chemicals exposed at their IC10 concentration was determined. In addition, the applicability of both prediction models on a publicly available gene expression dataset, generated with RNA-sequencing, was investigated. Overall, the RF and SVM models were complementary in their classification of chemicals for genotoxicity. To facilitate data analysis, an online application was developed, combining the outcomes of both prediction models. This research demonstrates that the combination of gene expression data with supervised machine learning algorithms can contribute to the ongoing paradigm shift towards a more human-relevant in vitro genotoxicity testing strategy without the use of experimental animals.</p>","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"40 2","pages":"271-286"},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9616823","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}

{"title":"How to formulate hypotheses and IATAs to support grouping and read-across of nanoforms.","authors":"Fiona A Murphy,&nbsp;Helinor J Johnston,&nbsp;Susan Dekkers,&nbsp;Eric A J Bleeker,&nbsp;Agnes G Oomen,&nbsp;Teresa F Fernandes,&nbsp;Kirsten Rasmussen,&nbsp;Paula Jantunen,&nbsp;Hubert Rauscher,&nbsp;Neil Hunt,&nbsp;Luisana di Cristos,&nbsp;Hedwig M Braakhuis,&nbsp;Andrea Haase,&nbsp;Danail Hristozov,&nbsp;Wendel Wohlleben,&nbsp;Stefania Sabella,&nbsp;Vicki Stone","doi":"10.14573/altex.2203241","DOIUrl":"https://doi.org/10.14573/altex.2203241","url":null,"abstract":"<p><p>Manufacturing and functionalizing materials at the nanoscale has led to the generation of a whole array of nanoforms (NFs) of substances varying in size, morphology, and surface characteristics. Due to financial, time, and ethical considerations, testing every unique NF for adverse effects is virtually impossible. Use of hypothesis-driven grouping and read-across approaches, as supported by the GRACIOUS Framework, represents a promising alternative to case-by-case testing that will make the risk assessment process more efficient. Through application of appropriate grouping hypotheses, the Framework facilitates the assessment of similarity between NFs, thereby supporting grouping and read-across of information, minimizing the need for new testing, and aligning with the 3R principles of replacement, reduction, and refinement of animals in toxicology studies. For each grouping hypothesis an integrated approach to testing and assessment (IATA) guides the user in data gathering and acquisition to test the hypothesis, following a structured format to facilitate efficient decision-making. Here we present the template used to generate the GRACIOUS grouping hypotheses encompassing information relevant to “Lifecycle, environmental release, and human exposure”, “What they are: physicochemical characteristics”, “Where they go: environmental fate, uptake, and toxicokinetics”, and “What they do: human and environmental toxicity”. A summary of the template-derived hypotheses focusing on human health is provided, along with an overview of the IATAs generated by the GRACIOUS project. We discuss the application and flexibility of the template, providing the opportunity to expand the application of grouping and read-across in a logical, evidence-based manner to a wider range of NFs and substances.</p>","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"40 1","pages":"125-140"},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9225071","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}

{"title":"The importance of variations in in vitro dosimetry to support risk assessment of inhaled toxicants_suppl3","authors":"Yvonne Staal","doi":"10.14573/altex.2305311s3","DOIUrl":"https://doi.org/10.14573/altex.2305311s3","url":null,"abstract":"","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"52 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136367872","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}

{"title":"Comparing translational success rates across medical research fields_suppl","authors":"Gwen Van de Wall","doi":"10.14573/altex.2208261s","DOIUrl":"https://doi.org/10.14573/altex.2208261s","url":null,"abstract":"","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"7 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84889569","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}

{"title":"Incorporating new approach methodologies into regulatory nonclinical pharmaceutical safety assessment_suppl","authors":"Jan Turner","doi":"10.14573/altex.2212081s","DOIUrl":"https://doi.org/10.14573/altex.2212081s","url":null,"abstract":"","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"97 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91033920","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}

{"title":"Linking nanomaterial-induced mitochondrial dysfunction to existing adverse outcome pathways for chemicals_suppl1","authors":"S. Murugadoss","doi":"10.14573/altex.2305011s1","DOIUrl":"https://doi.org/10.14573/altex.2305011s1","url":null,"abstract":"","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"29 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76889587","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}

{"title":"4.2 million and counting… The animal toll for REACH systemic toxicity studies.","authors":"Jean Knight,&nbsp;Thomas Hartung,&nbsp;Costanza Rovida","doi":"10.14573/altex.2303201","DOIUrl":"https://doi.org/10.14573/altex.2303201","url":null,"abstract":"<p><p>The EU's chemicals regulation, REACH, requires that most chemicals in the EU be evaluated for human health and ecosystem risks, with a mandate to minimize use of animal tests for these evaluations. The REACH process has been ongoing since about 2008, but a calculation of the resulting animal use is not publicly available. For this reason, we have undertaken a count of animals used for REACH. With EU legislators set to consider REACH revisions that could expand animal testing, we are releasing results for test categories counted to date: reproductive toxicity tests, developmental toxicity tests, and repeat-ed-dose toxicity tests for human health. The total animal count as of December 2022 for these categories is about 2.9 million. Additional tests involving about 1.3 million animals are currently required by a final proposal authorization or compliance check but not yet completed. The total, 4.2 million, for just these three test categories exceeds the original European Com-mission forecast of 2.6 million for all REACH tests. The difference is primarily because the European Commission estimate excluded offspring, which are most of the animals used for REACH. Other reasons for the difference are extra animals included in tests to ensure sufficient survive to meet the minimum test requirement; dose range-finding tests; extra test animal groups, e.g., for recovery analysis; and a high rejection rate of read-across studies. Given higher than forecast animal use, the upcoming debate on proposed REACH revisions is an opportunity to refocus on reducing animal numbers in keeping with the REACH mandate.</p>","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"40 3","pages":"389-407"},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9899430","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}

{"title":"Off to a good start? Review of the predictivity of reactivity methods modelling the molecular initiating event of skin sensitization.","authors":"Nathalie Alépée,&nbsp;Fleur Tourneix,&nbsp;Akanksha Singh,&nbsp;Nadège Ade,&nbsp;Sébastien Grégoire","doi":"10.14573/altex.2212201","DOIUrl":"10.14573/altex.2212201","url":null,"abstract":"<p><p>The assessment of skin sensitizing properties of chemicals has moved away from animal methods to new approach methodologies (NAM), guided by qualitative mechanistic understanding operationalized in an adverse outcome pathway (AOP). As with any AOP, the molecular initiating event (MIE) of covalent binding of a chemical to skin proteins is particularly important. This MIE has been modelled by several test methods by measuring the reaction of a test chemical with model peptides in chemico. To better understand the similarities and differences, a data repository with publicly available data for the direct peptide reactivity assay (DPRA), amino acid derivative reactivity assay (ADRA) and kinetic DPRA (kDPRA), as well as the peroxidase peptide reactivity assay (PPRA) was assembled. The repository comprises 260 chemicals with animal and human reference data, data on four relevant physicochemical properties, and between 161 to 242 test chemical results per test method. First, an overview of the experimental conditions of the four test methods was compiled allowing to readily compare them. Second, data analyses demonstrated that the test methods’ predictivity was consistently reduced for poorly watersoluble chemicals and that the DPRA and ADRA can be used interchangeably. It also revealed new categorization thresholds for the DPRA and ADRA that are potentially relevant for strategic uses. In summary, a detailed assessment of reactivity test methods is provided, highlighting their potential and limitations. The results presented are intended to stimulate scientific discussion around test methods modelling the MIE of the skin sensitization AOP.</p>","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":" ","pages":"606-618"},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9619045","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}