Altex-Alternatives To Animal Experimentation最新文献

{"title":"Challenges and opportunities for overcoming dog use in agrochemical evaluation and registration.","authors":"Patricia L Bishop, Susy Brescia, Rachel Brunner, Warren Casey, Kathleen Conlee-Griffin, Richard A Currie, Jeanne Domoradzki, Michelle Embry, Maria Ines Harris, Thomas Hartung, Gina M Hilton, Barry Hooberman, Brandall Ingle, Kyung-Jin Jang, Lewis Kinter, Caroline Krall, Joseph Leedale, Anna Lowit, Jyotigna Mehta, Elizabeth Mendez, Bob Mingoia, Eliana Munarriz, Lynea Murphy, Angela Myer, Antoniana Ottoni, Martina Panzarea, Monique Perron, Juan Pina, Deborah Ramsingh, Fiona Sewell, Jennifer Swanson, Yu-Mei Tan, Andrea Terron, Maria A Trainer, Marize Campos Valadares, Steven Webb, Elizabeth Webb, Catherine Willett, Douglas C Wolf","doi":"10.14573/altex.2302151","DOIUrl":"10.14573/altex.2302151","url":null,"abstract":"<p><p>Progress in developing new tools, assays, and approaches to assess human hazard and health risk provides an opportunity to re-evaluate the necessity of dog studies for the safety evaluation of agrochemicals. A workshop was held where partic­ipants discussed the strengths and limitations of past use of dogs for pesticide evaluations and registrations. Opportunities were identified to support alternative approaches to answer human safety questions without performing the required 90-day dog study. Development of a decision tree for determining when the dog study might not be necessary to inform pesticide safety and risk assessment was proposed. Such a process will require global regulatory authority participation to lead to its acceptance. The identification of unique effects in dogs that are not identified in rodents will need further evaluation and determination of their relevance to humans. The establishment of in vitro and in silico approaches that can provide critical data on relative species sensitivity and human relevance will be an important tool to advance the decision process. Promising novel tools including in vitro comparative metabolism studies, in silico models, and high-throughput assays able to identify metabolites and mechanisms of action leading to development of adverse outcome pathways will need further development. To replace or eliminate the 90-day dog study, a collaborative, multidisciplinary, international effort that transcends organi­zations and regulatory agencies will be needed in order to develop guidance on when the study would not be necessary for human safety and risk assessment.</p>","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"40 3","pages":"534-540"},"PeriodicalIF":4.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11487581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9831516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of physiologically-based gut absorption model for probabilistic prediction of environmental chemical bioavailability.","authors":"Hsing-Chieh Lin, Weihsueh A Chiu","doi":"10.14573/altex.2210031","DOIUrl":"10.14573/altex.2210031","url":null,"abstract":"<p><p>Absorption in the gastrointestinal tract is a key factor determining the bioavailability of chemicals after oral exposure but is frequently assumed to have a conservative value of 100% for environmental chemicals, particularly in the context of high-throughput toxicokinetics for in vitro-to-in vivo extrapolation (IVIVE). For pharmaceutical compounds, the physiologically based advanced compartmental absorption and transit (ACAT) model has been used extensively to predict gut absorption but has not generally been applied to environmental chemicals. Here we develop a probabilistic environmental compart­mental absorption and transit (PECAT) model, adapting the ACAT model to environmental chemicals. We calibrated the model parameters to human in vivo, ex vivo, and in vitro datasets of drug permeability and fractional absorption by con­sidering two key factors: (1) differences between permeability in Caco-2 cells and in vivo permeability in the jejunum, and (2) differences in in vivo permeability across different gut segments. Incorporating these factors probabilistically, we found that given Caco-2 permeability measurements, predictions of the PECAT model are consistent with the (limited) available gut absorption data for environmental chemicals. However, the substantial chemical-to-chemical variability observed in the cal­ibration data often led to wide probabilistic confidence bounds in the predicted fraction absorbed and resulting steady state blood concentration. Thus, while the PECAT model provides a statistically rigorous, physiologically based approach for incor­porating in vitro data on gut absorption into toxicokinetic modeling and IVIVE, it also highlights the need for more accurate in vitro models and data for measuring gut segment-specific in vivo permeability of environmental chemicals.</p>","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"40 3","pages":"471-484"},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10898273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9841789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploration of the GARD™skin applicability domain: Indirectly acting haptens, hydrophobic substances and UVCBs.","authors":"Andy Forreryd,&nbsp;Robin Gradin,&nbsp;Charles Humfrey,&nbsp;Len Sweet,&nbsp;Henrik Johansson","doi":"10.14573/altex.2201281","DOIUrl":"https://doi.org/10.14573/altex.2201281","url":null,"abstract":"<p><p>Hazard assessments of skin sensitizers are increasingly performed using new approach methodologies (NAMs), with several in chemico, in vitro, and most recently, also defined approaches accepted for regulatory use. However, keeping track of potential limitations of each method to define applicability domains remains a crucial component to ensure adequate predictivity and to facilitate the appropriate selection of method(s) for each hazard assessment task. The objective of this report is to share test results generated with the GARD™skin assay on chemicals that have traditionally been considered difficult to test in some of the conventional in vitro and in chemico OECD Test Guidelines for skin sensitization. Such compounds may include, for example, indirectly acting haptens, hydrophobic substances, and substances of unknown or variable composition, complex reaction products or biological substances (UVCBs). Based on the results of this study, the sensitivity for prediction of skin sensitizing hazard of indirectly acting haptens was 92.4% and 87.5% when compared with local lymph node assay (LLNA) (n = 25) and human data (n = 8), respectively. Similarly, the sensitivity for prediction of skin sensitizing hazard of hydrophobic substances was 85.1% and 100% when compared with LLNA (n = 24) and human data (n = 9), respectively. Lastly, a case study involving assessment of a set of hydrophobic UVCBs (n = 7) resulted in a sensitivity of 100% compared to available reference data. These data provide support for the inclusion of such chemistries in the GARD™skin applicability domain without an increased risk of false negative classifications.</p>","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"40 1","pages":"53-60"},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10595726","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":"Animal research ethics as interaction of research ethics, animal ethics, and (animal protection) law.","authors":"Felicitas Selter,&nbsp;Tatiana Hetzel,&nbsp;Hannes Kahrass,&nbsp;Marcel Mertz","doi":"10.14573/altex.2301171","DOIUrl":"https://doi.org/10.14573/altex.2301171","url":null,"abstract":"","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"40 3","pages":"541-544"},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10203268","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":"Proceedings of a workshop to address animal methods bias in scientific publishing.","authors":"Catharine E Krebs,&nbsp;Celean Camp,&nbsp;Helder Constantino,&nbsp;Lilas Courtot,&nbsp;Owen Kavanagh,&nbsp;Sofia Batista Leite,&nbsp;Judith Madden,&nbsp;Alicia Paini,&nbsp;Brinda Poojary,&nbsp;Ignacio J Tripodi,&nbsp;Emily R Trunnell","doi":"10.14573/altex.2210211","DOIUrl":"10.14573/altex.2210211","url":null,"abstract":"<p><p>Animal methods bias in scientific publishing is a newly defined type of publishing bias describing a preference for animal-based methods where they may not be necessary or where nonanimal-based methods may already be suitable, which impacts the likelihood or timeliness of a manuscript being accepted for publication. This article covers the output from a workshop between stakeholders in publishing, academia, industry, government, and non-governmental organizations. The intent of the workshop was to exchange perspectives on the prevalence, causes, and impact of animal methods bias in scientific publishing, as well as to explore mitigation strategies. Output from the workshop includes summaries of presentations, breakout group discussions, participant polling results, and a synthesis of recommendations for mitigation. Overall, participants felt that animal methods bias has a meaningful impact on scientific publishing, though more evidence is needed to demonstrate its prevalence. Significant consequences of this bias that were identified include the unnecessary use of animals in scientific procedures, the continued reliance on animals in research – even where suitable nonanimal methods exist, poor rates of clinical translation, delays in publication, and negative impacts on career trajectories in science. Workshop participants offered recommendations for journals, publishers, funders, governments, and other policy makers, as well as the scientific community at large, to reduce the prevalence and impacts of animal methods bias. The workshop resulted in the creation of working groups committed to addressing animal methods bias, and activities are ongoing.</p>","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":" ","pages":"677-688"},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40440123","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":"Report of the 3rd and 4th Mystery of Reactive Oxygen Species Conference.","authors":"Shihori Tanabe,&nbsp;Danielle Beaton,&nbsp;Vinita Chauhan,&nbsp;Ian Choi,&nbsp;Judy Choi,&nbsp;Laure-Alix Clerbaux,&nbsp;Lucia Coppola,&nbsp;Antonio Fernandez Dumont,&nbsp;Maranda Esterhuizen,&nbsp;Julija Filipovska,&nbsp;Rex FitzGerald,&nbsp;Ellen Fritsche,&nbsp;Natalia Garcia-Reyero,&nbsp;Anna Goralczyk,&nbsp;Elizabeth Huliganga,&nbsp;Young-Jun Kim,&nbsp;Jördis Klose,&nbsp;Cinzia La Rocca,&nbsp;Brigitte Landesmann,&nbsp;Angela Mally,&nbsp;Sivakumar Murugadoss,&nbsp;Elma Omeragic,&nbsp;Gladys Ouédraogo,&nbsp;Jorge Matias Pereira,&nbsp;Baki Sadi,&nbsp;Alexandra Schaffert,&nbsp;You Song,&nbsp;Iva Sovadinova,&nbsp;Tobias Stöger,&nbsp;Knut Erik Tollefsen,&nbsp;Clemens Wittwehr,&nbsp;Carole Yauk","doi":"10.14573/altex.2307041","DOIUrl":"10.14573/altex.2307041","url":null,"abstract":"The main MoR discussion led to further suggestions on KE terminology, including ensuring coherence to directionality in terms of the KE descriptions (e.g., specifying increase, decrease, altered, no direction, etc.) and clarifying differences in ROS and reactive oxygen and nitrogen species (RONS), and enzymatic and non-enzymatic events. The consortium highlighted the importance of the role of ROS as a KE and an associative event in the AOP framework. Additionally, participants highlighted modification to macromolecules from the resultant RONS generation (e.g., lipid peroxidation) as a relevant endpoint to include in the KE. The possibility of grouping ROS-related KEs in the AOP framework needs to be discussed further.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"40 4","pages":"689-693"},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54232059","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":"Beyond Animal Testing Index: Benchmarking tool for a world beyond animal testing_suppl1","authors":"C. Krul","doi":"10.14573/altex.2304161s1","DOIUrl":"https://doi.org/10.14573/altex.2304161s1","url":null,"abstract":"","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"44 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86484080","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":"Russell and Burch's 3Rs then and now: The case of Switzerland.","authors":"Christian Rodriguez Perez,&nbsp;Kirsten Persson,&nbsp;Rosa M Cajiga Morales,&nbsp;Bernice S Elger,&nbsp;David M Shaw","doi":"10.14573/altex.2303061","DOIUrl":"10.14573/altex.2303061","url":null,"abstract":"<p><p>Since Russell and Burch introduced and defined the 3Rs, i.e., the replacement, reduction, and refinement of animal use in research, in 1959, different definitions have emerged and been implemented in guidelines and policies. Switzerland is known for having some of the most restrictive legislation regarding the use of animals, in which the 3Rs are also defined and implemented. To our knowledge, the purpose and definitions of the 3Rs used in the Swiss Animal Welfare Act, Animal Protection Ordinance, and Animal Experimentation Ordinance have never been compared with Russell and Burch’s original purpose and definitions. In this paper we make this comparison with two aims: to reveal ethically relevant departures from the original purpose and definitions, and to provide an ethical evaluation of the current Swiss law regarding the 3Rs. In doing so, we first expose the similarity of purposes. We then identify one risky departure from the original definition of replacement in Swiss law, which shows a problematic focus on species. Finally, we address Swiss law’s failure to apply the 3Rs in the most effective way. With respect to this last point, we discuss the need for 3R conflict resolution, the timing of application of the 3Rs, problematic prioritizations and choices of convenience as well as a solution to apply the 3Rs more effectively using Russell and Burch’s concept of total sum of distress.</p>","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":" ","pages":"635-648"},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9820153","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 human iPSC-based in vitro neural network formation assay to investigate neurodevelopmental toxicity of pesticides.","authors":"Kristina Bartmann,&nbsp;Farina Bendt,&nbsp;Arif Dönmez,&nbsp;Daniel Haag,&nbsp;H Eike Keßel,&nbsp;Stefan Masjosthusmann,&nbsp;Christopher Noel,&nbsp;Ji Wu,&nbsp;Peng Zhou,&nbsp;Ellen Fritsche","doi":"10.14573/altex.2206031","DOIUrl":"https://doi.org/10.14573/altex.2206031","url":null,"abstract":"<p><p>Proper brain development is based on the orchestration of key neurodevelopmental processes (KNDP), including the for­mation and function of neural networks. If at least one KNDP is affected by a chemical, an adverse outcome is expected. To enable a higher testing throughput than the guideline animal experiments, a developmental neurotoxicity (DNT) in vitro testing battery (DNT IVB) comprising a variety of assays that model several KNDPs was set up. Gap analysis revealed the need for a human-based assay to assess neural network formation and function (NNF). Therefore, we established the human NNF (hNNF) assay. A co-culture comprised of human induced pluripotent stem cell (hiPSC)-derived excitatory and inhibitory neurons as well as primary human astroglia was differentiated for 35 days on microelectrode arrays (MEA), and spontaneous electrical activity, together with cytotoxicity, was assessed on a weekly basis after washout of the compounds 24 h prior to measurements. In addition to the characterization of the test system, the assay was challenged with 28 com­pounds, mainly pesticides, identifying their DNT potential by evaluating specific spike-, burst-, and network parameters. This approach confirmed the suitability of the assay for screening environmental chemicals. Comparison of benchmark con­centrations (BMC) with an NNF in vitro assay (rNNF) based on primary rat cortical cells revealed differences in sensitivity. Together with the successful implementation of hNNF data into a postulated stressor-specific adverse outcome pathway (AOP) network associated with a plausible molecular initiating event for deltamethrin, this study suggests the hNNF assay as a useful complement to the DNT IVB.</p>","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"40 3","pages":"452-470"},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9841791","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 rodent thyroid-liver chip to capture thyroid toxicity on organ function level.","authors":"Diana Karwelat,&nbsp;Julia Kühnlenz,&nbsp;Thomas Steger-Hartmann,&nbsp;Remi Bars,&nbsp;Helen Tinwell,&nbsp;Uwe Marx,&nbsp;Sophie Bauer,&nbsp;Oliver Born,&nbsp;Marian Raschke","doi":"10.14573/altex.2108262","DOIUrl":"https://doi.org/10.14573/altex.2108262","url":null,"abstract":"<p><p>Endocrine disruption by environmental chemicals continues to be a concern for human safety. The rat, a widely used model organism in toxicology, is very sensitive to chemical-induced thyroid perturbation, e.g., histopathological alterations in thyroid tissue. Species differences in the susceptibility to thyroid perturbation lead to uncertainty in human safety risk assessments. Hazard identification and characterization of chemically induced thyroid perturbation would therefore benefit from in vitro models addressing different mechanisms of action in a single functional assay, ideally across species. We here introduce a rat thyroid-liver chip that enables simultaneous identification of direct and indirect (liver-mediated) thyroid perturbation on organ-level functions in vitro. A second manuscript describes our work toward a human thyroid-liver chip (Kühnlenz et al., 2022). The presented microfluidic model consisting of primary rat thyroid follicles and liver 3D spheroids maintains a tissue-specific phenotype for up to 21 days. More precisely, the thyroid model exhibits a follicular architecture expressing basolateral and apical markers and secretes T4. Likewise, liver spheroids retain hepatocellular characteristics, e.g., a stable release of albumin and urea, the presence of bile canalicular networks, and the formation of T4-glucuronide. Experiments with reference chemicals demonstrated proficiency to detect direct and indirect mechanisms of thyroid perturbation through decreased thyroid hormone secretion and increased gT4 formation, respectively. Prospectively this rat thyroid-liver chip model, together with its human counterpart, may support a species-specific quantitative in vitro to in vivo extrapolation to improve a data-driven and evidence-based human safety risk assessment with significant contributions to the 3R principles.</p>","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"40 1","pages":"83-102"},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10539886","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}