ALTEX Pub Date : 2019-01-01 Epub Date: 2019-04-18 DOI: 10.14573/altex.1811012

Jeanelle M Martinez, Thomas E Eling

{"title":"Activation of TRPA1 by volatile organic chemicals leading to sensory irritation.","authors":"Jeanelle M Martinez, Thomas E Eling","doi":"10.14573/altex.1811012","DOIUrl":"10.14573/altex.1811012","url":null,"abstract":"Many volatile organic chemicals (VOCs) have not been tested for sensory pulmonary irritation. Development of in vitro non-animal sensory irritation assay suitable for a large number of chemicals is needed to replace the mouse assay. An adverse outcome pathway (AOP) is designed to provide a clear description of the biochemical and cellular processes leading to toxicological effects or an adverse outcome. The AOP for chemical sensory pulmonary irritation was developed according to the Organization for Economic Co-operation and Development guidance including the Bradford Hill criteria for a weight of evidence to determine the confidence of the AOP. The proposed AOP is based on an in-depth review of the relevant scientific literature to identify the initial molecular event for respiratory irritation. The activation of TRPA1 receptor (transient receptor potential cation channel, subfamily A, member 1) is the molecular initial event (MIE) leading to sensory irritation. A direct measure of TRPA1 activation in vitro should identify chemical sensory irritants and provide an estimate of potency. Fibroblasts expressing TRPA1 are used to determine TRPA1 activation and irritant potency. We report a linear relationship between the in vivo RD₅₀ and the in vitro pEC₅₀ values (R=0.81) to support this hypothesis. We propose that this in vitro assay after additional analysis and validation could serve as a suitable candidate to replace the mouse sensory irritation assay.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"572-582"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829608/pdf/nihms-1529994.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37188660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Chemical concentrations in cell culture compartments (C5) - concentration definitions. 细胞培养室中的化学浓度(C5) .浓度定义

IF 5.6

ALTEX Pub Date : 2019-01-01 DOI: 10.14573/altex.1901031

Jaffar Kisitu, Susanne Hougaard Bennekou, Marcel Leist

{"title":"Chemical concentrations in cell culture compartments (C5) - concentration definitions.","authors":"Jaffar Kisitu, Susanne Hougaard Bennekou, Marcel Leist","doi":"10.14573/altex.1901031","DOIUrl":"https://doi.org/10.14573/altex.1901031","url":null,"abstract":"Some laboratory issues are taken for granted as they seem to be simple and not worth much thought. This applies to \"concentrations of a chemical tested for bioactivity/toxicity\". Can there be any issue about weighing a compound, diluting it in culture medium and calculating the final mass (or particle number)-to-volume ratio? We discuss here some basic concepts about concentrations and their units, addressing also differences between \"dose\" and \"concentration\". The problem of calculated nominal concentrations not necessarily corresponding to local concentrations (relevant for biological effects of a chemical) is highlighted. We present and exemplify different concentration measures, for instance those relying on weight, volume, or particle number of the test compound in a given volume; we also include normalizations to the mass, protein content, or cell number of the reference system. Interconversion is discussed as a major, often unresolved, issue. We put this into the context of the overall objective of defining concentrations, i.e., the determination of threshold values of bioactivity (e.g., an EC50). As standard approach for data display, the negative decadic logarithm of the molar concentrations (-log(M)) is recommended here, but arguments are also presented for exceptions from such a rule. These basic definitions are meant as a foundation for follow-up articles that examine the concepts of nominal, free, and intracellular concentrations to provide guidance on how to relate in vitro concentrations to in vivo doses by in vitro-to-in vivo extrapolation (IVIVE) in order to advance the use of new approach methods (NAM) in regulatory decision making.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"154-160"},"PeriodicalIF":5.6,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36854879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 11

The HaCaT/THP-1 Cocultured Activation Test (COCAT) for skin sensitization: a study of intra-lab reproducibility and predictivity. HaCaT/THP-1共培养激活试验(COCAT)用于皮肤致敏:实验室内可重复性和预测性的研究

IF 5.6

ALTEX Pub Date : 2019-01-01 Epub Date: 2019-05-27 DOI: 10.14573/altex.1905031

Chantra Eskes, Jennifer Hennen, Mario T Schellenberger, Sebastian Hoffmann, Sabine Frey, Daniela Goldinger-Oggier, Niklas Peter, Erwin Van Vliet, Brunhilde Blömeke

{"title":"The HaCaT/THP-1 Cocultured Activation Test (COCAT) for skin sensitization: a study of intra-lab reproducibility and predictivity.","authors":"Chantra Eskes, Jennifer Hennen, Mario T Schellenberger, Sebastian Hoffmann, Sabine Frey, Daniela Goldinger-Oggier, Niklas Peter, Erwin Van Vliet, Brunhilde Blömeke","doi":"10.14573/altex.1905031","DOIUrl":"https://doi.org/10.14573/altex.1905031","url":null,"abstract":"The Cocultured Activation Test (COCAT) consists of cocultured HaCaT (human keratinocyte cell line) and THP-1 cells (surrogate of antigen presenting cells). Individually, these cell lines are used to address key event 2 and 3 of the skin sensitization Adverse Outcome Pathway (AOP). Their exposure in coculture was found to have the potential to increase their response to sensitizing chemicals, enable the detection of pro-haptens and support the identification of skin sensitization potency. The present study was undertaken to assess the predictive capacity of COCAT to both skin sensitization hazard and potency and to assess the intra-laboratory reproducibility of COCAT based on the blind testing of chemicals. Results showed a reproducibility between runs of 80 % for 15 coded chemicals. 100 % sensitivity (9/9), 75 % specificity (3/4) and 92.3 % accuracy (12/13) was found for skin sensitization hazard prediction, while the tests of two chemicals were inconclusive. Including additional chemicals tested during the optimization phase in addition to the blind tested chemicals, the skin sensitization UN GHS sub-categories were correctly predicted for 85.7 % (12/14) Sub-category 1A chemicals, 83.3 % (10/12) Sub-category 1B chemicals and 92.3 % (12/13) 'No Category' chemicals, resulting in an overall accuracy of 87.4 % (34/39). The present study shows the COCAT to be a promising method for the identification of skin sensitization hazard and potency sub-categorization according to the UN GHS classification.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"613-622"},"PeriodicalIF":5.6,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37276269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 11

Botulinum toxin testing on animals is still a Europe-wide issue. 对动物进行肉毒杆菌毒素检测仍然是一个欧洲范围内的问题。

IF 5.6

ALTEX Pub Date : 2019-01-01 Epub Date: 2018-10-10 DOI: 10.14573/altex.1807101

Katy Taylor, Corina Gericke, Laura Rego Alvarez

{"title":"Botulinum toxin testing on animals is still a Europe-wide issue.","authors":"Katy Taylor, Corina Gericke, Laura Rego Alvarez","doi":"10.14573/altex.1807101","DOIUrl":"https://doi.org/10.14573/altex.1807101","url":null,"abstract":"There have been significant developments in the use of animals to test Botulinum toxin products in Europe in recent years. This paper summarises and discusses these from the perspective of the animal protection organisation. A cell-based assay has been validated by Allergan and is now being used for the replacement of the mouse bioassay for the batch testing of their Botulinum toxin A products. Two further companies (Merz and Ipsen) have recently validated similar cell-based assays to replace animals in their batch testing. However, the number of animals being used in batch tests across Europe remains at record levels; an estimated 400,000 animals per year, based on official statistics and non-technical summaries. There are concerns from animal protection organisations about the authorisation of animal testing for Botulinum toxin products that are to be used for aesthetic purposes. Furthermore, should testing for companies that have not yet implemented the alternative method continue to be permitted under the EU Directive 2010/63 on the use of animals for scientific purposes? Whilst we are on the cusp of an era where the mouse bioassay has been replaced for the potency testing of Botulinum toxin A for injection, it is important that Europe sees a reduction of animal testing in real terms.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"81-90"},"PeriodicalIF":5.6,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36571792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 15

Organ-on-chip in development: Towards a roadmap for organs-on-chip. 开发中的片上器官：为芯片上器官绘制路线图。

IF 5.6

ALTEX Pub Date : 2019-01-01 DOI: 10.14573/altex.1908271

Massimo Mastrangeli, Sylvie Millet, The Orchid Partners, Janny Van den Eijnden-van Raaij

引用次数: 40

An intact insect embryo for developmental neurotoxicity testing of directed axonal elongation. 用于定向轴突伸长发育性神经毒性试验的完整昆虫胚胎。

IF 5.6

ALTEX Pub Date : 2019-01-01 Epub Date: 2019-05-29 DOI: 10.14573/altex.1901292

Gregor A Bergmann, Sarah Froembling, Nina Joseph, Karsten Bode, Gerd Bicker, Michael Stern

{"title":"An intact insect embryo for developmental neurotoxicity testing of directed axonal elongation.","authors":"Gregor A Bergmann, Sarah Froembling, Nina Joseph, Karsten Bode, Gerd Bicker, Michael Stern","doi":"10.14573/altex.1901292","DOIUrl":"https://doi.org/10.14573/altex.1901292","url":null,"abstract":"Developmental neurotoxicity (DNT) of chemicals poses a serious threat to human health worldwide. Current in vivo test methods for assessing DNT require the use of high numbers of laboratory animals. Most alternative in vitro testing methods monitor rather simple toxicological endpoints, whereas the formation of a functional brain requires precisely timed navigation of axons within a complex tissue environment. We address this complexity by monitoring defects in axonal navigation of pioneer axons of intact locust embryos after exposure to chemicals. Embryos develop in serum-free culture with test chemicals, followed by immunolabeling of pioneer neurons. Defects in axon elongation of pioneer axons are quantified in concentration-response curves and compared to the general viability of the embryo, as measured by a resazurin assay. We show that selected chemical compounds interfering with calcium signaling, the cytoskeletal organization, and the reference developmental neurotoxicant rotenone, can be classified as DNT positive. The pesticide rotenone inhibits pioneer neuron elongation with a lower IC50 than the viability assay. The rho kinase inhibitor Y27632 can partially rescue outgrowth inhibition, supporting the classification of rotenone as a specific DNT positive compound. Since mechanisms of axonal guidance, such as growth cone navigation along molecular semaphorin gradients are conserved between locust and mammalian nervous systems, we will further explore the potential of this invertebrate preparation as an assay for testing the DNT potential of chemicals in humans.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"643-649"},"PeriodicalIF":5.6,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37343248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 8

Preclinical alternative model for analysis of porous scaffold biocompatibility in bone tissue engineering. 骨组织工程多孔支架生物相容性分析的临床前替代模型。

IF 5.6

ALTEX Pub Date : 2019-01-01 Epub Date: 2018-11-23 DOI: 10.14573/altex.1807241

Eva Petrovova, Maria Giretova, Alena Kvasilova, Oldrich Benada, Jan Danko, Lubomir Medvecky, David Sedmera

{"title":"Preclinical alternative model for analysis of porous scaffold biocompatibility in bone tissue engineering.","authors":"Eva Petrovova, Maria Giretova, Alena Kvasilova, Oldrich Benada, Jan Danko, Lubomir Medvecky, David Sedmera","doi":"10.14573/altex.1807241","DOIUrl":"https://doi.org/10.14573/altex.1807241","url":null,"abstract":"Using scaffolds with appropriate porosity represents a potential approach for repair of critical-size bone defects. Vascularization is essential for bone formation and healing. This study investigates methods for monitoring angiogenesis within porous biopolymer scaffolds on the basis of polyhydroxybutyrate (PHB)/chitosan. We use the chick and quail chorioallantoic membrane (CAM) assay as an in vivo model focused on the formation of new blood vessels inside the implant structure. Chemical properties of the surface in biopolymer scaffold matrix were characterized as well as the tissue reaction of the CAM. Implantation of a piece of polymer scaffold results in vascular reaction, documented visually and by ultrasound biomicroscopy. Histological analysis shows myofibroblast reaction (smooth muscle actin-positive cells) without excessive collagen deposition. Cell invasion is observed inside the implant, and QH1 marker, detecting hemangioblasts and endothelial cells of quail origin, confirms the presence of vascular network. The CAM assay is a rapid and easy way to test biocompatibility and vasculogenic potential of new candidate scaffolds for bone tissue bioengineering with respect to the 3R´ s.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"121-130"},"PeriodicalIF":5.6,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36714865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 19

Investigating cell type specific mechanisms contributing to acute oral toxicity. 研究导致急性口腔毒性的细胞类型特异性机制。

IF 5.6

ALTEX Pub Date : 2019-01-01 Epub Date: 2018-07-12 DOI: 10.14573/altex.1805181

Pilar Prieto, Rabea Graepel, Kirsten Gerloff, Lara Lamon, Magdalini Sachana, Francesca Pistollato, Laura Gribaldo, Anna Bal-Price, Andrew Worth

{"title":"Investigating cell type specific mechanisms contributing to acute oral toxicity.","authors":"Pilar Prieto, Rabea Graepel, Kirsten Gerloff, Lara Lamon, Magdalini Sachana, Francesca Pistollato, Laura Gribaldo, Anna Bal-Price, Andrew Worth","doi":"10.14573/altex.1805181","DOIUrl":"https://doi.org/10.14573/altex.1805181","url":null,"abstract":"The replacement of animals in acute systemic toxicity testing remains a considerable challenge. Only animal data are currently accepted by regulators, including data generated by reduction and refinement methods. The development of Integrated Approaches to Testing and Assessment (IATA) is hampered by an insufficient understanding of the numerous toxicity pathways that lead to acute systemic toxicity. Therefore, central to our work has been the collection and evaluation of the mechanistic information on eight organs identified as relevant for acute systemic toxicity (nervous system, cardiovascular system, liver, kidney, lung, blood, gastrointestinal system and immune system). While the nervous and cardiovascular systems are the most frequent targets, no clear relationship emerged between specific mechanisms of target organ toxicity and the level (category) of toxicity. From a list of 114 chemicals with acute oral in vivo and in vitro data, 98 were identified with target organ specific effects, of which 93% were predicted as acutely toxic by the 3T3 neutral red uptake cytotoxicity assay and 6% as non-toxic. This analysis will help to prioritise the development of adverse outcome pathways for acute oral toxicity, which will support the assessment of chemicals using mechanistically informed IATA.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"39-64"},"PeriodicalIF":5.6,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36319815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 22

Developing context appropriate toxicity testing approaches using new alternative methods (NAMs). 使用新的替代方法(NAMs)开发适合环境的毒性测试方法。

IF 5.6

ALTEX Pub Date : 2019-01-01 DOI: 10.14573/altex.1906261

Melvin E Andersen, Patrick D McMullen, Martin B Phillips, Miyoung Yoon, Salil N Pendse, Harvey J Clewell, Jessica K Hartman, Marjory Moreau, Richard A Becker, Rebecca A Clewell

{"title":"Developing context appropriate toxicity testing approaches using new alternative methods (NAMs).","authors":"Melvin E Andersen, Patrick D McMullen, Martin B Phillips, Miyoung Yoon, Salil N Pendse, Harvey J Clewell, Jessica K Hartman, Marjory Moreau, Richard A Becker, Rebecca A Clewell","doi":"10.14573/altex.1906261","DOIUrl":"https://doi.org/10.14573/altex.1906261","url":null,"abstract":"In the past 10 years, the public, private, and non-profit sectors have found agreement that hazard identification and risk assessment should capitalize on the explosion of knowledge in the biological sciences, moving away from in life animal testing toward more human-relevant in vitro and in silico methods, collectively referred to as new approach methodologies (NAMs). The goals for implementation of NAMs are to efficiently identify possible chemical hazards and to gather dose-response data to inform more human-relevant safety assessment. While work proceeds to develop NAMs, there has been less emphasis on creating decision criteria or showing how risk context should guide selection and use of NAMs. Here, we outline application scenarios for NAMs in different risk contexts and place different NAMs and conventional testing approaches into four broad levels. Level 1 relies solely on computational screening; Level 2 consists of high throughput in vitro screening with human cells intended to provide broad coverage of possible responses; Level 3 focuses on fit-for-purpose assays selected based on presumptive modes of action (MOA) and designed to provide more quantitative estimates of relevant dose responses; Level 4 has a variety of more complex multi-dimensional or multi-cellular assays and might include targeted in vivo studies to further define MOA. Each level also includes decision-appropriate exposure assessment tools. Our aims here are to (1) foster discussion about context-dependent applications of NAMs in relation to risk assessment needs and (2) describe a functional roadmap to identify where NAMs are expected to be adequate for chemical safety decision-making.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"523-534"},"PeriodicalIF":5.6,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40453431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 35

Advanced in vitro models analysis. 先进的体外模型分析。

IF 5.6

ALTEX Pub Date : 2019-01-01 DOI: 10.14573/altex.1812131

Katarzyna S Kopanska, Markus Rimann, Sandra Latenser, Michael Raghunath

引用次数: 1

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