ALTEX最新文献

{"title":"In vitro and in vivo testing methods of epigenomic endpoints for evaluating endocrine disruptors.","authors":"John M Greally,&nbsp;Miriam N Jacobs","doi":"10.14573/altex.2013.4.445","DOIUrl":"https://doi.org/10.14573/altex.2013.4.445","url":null,"abstract":"<p><p>Epigenetic modulations underlie critical developmental processes and contribute to determining adult phenotype. Alterations to the phenotype, due to exposure to environmental insults during sensitive periods of development, are mediated through alterations in epigenetic programming in affected tissues. Originally prepared for the Organisation of Economic Cooperation and Development (OECD), this detailed review evaluates the potential role of chemical-induced epigenetic modifications to endocrine signaling pathways during sensitive windows of exposure as a mechanism of endocrine disruption, along with the examination of potential methods for assessing such disruption. Potential targets of disruption along putative adverse outcome pathways associated with the signaling pathways are identified, along with assays that show promise in evaluating the target in a screening and testing program such that in vitro methods are used where possible, and animal experiments only where in vitro methods are not available. Monitoring such epigenetic marks in response to toxicant exposure may in future provide a valuable tool for predicting adverse outcomes, but a more robust basis for Test Guideline recommendations is still needed. Although there is evidence to suggest that epigenomic dysregulation might mediate effects of exposures to endocrine disruptors, it is uncertain as to whether these changes are truly predictive of adverse outcome(s). Adverse effects observed in the OECD transgenerational assays could be used to inform future tests specifically designed to investigate the epigenetic mechanism of action. Follow-up studies should include both an epigenetic as well as a genomic component to differentiate between the contributions of potentially compensatory mechanisms.</p>","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"445-71"},"PeriodicalIF":5.6,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40277859","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}

{"title":"From pathways to people: applying the adverse outcome pathway (AOP) for skin sensitization to risk assessment.","authors":"Cameron MacKay,&nbsp;Michael Davies,&nbsp;Vicki Summerfield,&nbsp;Gavin Maxwell","doi":"10.14573/altex.2013.4.473","DOIUrl":"https://doi.org/10.14573/altex.2013.4.473","url":null,"abstract":"<p><p>Consumer safety risk assessment of skin sensitization requires information on both consumer exposure to the ingredient through product use and the hazardous properties of the ingredient. Significant progress has been made in determining the hazard potential of ingredients without animal testing. However, hazard identification is insufficient for risk assessment, and an understanding of the dose-response is needed. Obtaining such knowledge without animal testing is challenging and requires applying available mechanistic knowledge to both assay development and the integration of these data. The recent OECD report \"The Adverse Outcome Pathway for Skin Sensitization Initiated by Covalent Binding to Proteins\" presents the available mechanistic knowledge of the sensitization response within an adverse outcome pathway (AOP). We propose to use this AOP as the mechanistic basis for physiologically- and mechanistically-based toxicokinetic-toxicodynamic models of the sensitization response. The approach would be informed by non-animal data, provide predictions of the dose-response required for risk assessment, and would be evaluated against human clinical data.</p>","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"473-86"},"PeriodicalIF":5.6,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40275575","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}

{"title":"Immunotoxicology: challenges in the 21st century and in vitro opportunities.","authors":"Thomas Hartung,&nbsp;Emanuela Corsini","doi":"10.14573/altex.2013.4.411","DOIUrl":"https://doi.org/10.14573/altex.2013.4.411","url":null,"abstract":"<p><p>Over the last two decades, little has changed in the practice of immunotoxicity testing for regulatory purposes, especially for immunosuppression, and autoimmunity is still a challenge. Current guidelines still rely on animal tests, which include some immune endpoints in repeated dose tests and trigger dedicated tests only when certain alerts indicate a problem. At the same time, however, a wealth of in vitro approaches has been developed, but few have been adopted for routine testing. The extent to which immunotoxicity of chemicals represents a health problem for the human population at low levels of exposure is unclear: it appears that responses of healthy individuals to immunological challenges differ widely and most immunomodulators have few adverse effects except when they coincide with an infectious or malignant challenge or when early in life exposure is expected, in which cases the odds of progressing into infection, autoimmune diseases, or cancer can be changed. The enormous overcapacity of immune defense, the presence of compensatory mechanisms, and their fast restoration each contribute to limiting health threats for the individual, though on a population base also minor immunomodulation may result in increased morbidity. In vitro alternative approaches may allow screening for problematic substances and prioritize them for in vivo testing. New approaches are emerging from mapping pathways of immunotoxicity. Increasingly, the contribution of inflammatory and infectious components to the adverse outcome pathways of chemicals is recognized for various hazards, urging inclusion of tests for proinflammatory and immunomodulatory properties of chemicals into integrated testing strategies.</p>","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"411-26"},"PeriodicalIF":5.6,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40277857","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}

{"title":"A roadmap for hazard monitoring and risk assessment of marine biotoxins on the basis of chemical and biological test systems.","authors":"Mardas Daneshian,&nbsp;Luis M Botana,&nbsp;Marie-Yasmine Dechraoui Bottein,&nbsp;Gemma Buckland,&nbsp;Mònica Campàs,&nbsp;Ngaire Dennison,&nbsp;Robert W Dickey,&nbsp;Jorge Diogène,&nbsp;Valérie Fessard,&nbsp;Thomas Hartung,&nbsp;Andrew Humpage,&nbsp;Marcel Leist,&nbsp;Jordi Molgó,&nbsp;Michael A Quilliam,&nbsp;Costanza Rovida,&nbsp;Benjamin A Suarez-Isla,&nbsp;Aurelia Tubaro,&nbsp;Kristina Wagner,&nbsp;Otmar Zoller,&nbsp;Daniel Dietrich","doi":"10.14573/altex.2013.4.487","DOIUrl":"https://doi.org/10.14573/altex.2013.4.487","url":null,"abstract":"<p><p>Aquatic food accounts for over 40% of global animal food products, and the potential contamination with toxins of algal origin--marine biotoxins--poses a health threat for consumers. The gold standards to assess toxins in aquatic food have traditionally been in vivo methods, i.e., the mouse as well as the rat bioassay. Besides ethical concerns, there is also a need for more reliable test methods because of low inter-species comparability, high intra-species variability, the high number of false positive and negative results as well as questionable extrapolation of quantitative risk to humans. For this reason, a transatlantic group of experts in the field of marine biotoxins was convened from academia and regulatory safety authorities to discuss future approaches to marine biotoxin testing. In this report they provide a background on the toxin classes, on their chemical characterization, the epidemiology, on risk assessment and management, as well as on their assumed mode of action. Most importantly, physiological functional assays such as in vitro bioassays and also analytical techniques, e.g., liquid chromatography coupled mass spectrometry (LC-MS), as substitutes for the rodent bioassay are reviewed. This forms the basis for recommendations on methodologies for hazard monitoring and risk assessment, establishment of causality of intoxications in human cases, a roadmap for research and development of human-relevant functional assays, as well as new approaches for a consumer directed safety concept.</p>","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"487-545"},"PeriodicalIF":5.6,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40275576","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}

{"title":"Generation of genetically-modified human differentiated cells for toxicological tests and the study of neurodegenerative diseases.","authors":"Stefan Schildknecht,&nbsp;Christiaan Karreman,&nbsp;Dominik Pöltl,&nbsp;Liudmila Efrémova,&nbsp;Cornelius Kullmann,&nbsp;Simon Gutbier,&nbsp;Anne Krug,&nbsp;Diana Scholz,&nbsp;Hanne R Gerding,&nbsp;Marcel Leist","doi":"10.14573/altex.2013.4.427","DOIUrl":"https://doi.org/10.14573/altex.2013.4.427","url":null,"abstract":"<p><p>Human differentiated cell types, such as neurons or hepatocytes, are of limited availability, and their use for experiments requiring ectopic gene expression is challenging. Using the human conditionally-immortalized neuronal precursor line LUHMES, we explored whether genetic modification in the proliferating state could be used for experiments in the differentiated post-mitotic neurons. First, alpha-synuclein (ASYN), a gene associated with the pathology of Parkinson's disease, was overexpressed. Increased amounts of the protein were tolerated without change of phenotype, and this approach now allows further studies on protein variants. Knockdown of ASYN attenuated the toxicity of the parkinsonian toxicant 1-methyl-4-phenylpyridinium (MPP+). Different lentiviral constructs then were tested: cells labeled ubiquitously with green (GFP) or red fluorescent protein (RFP) allowed the quantification of neurite growth and of its disturbance by toxicants; expression of proteins of interest could be targeted to different organelles; production of two different proteins from a single read-through construct was achieved successfully by an expression strategy using a linker peptide between the two proteins, which is cleaved by deubiquitinases; LUHMES, labeled with GFP in the cytosol and RFP in the mitochondria, were used to quantify mitochondrial mobility along the neurites. MPP+ reduced such organelle movement before any other detectable cellular change, and this toxicity was prevented by simultaneous treatment with the antioxidant ascorbic acid. Thus, a strategy has been outlined here to study new functional endpoints, and subtle changes of structure and proteostasis relevant in toxicology and biomedicine in post-mitotic human cells.</p>","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"427-44"},"PeriodicalIF":5.6,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40277858","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}

{"title":"Developing alternatives to systemic toxicity testing approaches.","authors":"Sonja von Aulock","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"1"},"PeriodicalIF":5.6,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40156433","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}

{"title":"Open letter to the German Chancellor Dr. Angela Merkel. Council Directive on the approximation of laws, regulations and administrative provisions of the Member States regarding the protection of animals used for experimental and other scientific purposes.","authors":"Kurt W Simons","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"70-3"},"PeriodicalIF":5.6,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28926065","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}

{"title":"The Center for Alternatives to Animal Testing - Europe (CAAT-EU): a transatlantic bridge for the paradigm shift in toxicology.","authors":"Mardas Daneshian,&nbsp;Marcel Leist,&nbsp;Thomas Hartung","doi":"10.14573/altex.2010.1.63","DOIUrl":"https://doi.org/10.14573/altex.2010.1.63","url":null,"abstract":"<p><p>The Center for Alternatives to Animal Testing - Europe (CAAT-EU) was founded based collaboration between the Johns Hopkins Bloomberg School of Public Health and the University of Konstanz. CAAT-EU, housed at the University of Konstanz, will coordinate transatlantic activities to promote humane science in research and education, and participate, as partner or coordinator, in publicly and privately funded European projects. Thomas Hartung will serve as program liaison representing Johns Hopkins University and Marcel Leist as the University of Konstanz liaison. CAAT-EU aims to: 1) Set up transatlantic consortia for international research projects on alternative methods. 2) Establish a CAAT Europe faculty and advisory board composed of sponsor representatives and prominent academics from Europe . 3) Participate in the Transatlantic Think Tank for Toxicology (t4) devoted to conceptual work for the paradigm shift in toxicology. 4) Coordinate a series of information days in Europe on relevant developments in the US, similar to the 2009 series CAAT held in the US on EU issues (one on the 7th Amendment to the EU Cosmetics Directive and one on EU and US chemical regulation). 5) Support ALTEX as the official journal of CAAT and CAAT-EU. 6) Develop strategic projects with sponsors to promote humane science and new toxicology, especially with CAAT faculty members. 7) Develop a joint education program between Johns Hopkins and the University of Konstanz, such as e-courses and the existing Humane Science Certificate program developed by CAAT, a student exchange program, and collaboration with the International Graduate School \"Cell-based Characterization of De- and Regeneration\" in Konstanz.</p>","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"63-9"},"PeriodicalIF":5.6,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28920802","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}

{"title":"Food for thought...on alternative methods for chemical safety testing.","authors":"Thomas Hartung","doi":"10.14573/altex.2010.1.3","DOIUrl":"https://doi.org/10.14573/altex.2010.1.3","url":null,"abstract":"About 70 million chemicals have been synthesized, as registered in Chemical Abstracts Service. It is not really clear how many are found in consumer products and the environment. Why not? First, because registrations are only required for certain production volumes. Second, no organization or entity tracks increases in production volumes. I am not aware, for example, of very many new chemicals (in Europe, those notified after September 1981) that have been reregistered and subjected to additional testing demands due to higher production volume; this might be a reason why practically all new chemicals (registered from 1981-2006) have been pre-registered again for ReACH, from which they are exempted in principle. Similarly, no procedures exist to track when thresholds for registration are exceeded on a european level by different manufacturers combined, when originally only tiny amounts were produced. In europe, until 2007, the threshold for notification was 100 kg (now 1 ton) per year, which resulted in about 300 files per year. In the smaller US chemical industry the number of premarketing notifications is about 2,000 per year, giving us an idea about how few chemicals are accurately monitored in europe. third, requirements for registration differ considerably. Many chemicals enter our markets as components of products. Who registers when a sport shoe manufactured somewhere in Asia is imported and its fashionable, decorative glitter is produced by chemicals? Sure customs (and prior to ReACH directive 67/548/eeC) ask for documentation but in practice many importers are not aware of every component of the product. Fourth, many additional compounds, especially in the environment, are decomposition and reaction products. Fifth, things get really difficult when we also have to think of different formulations as particles. It is well known that nanoparticles (i.e. chemical particles typically between 1 and 100 nm) change their behavior depending on size and shape. A whole new field of nanotoxicology is emerging, which will be the subject of a future article in this series. But effects relevant to toxicity also occur on a larger scale. We know that both crystal sizes and shapes of drugs affect bioavailability and side-effects. A reasonable estimate is that people are exposed to about 100,000 relevant synthetic chemicals (84,000 are listed in the cumulative US tSCA inventory, 100,000 in the eU eINeCS inventory) in contrast to the 5,000 to 10,000 for which actually (widely varying in depth) safety assessments exist. the knowledge gap is, from this view, tremendous. this gap is even deeper if we consider the effect of chemicals in mixtures, where synergies may occur as recently addressed by the eU Council of environment Ministers (http:// register.consilium.europa.eu/pdf/en/09/st17/st17820.en09.pdf). However, we are most likely exposed to an even larger number of chemicals, given all the naturally occurring sources. I was once very much impressed when I le","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"3-14"},"PeriodicalIF":5.6,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28920799","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}

{"title":"First alternative method validated by a retrospective weight-of-evidence approach to replace the Draize eye test for the identification of non-irritant substances for a defined applicability domain.","authors":"Thomas Hartung,&nbsp;Leon Bruner,&nbsp;Rodger Curren,&nbsp;Chantra Eskes,&nbsp;Alan Goldberg,&nbsp;Pauline McNamee,&nbsp;Laurie Scott,&nbsp;Valérie Zuang","doi":"10.14573/altex.2010.1.43","DOIUrl":"https://doi.org/10.14573/altex.2010.1.43","url":null,"abstract":"<p><p>A replacement alternative to the rabbit eye irritation test has been sought for many years. First published in 1944 by FDA toxicologist J. H. Draize, the test, now known as the Draize Eye Test, has been used extensively to assess eye safety. It has also been a focal point for concern regarding its animal use. In 1992, Molecular Devices developed the Cytosensor Microphysiometer (CM) technology, an automated potentiometric online measurement of pH changes in cells, and evaluated it also for chemically induced irritation. The method was included in some of the six major validation studies for eye irritation from 1991-1997. The results for CM were inconclusive as were those from other tests evaluated as stand-alone methods to fully replace the animal test. In 2002, the European Centre for the Validation of Alternative Methods (ECVAM) started applying concepts from evidence-based medicine, and opened validation to retrospective meta-analysis. This activity was done in collaboration with US counterpart ICCVAM/NICEATM, and the European Cosmetics Association, Colipa. After a new, comprehensive evaluation of the prior available data, the ECVAM scientific advisory committee (ESAC) has recently accepted the CM as capable of identifying non-irritants for testing limited to water-soluble surfactants and water-soluble surfactant-containing mixtures. This 25-year development is remarkable and instructive in many respects. The authors see this as opening the door, at last, for an end to the use of animals as a standard requirement for eye irritation. Here, several of the people critically involved in this processes have summarized the important aspects of this history.</p>","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"43-51"},"PeriodicalIF":5.6,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28920800","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}