toxicity

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An Evaluation of Sterilisation Processes

Dariusz Śladowski, Iwona Grabska-Liberek, Joanna Olkowska-Truchanowicz, Kamil Lipski and Grzegorz Gut

A sterile environment is one of the basic elements of in vitro cell culture. When choosing an appropriate sterilisation method, the possibility that the physical and chemical properties of the sterilised material could be altered by the sterilisation process itself, should be considered. Avoiding any potential problems of toxicity arising as a consequence of the sterilisation process is essential, not only in in vitro cell culture procedures, but especially in the case of the sterilisation of medical devices which come into contact with human tissue (e.g. catheters, surgical tools, and containers used for transplant preparation and storage). As it is not possible to predict the potential effects of every combination of test material and sterilisation process, we have designed a simple test, which can be easily performed to ensure the absence of cytotoxicity. The test involves the culturing of a non-adherent cell line in direct contact with the test material, in micro-wells attached to the surface of the test device. By using this novel test method, three sterilisation procedures were compared for each material. The results indicated that, neither ionising irradiation nor ethylene oxide left toxic residues on the surface of polystyrene; and that, in the case of steel, neither steam sterilisation nor ethylene oxide left toxic residues on the metal. The cold plasma system, which left toxic residues on the surface of both materials, required a post-sterilisation period of 24 hours in the case of steel, and 10 days in the case of polystyrene, in order to eliminate toxic residues prior to their use.
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Ammonia-containing Industrial Effluents, Lethal to Rainbow Trout, Induce Vacuolisation and Neutral Red Uptake in the Rainbow Trout Gill Cell Line, RTgill-W1

Vivian R. Dayeh, Kristin Schirmer, and Niels C. Bols

Nine samples of whole effluent from the operation of an industrial plant over the course of one year, were tested on rainbow trout for lethality and on the rainbow trout gill cell line, RTgill-W1, for metabolic activity, plasma membrane integrity, and lysosomal activity, as measured by using the alamar Blue (AB), 5-carboxyfluorescein diacetate acetoxymethyl (CFDA-AM), and neutral red (NR) assays, respectively. None of the nine samples caused a loss of plasma membrane integrity, and only two caused a transitory decline in metabolism. Three samples caused massive vacuolisation in RTgill-W1 cells, which was accompanied by increased uptake of NR, and only these three samples were lethal to the rainbow trout. The addition of ammonia to RTgill-W1 cultures also induced vacuolisation and NR uptake, with little change in plasma membrane integrity or metabolism. Subsequently, the effluent source was identified as a nitrogen product producer, and variable levels of ammonia were found in the nine samples. Three of the four samples with the highest non-ionised ammonia levels were those which were toxic to rainbow trout and which caused vacuoles in RTgill-W1 cells. The close correlation between rainbow trout-killing and RTgill-W1 vacuolisation by the effluents, suggests that vacuolisation of RTgill-W1 cells could be used to indicate effluents which would be toxic to rainbow trout as a result of their ammonia content.
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Can Drug Safety be Predicted and Animal Experiments Reduced by Using Isolated Mitochondrial Fractions?

Susana P. Pereira, Gonçalo C. Pereira, António J. Moreno and Paulo J. Oliveira

Mitochondrial toxicity has resulted in the withdrawal of several drugs from the market. One particular example is nefazodone, an anti-depressant withdrawn in the USA due to hepatoxicity caused by drug-induced mitochondrial dysfunction. Drug development and safety testing can involve the use of large numbers of laboratory animals, which, without a decisive pre-screening for mitochondrial toxicity, are often unable to pre-empt higher mortality rates in some patient groups. The use of isolated mitochondria as a screening tool for drug safety can decrease the number of laboratory animals used in pre-clinical studies, thus improving animal welfare and healthcare outcomes and costs. Novel techniques involving highthroughput methods can be used to investigate whether a molecule is a mitochondrial toxicant. Moreover, these screens are mechanistically-based, since the effects of the drug on oxidative phosphorylation, calcium homeostasis and mitochondrial genetics can be assessed. This review is intended to demonstrate that isolated mitochondrial fractions are suitable for predicting drug and general chemical safety in toxicological screenings, thus contributing to the refinement and reduction of animal use in laboratory research.
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The In ChemicoIn Silico Interface: Challenges for Integrating Experimental and Computational Chemistry to Identify Toxicity

Mark T.D. Cronin, Fania Bajot, Steven J. Enoch, Judith C. Madden, David W. Roberts and Johannes Schwöbel

A number of toxic effects are brought about by the covalent interaction between the toxicant and biological macromolecules. In chemico assays are available that attempt to identify reactive compounds. These approaches have been developed independently for pharmaceuticals and for other nonpharmaceutical compounds. The assays vary widely in terms of the macromolecule (typically a peptide) and the analytical technique utilised. For both sets of methods, there are great opportunities to capture in chemico information by using in silico methods to provide computational tools for screening purposes. In order to use these in chemico and in silico methods, integrated testing strategies are required for individual toxicity endpoints. The potential for the use of these approaches is described, and a number of recommendations to improve this extremely useful technique, in terms of implementing the Three Rs in toxicity testing, are presented.
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The Use of Mechanisms and Modes of Toxic Action inIntegrated Testing Strategies: The Report and Recommendations of a Workshop held as part of the European Union OSIRIS Integrated Project

J. Arie Vonk, Romualdo Benigni, Mark Hewitt, Monika Nendza, Helmut Segner, Dik van de Meent1 and Mark T.D. Cronin

This report on The Potential of Mode of Action (MoA) Information Derived from Non-testing and Screening Methodologies to Support Informed Hazard Assessment, resulted from a workshop organised within OSIRIS (Optimised Strategies for Risk Assessment of Industrial Chemicals through Integration of Non-test and Test Information), a project partly funded by the EU Commission within the Sixth Framework Programme. The workshop was held in Liverpool, UK, on 30 October 2008, with 35 attendees. The goal of the OSIRIS project is to develop integrated testing strategies (ITS) fit for use in the REACH system, that would enable a significant increase in the use of non-testing information for regulatory decision making, and thus minimise the need for animal testing. One way to improve the evaluation of chemicals may be through categorisation by way of mechanisms or modes of toxic action. Defining such groups can enhance read-across possibilities and priority settings for certain toxic modes or chemical structures responsible for these toxic modes. Overall, this may result in a reduction of in vivo testing on organisms, through combining available data on mode of action and a focus on the potentially most-toxic groups. In this report, the possibilities of a mechanistic approach to assist in and guide ITS are explored, and the differences between human health and environmental areas are summarised.
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De-Risking Drug Discovery with ADDME — Avoiding Drug Development Mistakes Early

Katya Tsaioun and Mary Jacewicz

The advent of early Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) screening has increased the elimination rate of weak drug candidates early in the drug-discovery process, and decreased the proportion of compounds failing in clinical trials for ADMET reasons. This paper reviews the history of ADMET screening and why it has become so important in drug discovery and development. Assays that have been developed in response to specific needs, and improvements in technology that result in higher throughput and greater accuracy of prediction of human mechanisms of toxicity, are discussed. The paper concludes with the authors’ forecast of new models that will better predict human efficacy and toxicity.
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Responses of Human Gingival and Periodontal Fibroblasts to a Low-Zinc Environment

Emil Rudolf and Miroslav Červinka

Morphology, motility, proliferation rate and markers of oxidative stress in primary human gingival fibroblasts (GF) and periodontal ligamental fibroblasts (PDL-F) grown in zinc-deficient cultivation medium (ZDM), were studied over a 5-week culture period. A low-zinc environment effectively reduced the total, as well as the free, intracellular zinc content in both cell types, over the course of the experiment. Decreased intracellular zinc content resulted in altered cellular morphology, reduced motility, and rearrangement of actin and tubulin in the cytoskeleton. In addition, fibroblasts with low zinc content exhibited decreased proliferation, accompanied by changes in cell cycle distribution, expression of specific biochemical markers, increased oxidative stress and the activation of caspase-3. Supplementation of ZDM with exogenous zinc prevented the loss of intracellular zinc, while also restoring the morphology, cell proliferation and mitogenic signalling of the cultured cells. Moreover, such supplemented cells were protected against oxidative stress and cell death. Of the two primary cell cultures examined, GF were more sensitive to decreased intracellular zinc content, when compared to PDL-F. The results obtained suggest that the human primary cell cultures can be useful for the longer-term evaluation of the effects of nutritional factors originating from the environment.
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Comparing In Vivo, In Vitro and In Silico Methods and Integrated Strategies for Chemical Assessment: Problems and Prospects

Emilio Benfenati, Giuseppina Gini, Sebastian Hoffmann and Robert Luttik

The RAINBOW workshop addressed the background for the integration of in vivo, in vitro and computer-based (in silico) methods, to facilitate the study of the toxic properties of chemicals. On the basis of these discussions, we prepared the present paper, outlining the strengths, weaknesses, opportunities and threats of each approach, both alone and integrated into a single testing strategy. The current scheme for evaluation of chemicals needs to be reshaped, in the face of the much larger numbers of chemicals which need to be examined and the availability of a diversified set of tools.
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