toxicity

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Neurotoxicity of Seven MEIC Chemicals Evaluated in Organotypic Cultures of Chick Embryonic Dorsal Root Ganglia

Václav Mandys, Katerina Jirsová and Jirí Vrana

The neurotoxic effects of seven selected Multicenter Evaluation of In Vitro Cytotoxicity programme chemicals (methanol, ethanol, isopropanol, sodium chloride, potassium chloride, iron [II] sulphate and chloroform) were evaluated in organotypic cultures of chick embryonic dorsal root ganglia (DRG), maintained in a soft agar culture medium. Two growth parameters of neurite outgrowth from the ganglia — the mean radial length of neurites and the area of neurite outgrowth — were used to evaluate the toxicities of the chemicals. Dose-dependent decreases of both parameters were observed in all experiments. IC50 values (the concentration causing 50% inhibition of growth) were calculated from the dose-response curves established at three time-points during culture, i.e. 24, 48 and 72 hours. The lowest toxic effect was observed in cultures exposed to methanol (the IC50 ranging from 580mM to 1020mM). The highest toxic effect was observed in cultures exposed to iron (II) sulphate (the IC50 ranging from 1.2mM to 1.7mM). The results of other recent experiments suggest that organotypic cultures of DRG can be used during in vitro studies on target organ toxicity within the peripheral nervous system. Moreover, these cultures preserve the internal organisation of the tissue, maintain intercellular contacts, and thus reflect the in vitro situation, more precisely than other cell cultures.
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A Comparison of the Acute and Chronic Effects of Antidepressants in Cultured C6 and 1321N1 Cells

N. Debbie Slamon and Vic W. Pentreath

The cytotoxicities of the antidepressants amitriptyline, imipramine (both tricyclic), fluoxetine (a selective serotonin re-uptake inhibitor) and tranylcypromine (a monoamine oxidase inhibitor) were compared in vitro in rat (C6) glioma and human (1321N1) astrocytoma cell lines. Differences in toxicity were determined after acute (24-hour) and chronic (7-day) administration and assessed by using the neutral red uptake (NRU) assay, the MTT assay, increased expression of glial fibrillary acidic protein (GFAp), and reactive morphology criteria. The relative toxicities (EC50 [concentration causing an effect in 50% of cells] value range) were fluoxetine > amitriptyline > imipramine > tranylcypromine for all the tests employed, in both cell lines and at both exposure times. There was a high and significant positive correlation between the different cell types, at both exposure times, with both the NRU and MTT assays. Increases in MTT reduction, NRU, and GFAp expression associated with cell activation were noted in C6 cells after exposure for 24 hours, but decreased after exposure for 7 days. For 1321N1 cells, increases in NRU were only observed after exposure for 24 hours. Reactive-type changes in morphology were seen after exposure to all the antidepressants, in both the C6 and 1321N1 cell lines. The data show that low concentrations of antidepressants induce metabolic changes in the astrocyte cell lines, with some significant differences in the patterns of toxicity of the tested substances.
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The Use of Biomarkers as Alternatives to Current Animal Tests on Food Chemicals1

Krys Bottrill

Recent developments in biomarkers relating to the interrelationship of diet, disease and health were surveyed. Most emphasis was placed on biomarkers of deleterious effects, since these are of greatest relevance to the subject of this review. The area of greatest activity was found to be that relating to biomarkers of mutagenic, genotoxic and carcinogenic effects. This is also one of the major areas of concern in considerations of the beneficial and deleterious effects of dietary components, and also the area in which regulatory testing requires studies of the longest duration. A degree of progress has also been made in the identification and development of biomarkers relating to certain classes of target organ toxicity. Biomarkers for other types of toxicity, such as immunotoxicity, neurotoxicity, reproductive toxicity and developmental toxicity, are less developed, and further investigation in these areas is required before a comprehensive biomarker strategy can be established. A criticism that recurs constantly in the biomarker literature is the lack of standardisation in the methods used, and the lack of reference standards for the purposes of validation and quality control. It is encouraging to note the growing acknowledgement of the need for validation of biomarkers and biomarker assays. Some validation studies have already been initiated. This review puts forward proposals for criteria to be used in biomarker validation. More discussion on this subject is required. It is concluded that the use of biomarkers can, in some cases, facilitate the implementation of the Three Rs with respect to the testing of food chemicals and studies on the effects of diet on health. The greatest potential is seen to be in the refinement of animal testing, in which biomarkers could serve as early and sensitive endpoints, in order to reduce the duration of the studies and also reduce the number of animals required. Biomarkers could also contribute to establishing a mechanistic basis for in vitro test systems and to facilitating their validation and acceptance. Finally, the increased information that could result from the incorporation of biomarker determinations into population studies could reduce the need for supplementary animal studies. This review makes a number of recommendations concerning the prioritisation of future activities on dietary biomarkers in relation to the Three Rs. It is emphasised, however, that further discussions will be required among toxicologists, epidemiologists and others researching the relationship between diet and health.
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2017-01-09T06:26:45+00:00 Tags: , , , , |

The Integrated Use of Alternative Methods in Toxicological Risk Evaluation

Bas J. Blaauboer, Martin D. Barratt and J. Brian Houston

The ECVAM Task Force on Integrated Testing Strategies was established in December 1996, with the remit of assessing the current status of integrated toxicity testing, and of making proposals regarding the design and implementation of integrated testing strategies. The first step in an integrated testing strategy is usually to determine the chemical functionality of a substance, on the basis of its structure and physicochemical properties. The biokinetic and dynamic behaviours of the chemical in various in vitro systems are then assessed. The various elements are then integrated, in either a parallel or a stepwise fashion, to make predictions of the local or systemic toxicity of the chemical of interest. In this report, a generic scheme for local/systemic toxicity, and a specific scheme for target organ toxicity, are proposed. The scope and limitations of the approaches are discussed. The task force hopes that its proposals will stimulate a discussion on the feasibility of this type of approach and it welcomes any feedback. It is planned that the discussion points will be elaborated in a second task force report.
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Toxicity of Mercury to Hybridoma TA7 Cells

Inessa Remez, Pauls Andersons and Hackel Veksler

Environmental mercury and mercury compound contamination has increased dramatically since the industrial revolution. This paper describes the toxic effects of mercury on a culture of hybridoma TA7 cells, which produce antibodies against the A-subunit of viskumin. Cells were cultivated on 96-well flat-bottomed plates with RPMI-1640 medium supplemented with 10% fetal calf serum at 37°C in 5% CO2/95% air. The cells were exposed to 0.1nM/l–10μM/l Hg2(NO3)2.2H2O (mercury nitrate) during the exponential growth phase. Toxicity was assessed by using the colorimetric MTT (tetrazolium) assay after exposure for 48 hours. Cell growth and cell survival were evaluated by using percentage indices of cellular content in exposed cells when compared to non-exposed control cells. The concentrations of the noeffect level, the lowest observed effect level and the the highest toxic effect level were registered. The toxic effects of the mercury compound on the hybridoma cells occurred between 0.1μM/l and 10μM/l.
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Use of the Daphnia magna Test to Estimate the Toxicity of the Ozonation By-products of Phenols and Chlorophenols

Marina Trapido and Yelena Veressinina

The toxicities of the ozonation products of 18 phenols were assayed with the Daphnia magna 24-hour toxicity test. The toxicities of the ozonation products of eight individual chlorophenols, and a mixture of them, are significantly lower than the toxicities of untreated solutions of chlorophenols. For some other phenols, including ordinary phenol (oxybenzene), toxicity increased during ozonation, and the formation of very toxic products was observed.
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Cytotoxicity of Cadmium, Selenium, Zinc and Copper to Mouse Myeloma Sp2/0 Cells as Measured by the MTT Assay

Inessa Remez, Leonid Rabkin, Hackel Veksler and Maija Baumane

As part of our general programme to test the toxicity in vitro of heavy metals and, in particular, the interactive cytotoxicity of combinations of these metals, the MTT (tetrazolium) assay was used to test the cytotoxicities of cadmium [Cd(O2CCH3)2], selenium (Na2SeO3), zinc (ZnSO4) and copper (CuSO4) with an established mouse myeloma cell line (Sp2/0). The influence on the cytotoxicity of cadmium of added subtoxic concentrations of the other three metals was also studied. The IC50 values (50% inhibitory concentrations) to the Sp2/0 cells were as follows: Cd — 10μM, Se — 1μM, Zn — 10μM and Cu — 100μM. When selenium, zinc and copper at high, subtoxic concentrations (10nM, 1μM and 1μM, respectively) were each combined with clearly toxic concentrations of cadmium (10μM and 100μM), the cytotoxicity increase was significant for the cadmium-zinc combination. Previous studies showed that cadmium-zinc combinations at low concentration (5 × 10–9M) had a synergistic stimulatory effect on cell proliferation in vitro. The present study showed that a toxic concentration of cadmium (0.1mM) and a sub-toxic concentration of zinc (1μM) have a synergistic cytotoxic effect in vitro.
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Toxicity Testing of Polymer Materials for Dialysis Equipment: Reconsidering In Vivo Testing

Per Kjellstrand, Eva Lindqvist and Carin Nilsson-Thorell

The rationale for preclinical testing of plastic materials for medical devices is the protection of patients from leachable toxic substances. A controversial and costly part of this testing is the use of animal in vivo procedures. The objective of the present study was to analyse the importance of in vivo tests in relation to the decision to approve or not to approve materials for use. A total of 1044 plastic materials were analysed by employing chemical, in vitro and in vivo tests: 5708 in vivo tests were performed. In only one out of 2650 systemic injection tests on mice did a material fail. As that material also failed in chemical tests, the systemic injection test had no influence on the decision not to approve the material. Intradermal irritation (2644 tests), implantation (398 tests) and sensitivity (11 tests) procedures on rabbits and guinea-pigs were the other in vivo tests. However, in all except three cases, the same decision on whether or not to use a material would have been reached without any of these in vivo tests. Thus, little security appears to be gained from the in vivo tests, and abandoning them would save resources, probably without any additional risk.
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Toxic Effects of Chromium Acetate Hydroxide on Cells Cultivated In Vitro

Emil Rudolf, Jan Peychl and Miroslav Cervinka

Many human activities, particularly industrial ones, result in an ever-growing production of toxic waste materials. The dynamics of the toxic effects of chromium acetate hydroxide, which is found in high concentrations in a waste sediment produced in the Czech Republic, were assessed by using a battery of in vitro tests carried out on two cell lines: L-929 (mouse fibroblasts) and Hep 2 (human laryngeal cells). Various markers of cell damage were assessed by phase-contrast, video and fluorescence microscopy, fluorometry, and DNA analysis. Chromium acetate hydroxide, over a concentration range of 1–0.02mol/l induced immediate cell death by fixation, whereas, at 0.002mol/l, the treated cells died in a much slower, more discrete manner. All the detected markers of cell damage, whether immediate or slow, clearly demonstrated that the cells died by necrosis. On the other hand, test concentration of 0.001mol/l appeared to constitute a threshold at which no pathological changes of Hep 2 cells were observed over 96 hours. We conclude that chromium acetate hydroxide has a high toxic potential in vitro, which should be considered when studying the toxicity of waste materials containing it.
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Study of the Environmental Hazard Caused by the Oil Shale Industry Solid Waste

Lee Põllumaa, Alla Maloveryan, Marina Trapido, Helgi Sillak and Anne Kahru

The environmental hazard was studied of eight soil and solid waste samples originating from a region of Estonia heavily polluted by the oil shale industry. The samples were contaminated mainly with oil products (up to 7231mg/kg) and polycyclic aromatic hydrocarbons (PAHs; up to 434mg/kg). Concentrations of heavy metals and water-extractable phenols were low. The toxicities of the aqueous extracts of solid-phase samples were evaluated by using a battery of Toxkit tests (involving crustaceans, protozoa, rotifers and algae). Waste rock and fresh semi-coke were classified as of “high acute toxic hazard”, whereas aged semi-coke and most of the polluted soils were classified as of “acute toxic hazard”. Analysis of the soil slurries by using the photobacterial solid-phase flash assay showed the presence of particle-bound toxicity in most samples. In the case of four samples out of the eight, chemical and toxicological evaluations both showed that the levels of PAHs, oil products or both exceeded their respective permitted limit values for the living zone (20mg PAHs/kg and 500mg oil products/kg); the toxicity tests showed a toxic hazard. However, in the case of three samples, the chemical and toxicological hazard predictions differed markedly: polluted soil from the Erra River bank contained 2334mg oil/kg, but did not show any water-extractable toxicity. In contrast, spent rock and aged semi-coke that contained none of the pollutants in hazardous concentrations, showed adverse effects in toxicity tests. The environmental hazard of solid waste deposits from the oil shale industry needs further assessment.
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