MEIC

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The Björn Ekwall Memorial Award 2015

Introduction by Ada Kolman & lecture text by Michael Balls

A personal, and therefore unavoidably biased, review is given, of the significance of the contributions made by selected Scandinavian individuals, organisations and events, to the development of in vitro toxicology procedures as potential replacements for toxicity tests in laboratory animals. In addition to their wider significance, these contributions had a profound effect on whatever contributions I have been able to make, myself. Nevertheless, while there has been much progress in the last 35 years or so, and many lessons have been learned, there is still much to be done, especially as animal tests remain entrenched as the preferred methods which set the gold standards and make regulators feel comfortable. Many of the clues to dealing with the questions and concerns which plague hazard prediction and risk assessment have long been available, but they have been ignored, largely for reasons which have little to do with the science of toxicology and the need to maintain the highest scientific standards. I have little doubt that Björn Ekwall, whose memory I feel privileged to honour, would have agreed with that last statement.
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Toxicity of 20 Chemicals from the MEIC Programme Determined by Growth Inhibition of L-929 Fibroblast-like Cells

Lena Järkelid, Per Kjellstrand, Evi Martinson and Anders Wieslander

The Multicentre Evaluation of In vitro Cytotoxicity (MEIC) programme is an international project aimed at evaluating the relevance of in vitro tests in predicting human toxicity. We have screened 20 chemicals (MEIC codes 31–50) from the programme, by using a cytotoxicity test based on growth inhibition of the mouse fibroblast-like L-929 cell line. Inhibition of cell growth was determined by the neutral red uptake method, which is well established and is used for screening the cytotoxicity of chemicals and plastics for pharmaceuticals and medical devices. The concentrations causing 50% inhibition of cell growth after a 72-hour exposure period varied from 3.1μM for hexachlorophene, to 1.4mM for caffeine. This is within the same range as results recently obtained with five other cell models. However, with some chemicals (chloroform, carbon tetrachloride and dichloromethane), no reliable results were obtained. These substances could not be dissolved in a reproducible way in any of the solvents used and, furthermore, they were highly volatile, which led to difficulties in maintaining the concentrations.
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Cytotoxicity of MEIC Chemicals to Rainbow Trout R1 Cell Line and Multivariate Comparison with Ecotoxicity Tests

Helmut Segner and Gerrit Schüürmann

The cytotoxic effects of the first ten chemicals from the Multicenter Evaluation of In Vitro Cytotoxicity (MEIC) programme on the fibroblast-like R1 cell line, derived from rainbow trout (Oncorhynchus mykiss), were measured by using three endpoints: cell attachment (24-hour exposure, crystal violet protein stain); cell viability (24-hour exposure, neutral red uptake cytotoxicity assay); and cell growth (144-hour exposure, crystal violet protein stain). The results were compared with published MEIC toxicity data from fish and mammalian cells, and from ecotoxicity tests with bacteria, invertebrates and plants by using multivariate statistical techniques. For eight of the ten compounds under consideration, a high degree of correlation in toxicity ranking between the various bioassays was observed, irrespective of the test systems or endpoints utilised. This similarity might be explained by the basal cytotoxicity concept. The 20% dissimilarity of the results, however, indicates the influence of test system-specific or endpoint-specific sensitivities.
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An Animal Protection Sponsor’s View of MEIC

Ethel Thurston

The Multicenter Evaluation of In Vitro Cytotoxicity programme is most important to animal protection, since it has validated 64 in vitro tests using advanced human data for 50 chemicals as the “gold standard”. Therefore, it has been able to compare animal cell tests, human cell tests and whole-animal tests fairly with unbiased scientific evidence. Added bonuses have included the identification and development of missing in vitro information (“missing tests”), publication of time-related lethal blood concentrations for all 50 chemicals, and some preliminary plans to resolve the 50,000 untested (or poorly tested) chemicals in the chemical mountain.
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Evaluation of the Cytotoxic Effects of MEIC Chemicals 31–50 on Primary Culture of Rat Hepatocytes and Hepatic and Non-hepatic Cell Lines

Xavier Ponsoda, Cristina Núñez, José Vicente Castell and Maria
José Gómez-Lechón

The cytotoxicities of 20 chemicals (numbers 31–50) from the Multicenter Evaluation of In Vitro Cytotoxicity (MEIC) programme were assessed with a primary culture of rat hepatocytes and with two hepatic cell lines (Hep G2 and FaO) and one non-hepatic cell line (3T3). The cytotoxicities of the chemicals were evaluated by using the MTT test after the cells had been exposed to the chemicals for 24 hours. For a better evaluation of results, dose–response curves were mathematically linearised and cytotoxicity was expressed as IC50 values and IC10 values (the concentration causing 50% and 10% loss of cell viability, respectively). We found that all the compounds showed similar acute basal cytotoxicity in all four cellular systems (regardless of whether the cells were, or were not, metabolically competent or were or were not of human origin). When these results were used to predicit human toxicity in terms of a mathematical parameter (prediction error [PE]), we found that all four systems gave similar predictions of human toxicity. The best cytotoxicity parameter included in the PE calculation was the IC50/10, because of an underestimation of human toxicity by in vitro systems. However, when PEs were calculated for rodent toxicity, better results were obtained. Data from the literature obtained by using other experimental models for predicting human toxicity were analysed according to the same criteria. We conclude that cellular systems are better predictive tools for human toxicity than are prokaryotic cells or whole-organism models.
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MEIC Evaluation of Acute Systemic Toxicity

Cecilia Clemedson, Frank A. Barile, Christophe Chesné, Martine Cottin, Rodger Curren, Barbro Ekwall, Margherita Ferro, Maria José Gómez-Lechón, Koichi Imai, Jeffrey Janus, Richard B. Kemp, Gustaw Kerszman, Per Kjellstrand, Karel Lavrijsen, Pam Logemann, Elisabeth McFarlane-Abdulla, Roland Roguet, Helmut Segner, Ann Thuvander, Erik Walum and Björn Ekwall

The Multicenter Evaluation of In Vitro Cytotoxicity (MEIC) programme was set up to evaluate the relevance for human acute toxicity of in vitro cytotoxicity tests. By the end of the programme in 1996, 39 laboratories had tested the first 30 reference chemicals in 82 in vitro toxicity assays, and the last 20 chemicals had been tested in 67 assays. All in vitro results and the human database have been presented in five previous papers (Parts I–V). Part VI evaluated the in vitro results from the 61 assays used to test all 50 chemicals by comparisons of in vitro IC50 values (concentrations causing 50% inhibition) with LC50 values (blood concentration causing approximately 50% lethality) from human single-dose acute poisonings by the chemicals. These comparisons demonstrated a good prediction of human peak LC50 values (peaks from the LC50 curves over time) by most of the 61 assays, notably the human cell line assays (R2 = 0.74). The present paper is supplementary to Part VI, and presents a similar evaluation of the 27 new assays used to test the first 30 reference chemicals, as well as a lessdetailed analysis of the six new assays used to test the last 20 chemicals. Comparisons between the IC50 values from the 27 assays used to test the first 30 chemicals and peak LC50 values demonstrated that human cell line tests gave the best mean results (R2 = 0.76), followed by human primary culture assays (R2 = 0.75), animal cell line assays (R2 = 0.68), animal primary culture assays (R2 = 0.65), and bacterial assays (R2 = 0.43), and confirm the findings of Part VI. Some assays were evaluated separately. Firstly, mean IC50 values from three human keratinocyte assays were compared with human peak LC50 values, resulting in a very good correlation (R2 = 0.84). When the IC50 values for 19 chemicals which freely pass the blood–brain barrier were divided by a factor of ten (to compensate for a hypothetical extra sensitivity of the central nervous system to cytotoxicity), the correlation improved (R2 = 0.87). However, the pattern of outlier chemicals was found to be different to that of typical outliers for human cell line assays, which makes it difficult to use keratinocytes for acute systemic toxicity testing. Secondly, mean IC50 values from two human hepatocyte assays were compared with human peak LC50 values, resulting in a good direct correlation (R2 = 0.78) and an even better “blood–brain barrier-compensated” correlation (R2 = 0.81). The hepatocyte assays also had typical outlier chemicals without relevance for acute systemic toxicity. To find out whether typical hepatocyte responses could be used to predict lethal liver injury, a differential cytotoxicity study was conducted. The relatively high sensitivity of hepatocytes compared with human cell lines, as judged by the differences between the mean IC50 values for the two groups of assays, was compared with reported lethal liver injuries and the basal cytotoxicities of the human lethal blood concentrations of the 30 compounds. For three chemicals, i.e. methanol, phenol and arsenic trioxide, high sensitivity of the hepatocytes was indeed correlated with some liver injury. However,
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2017-01-09T06:27:59+00:00 Tags: |