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Accumulation of a parkinsonism-inducing neurotoxin in melanin-bearing neurons: autoradiographic studies on 3H-MPTP.Acta pharmacologica et toxicologica, 59 2
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An Animal Protection Sponsor's View of MEICAlternatives to Laboratory Animals, 25
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MEIC Evaluation of Acute Systemic Toxicity: Part V. Rodent and Human Toxicity Data for the 50 Reference Chemicals.Alternatives to laboratory animals : ATLA, 26 Suppl 2
M. Lden, H. Seibert (1996)
Cytotoxic and non-cytotoxic effects of the MEIC reference chemicals on spontaneously contracting primary cultured rat skeletal muscle cells.Toxicology in vitro : an international journal published in association with BIBRA, 10 4
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The use of cultured skeletal muscle cells in testing for acute systemic toxicity.Toxicology in vitro : an international journal published in association with BIBRA, 8 4
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Preliminary studies on the validity of in vitro measurement of drug toxicity using HeLa cells. II. Drug toxicity in the MIT-24 system compared with mouse and human lethal dosage of 52 drugs.Toxicology letters, 5 5
M. Weiss, T. Sawyer (1993)
Cytotoxicity of the MEIC test chemicals in primary neurone cultures.Toxicology in vitro : an international journal published in association with BIBRA, 7 5
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Toxic effects of chemicals: difficulties in extrapolating data from animals to man.Critical reviews in toxicology, 16 1
L. Romert, Tommy Jansson, Dag Jenssen (1994)
The cytotoxicity of 50 chemicals from the MEIC study determined by growth inhibition of ascites sarcoma BP8 cells: a comparison with acute toxicity data in man and rodents.Toxicology letters, 71 1
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RELATIONSHIP BETWEEN CYTOTOXICITY IN VITRO AND WHOLE ANIMAL TOXICITY.Cancer chemotherapy reports, 30
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Evaluation of the cytotoxicity of ten chemicals on human cultured hepatocytes: Predictability of human toxicity and comparison with rodent cell culture systems.Toxicology in vitro : an international journal published in association with BIBRA, 6 1
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Main Features of Basal Cytoxicity: Sites of Toxic Action and Interaction in the Pollen Tube CellAlternatives to Laboratory Animals, 24
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Correlation between cytotoxicity in vitro and LD50-values.Acta pharmacologica et toxicologica, 52 Suppl 2
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Potential of Human Lung Cells for Predicting Acute CytotoxicityAlternatives to Laboratory Animals, 23
B. Ekwall, I. Bondesson, J. Castell, M. Gómez‐Lechón, S. Hellberg, J. Högberg, R. Jover, X. Ponsoda, L. Romert, K. Stenberg, E. Walum (1989)
Cytotoxicity Evaluation of the First Ten MEIC Chemicals: Acute Lethal Toxicity in Man Predicted by Cytotoxicity in Five Cellular Assays and by Oral LD50 Tests in RodentsAlternatives to Laboratory Animals, 17
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MEIC evaluation of acute systemic toxicity for the first 30 reference chemicals: Part II. In vitro results from 68 methods and comparative cytotoxicity analysis, 24
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Hepatocytes in Primary Culture: An Alternative to LD50 Testing? Validation of a Predictive Model by Multivariate AnalysisAlternatives to Laboratory Animals, 20
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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 LinesAlternatives to Laboratory Animals, 25
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Principles for the validation of in vitro toxicology test methods.Toxicology in vitro : an international journal published in association with BIBRA, 8 4
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Human acute toxicity prediction of the first 50 MEIC chemicals by a battery of ecotoxicological tests and physicochemical properties.Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 32 2
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. At the end of the project in 1996, 29 laboratories had tested all 50 reference chemicals in 61 cytotoxicity assays. Five previous articles have presented the in vitro data and the human database to be used in the evaluation. This article presents three important parts of the final evaluation: a) a comparison of rat and mouse oral LD50 with human acute lethal doses for all 50 chemicals; b) a display of the correlations between IC50 (concentration causing 50% inhibition) values from all 61 assays and three independent sets of human acute lethal blood concentrations, i.e. clinical lethal concentrations, forensic lethal concentrations, and peak concentrations; and c) a series of comparisons between average IC50 values from ten human cell line 24-hour assays and human lethal blood concentrations. In the latter comparisons, results from correlations were linked with known human toxicity data for the chemicals, to provide an understanding of correlative results. This correlative/mechanistic approach had the double purpose of assessing the relevance of the in vitro cytotoxicities, and of testing a series of hypotheses connected with the basal cytotoxicity concept. The results of the studies were as follows. Rat LD50 predictions of human lethal dosage were only relatively good (R2 = 0.61), while mouse LD50s gave a somewhat better prediction (R2 = 0.65). Comparisons performed between IC50 values from the 61 assays and the human lethal peak concentrations demonstrated that human ceil line tests gave the best average results (R2 = 0.64), while mammalian and fish cell tests correlated less well (R2 = 0.52–0.58), followed by non-fish ecotoxicological tests (R2 = 0.36). Most of the 61 assays underpredicted human toxicity for digoxin, malathion, carbon tetrachloride and atropine sulphate. In the correlative/mechanistic study, the 50 chemicals were first separated into three groups: A = fast-acting chemicals with a restricted passage across the blood–brain barrier; B = slow-acting chemicals with a restricted passage across the blood–brain barrier; and C = chemicals which cross the blood–brain barrier freely, while inducing a non-specific excitation/depression of the central nervous system (CNS). The IC50 values for chemicals in group C were divided by a factor of ten to compensate for a hypothetical extra vulnerability of the CNS to cytotoxicity. Finally, the average human cell line IC50 values (24-hour IC50 for groups A and C, and after 48-hour for group B) were compared with relevant human lethal blood concentrations (peak concentrations for groups A and C, and 48-hour concentrations for group B). As a result, in vitro toxicity and in vivo toxicity correlated very well for all groups (R2 = 0.98, 0.82 and 0.85, respectively). No clear overprediction of human toxicity was made by the human cell tests. The human cell line tests underpredicted human toxicity for only four of the 50 chemicals. These outlier chemicals were digoxin, malathion, nicotine and atropine sulphate, all of which have a lethal action in man through interaction with specific target sites not usually found in cell lines. Potassium cyanide has a cellular human lethal action which cannot be measured by standard anaerobic cell lines. The good prediction of the human lethal whole-blood concentration of this chemical was not conclusive, i.e. was probably a “false good correlation”. Another two chemicals in group C resulted in “false good correlations”, i.e. paracetamol and paraquat. The comparisons thus indicated that human cell line cytotoxicities are relevant for the human acute lethal action for 43 of the 50 chemicals. The results strongly support the basal cytotoxicity concept, and further point to the non-specific CNS depression being the obligatory reaction of humans to cytotoxic concentrations of chemicals, provided that the chemicals are able to pass the blood–brain barrier.
Alternatives to Laboratory Animals – SAGE
Published: Aug 1, 1998
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