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 Rodents

Ekwall, Björn; Bondesson, Inger; Castell, José V.; Gómez-Lechón, Marı́a José; Hellberg, Sven; Högberg, Johan; Jover, Ramiro; Ponsoda, Xavier; Romert, Lennart; Stenberg, K; Walum, Erik

doi:10.1177/026119298901700205

Cited by 29 publications

(12 citation statements)

References 16 publications

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“…Recently, the Multicenter Evaluation of In Vitro Cytotoxicity (MEIC) programme to evaluate the relevance of in vitro cytotoxicity tests as a part of a test battery for acute systemic toxicity of chemicals was finalised (1)(2)(3)(4)(5). In this international programme (directed by the Cytotoxicology Laboratory, Uppsala [CTLU]), 50 reference chemicals were tested in 61 cytotoxicity assays.…”

Section: Introductionmentioning

confidence: 99%

“…paracetamol, digoxin, malathion, nicotine, cyanide, paraquat and atropine, which are all known to lead to lethality by actions on specific receptors or cells (3,4). Moreover, knowledge of human toxicokinetics (absorption in the intestine and distribution volumes), used together with the 24-hour human cell line concentration for the first ten reference chemicals (Stage 2 modelling), has resulted in a good prediction of human lethal dosage (2). As a practical result of MEIC, a battery of three 24-hour human cell line assays could be selected with use of multivariate partial least squares analysis, which had a good direct prediction (R 2 = 0.77) of human lethal peak concentrations.…”

Section: Introductionmentioning

confidence: 99%

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EDIT: A New International Multicentre Programme to Develop and Evaluate Batteries of In Vitro Tests for Acute and Chronic Systemic Toxicity

Ekwall¹,

Clemedson²,

Ring³

et al. 1999

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The Multicenter Evaluation of In Vitro Cytotoxicity (MEIC) programme provided a battery of three basal cytotoxicity tests with a good (R2 = 0.77) prediction of human acute lethal blood concentrations. The predictive power of this battery would be considerably improved by the addition of new supplementary in vitro tests. The development of these new tests will be facilitated by a close coupling of test development to evaluation. The Cytotoxicology Laboratory, Uppsala (CTLU), is therefore inviting all interested in vitro toxicologists to take part in the Evaluation-guided Development of In Vitro Toxicity and Toxicokinetic Tests (EDIT). All EDIT activities (subprojects) will be designed on a case-by-case basis, but will follow a common pattern. The CTLU will use the accumulated MEIC/EDIT data, and its experience from the previous MEIC evaluation, to suggest priority areas, i.e. the need for certain in vitro toxicity data/tests as supplements to existing in vitro models/batteries on human systemic toxicity. Detailed research programmes corresponding to these areas will be published on the Internet. The CTLU will also try to raise funds for some projects and will coordinate multilaboratory studies. Interested laboratories developing or already using priority tests are encouraged to join the subprojects and to test specific sets of substances (usually sets of MEIC reference chemicals) in their new assays. The CTLU will provide adequate human reference data and will also evaluate results as single components of complex models, together with the laboratory conducting the test. At present, ten priority areas have been identified: a) repeat dose toxicity in vitro; b) urgent mechanistic information from in vitro studies of protein denaturation, morphology of cell injury, differential toxicity between various rapidly measured end-points (10–60 minutes) and 24-hour cytotoxicity, toxicity to aerobic cells, and discrimination between rapid and slow cytotoxic mechanisms; c) in vitro tests on vitally important, specific receptor toxicity in humans; d) excitatory cytotoxicity; e) reversibility of cell toxicity; f) in vitro tests on passage across the blood–brain barrier; g) in vitro tests on absorption in the gut; h) protein binding in vitro; i) in vitro tests on distribution volumes (Vd); and j) in vitro tests on bio-transformation to more-toxic metabolites (hepatocytes plus target cells). This paper gives a short presentation of the rationale for each subproject and reports on ongoing activities.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

EDIT: A New International Multicentre Programme to Develop and Evaluate Batteries of In Vitro Tests for Acute and Chronic Systemic Toxicity

Ekwall¹,

Clemedson²,

Ring³

et al. 1999

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“…The amounts of money, labour and animal lives that could have been saved by omitting the in vivo tests are considerable. More importantly, there seems to be little reason to believe that the safety of patients would have been in any way compromised, provided that a sufficiently sensitive in vitro cell test battery had been used (18).…”

Section: Discussionmentioning

confidence: 99%

Toxicity Testing of Polymer Materials for Dialysis Equipment: Reconsidering In Vivo Testing

2000

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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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“…Knowledge of absorption in the intestine is important in relation to converting concentrations (obtained in vitro) to human lethal oral doses (22,23). Several in vitro assays for predicting the intestinal absorption of chemicals have been developed.…”

Section: Models For Predicting Absorption In the Gutmentioning

confidence: 99%

“…Another necessary conversion factor is the distribution volume (Vd), i.e. the volume of distribution in the body of an absorbed dose (22,23). The possibility of developing a simple in vitro test for Vd was discussed.…”

Section: Determination Of Distribution Volumesmentioning

confidence: 99%

Development of an In Vitro Test Battery for the Estimation of Acute Human Systemic Toxicity: An Outline of the EDIT Project

Clemedson¹,

Nordin-Andersson

Bjerregaard

et al. 2002

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The aim of the Evaluation-guided Development of New In Vitro Test Batteries (EDIT) multicentre programme is to establish and validate in vitro tests relevant to toxicokinetics and for organ-specific toxicity, to be incorporated into optimal test batteries for the estimation of human acute systemic toxicity. The scientific basis of EDIT is the good prediction of human acute toxicity obtained with three human cell line tests (R2 = 0.77), in the Multicentre Evaluation of In Vitro Cytotoxicity (MEIC) programme. However, the results from the MEIC study indicated that at least two other types of in vitro test ought to be added to the existing test battery to improve the prediction of human acute systemic toxicity — to determine key kinetic events (such as biotransformation and passage through biological barriers), and to predict crucial organ-specific mechanisms not covered by the tests in the MEIC battery. The EDIT programme will be a case-by-case project, but the establishment and validation of new tests will be carried through by a common, step-wise procedure. The Scientific Committee of the EDIT programme defines the need for a specific set of toxicity or toxicokinetic data. Laboratories are then invited to perform the defined tests in order to provide the “missing” data for the EDIT reference chemicals. The results obtained will be evaluated against the MEMO (the MEIC Monograph programme) database, i.e. against human acute systemic lethal and toxicity data. The aim of the round-table discussions at the 19th Scandinavian Society for Cell Toxicology (SSCT) workshop, held in Ringsted, Denmark on 6–9 September 2001, was to identify which tests are the most important for inclusion in the MEIC battery, i.e. which types of tests the EDIT programme should focus on. It was proposed that it is important to include in vitro methods for various kinetic events, such as biotransformation, absorption in the gut, passage across the blood–brain barrier, distribution volumes, protein binding, and renal clearance/accumulation. Models for target organ toxicity were also discussed. Because several of the outlier chemicals (paracetamol, digoxin, malathion, nicotine, paraquat, atropine and potassium cyanide) in the MEIC in vivo–in vitro evaluation have a neurotoxic potential, it was proposed that the development within the EDIT target organ programme should initially be focused on the nervous system.

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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 Rodents

Cited by 29 publications

References 16 publications

EDIT: A New International Multicentre Programme to Develop and Evaluate Batteries of In Vitro Tests for Acute and Chronic Systemic Toxicity

EDIT: A New International Multicentre Programme to Develop and Evaluate Batteries of In Vitro Tests for Acute and Chronic Systemic Toxicity

Toxicity Testing of Polymer Materials for Dialysis Equipment: Reconsidering In Vivo Testing

Development of an In Vitro Test Battery for the Estimation of Acute Human Systemic Toxicity: An Outline of the EDIT Project

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