Overview of the Final MEIC Results: II. The In Vitro--In Vivo Evaluation, Including the Selection of a Practical Battery of Cell Tests for Prediction of Acute Lethal Blood Concentrations in Humans

Ekwall, Björn

doi:10.1016/s0887-2333(99)00061-2

Cited by 97 publications

(74 citation statements)

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“…An average IC50 for the ten 24-hour human cell line tests predicted peak LCs better (R 2 0.74) than other groups of tests (Ekwall, 1999). This claimed predictivity formed the basis for the A-cute-Tox project (Clemedson, 2008).…”

Section: Consideration 4: Kinetics Cannot Explain All Organ Selectivimentioning

confidence: 93%

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Cellular resilience

Smirnova

Harris

Leist

et al. 2015

ALTEX

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Section: Consideration 4: Kinetics Cannot Explain All Organ Selectivimentioning

confidence: 93%

“…In MEIC, 50 reference chemicals were tested in 61 in vitro assays (Ekwall, 1999 (Clemedson and Ekwall, 1999)." tial effects in fresh primary hepatocytes due to metabolic activation or deactivation not taking place in other cells.…”

Section: Consideration 3: All Cells Are Equal(ly Vulnerable)mentioning

confidence: 99%

Cellular resilience

Smirnova

Harris

Leist

et al. 2015

ALTEX

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“…The fundamentals for the test are that the in vitro tests of basal cytotoxicity are sufficiently predictive for the rodent in vivo LD 50 assay (Ekwall, 1999;Spielmann et al, 1999) and that ESCs show alterations in their in vitro differentiation pattern when exposed to embryotoxic chemicals during EB differentiation (Wobus et al, 1994). The EST method is based on the potential of D3 mouse ESC to differentiate into beating cardiomyocytes and in determining how this differentiation is altered by exposure to chemicals, together with the cytotoxic insults in these cells and in a mouse adult cells model.…”

Section: Basis Of the Methodsmentioning

confidence: 99%

Embryonic Stem Cells in Toxicological Studies

Estevan¹,

Romero²,

Pamies³

et al. 2011

Embryonic Stem Cells - Basic Biology to Bioengineering

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“…Fifty chemicals were studied, including poisons, prescription drugs, substances of abuse, and common household chemicals. The in vitro cytotoxic concentrations were compared with known, acutely lethal doses in humans and showed predictive correlations of up to 88% [19]. The MEIC study suggested that assays with human cell lines give the best prediction and are independent of cell type, thereby indicating that the mechanism of toxicity was inhibition of a common, vital cell process.…”

Section: In Vitro Cytotoxicity and Predicting Drug Attritionmentioning

confidence: 99%

High-content analysis for drug delivery and nanoparticle applications

Brayden

Cryan

Dawson

et al. 2015

Drug Discovery Today

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Publication information Drug Discovery Today, 20 (8): 942-957Publisher Elsevier Item record/more information http://hdl.handle.net/10197/6636 Publisher's statementThis is the author's version of a work that was accepted for publication in Drug Discovery Today. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Drug Discovery Today, 20 (8), (2015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Page 1 of 26A c c e p t e d M a n u s c r i p t Sally-Ann CryanSally-Ann Cryan has a pharmacy degree and a PhD in pharmaceutics ( Jeremy SimpsonJeremy Simpson carried out his PhD at the University of Warwick, followed postdoctoral work at the Scripps Research Institute in San Diego, and the Imperial Cancer Research Fund in London. After 9 years as a staff member at the European Molecular Biology Laboratory (EMBL) in Heidelberg (Germany), he was appointed as professor of cell biology at UCD, in 2008. He currently applies high-throughput imaging technologies to study subcellular transport pathways and the internalization routes taken by nanoparticles in cells. He runs the UCD Cell Screening Laboratory and is the author of more than 80 publications.High-content analysis (HCA) provides quantitative multiparametric cellular fluorescence data. From its origins in discovery toxicology, it is now addressing fundamental questions in drug delivery. Nanoparticles (NPs), polymers, and intestinal permeation enhancers are being harnessed in drug delivery systems to modulate plasma membrane properties and the intracellular environment. Identifying comparative mechanistic cytotoxicity on sublethal events is crucial to expedite the development of such systems. NP uptake and intracellular routing pathways are also being dissected using chemical and genetic perturbations, with the potential to assess the intracellular fate of targeted and untargeted particles in vitro. As we discuss here, HCA is set to make a major impact in preclinical delivery research by elucidating the intracellular pathways of NPs and the in vitro mechanistic-based toxicology of formulation constituents. A brief recap of cytotoxicity assaysIn vitro cell-based assays have long been used to assess the cytotoxic effects of drug exposure [1]. Cells undergoing acute necrosis swell and lose metabolic capacity, thereby losing the capacity to maintain a barrier to the extracellular space and the ability ...

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Overview of the Final MEIC Results: II. The In Vitro--In Vivo Evaluation, Including the Selection of a Practical Battery of Cell Tests for Prediction of Acute Lethal Blood Concentrations in Humans

Cited by 97 publications

References 3 publications

Cellular resilience

Cellular resilience

Embryonic Stem Cells in Toxicological Studies

High-content analysis for drug delivery and nanoparticle applications

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