Validation of <i>In Vitro</i> Cytotoxicity Tests — Past and Present Strategies

Ekwall, Björn; Bondesson, Inger; Hellberg, Sven; Högberg, Johan; Romert, Lennart; Stenberg, K; Walum, Erik

doi:10.1177/026119299101900215

Cited by 13 publications

(3 citation statements)

References 16 publications

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“…They provide reasonably accurate information for higher levels of organisation such as tissues, organs and organisms (1,11). Today, the validity of these models is accepted for preliminary investigations, for example, in screening for genotoxicity or cytotoxicity (1,12,13).…”

Section: Introductionmentioning

confidence: 99%

Cellular and Molecular Targets of Benzo[a]pyrene and Metal Toxicity in Xenopus laevis Embryos and in Hep G2 Cells

et al. 1999

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This paper describes the use of two in vitro systems (stage 35 Xenopus laevis embryos and the human hepatoblastoma cell line, Hep G2) to study effects of some environmental contaminants (benzo[a]pyrene, copper and zinc), which are representative of chemicals with different cell targets and mechanisms of action. The ability to activate benzo[a]pyrene and to metabolise it with the cytochrome P4501A isozyme were demonstrated in both in vitro systems by assessing the formation of water-soluble and protein-bound benzo[a]pyrene metabolites and by immunochemical analysis. In X. laevis embryos, the formation of DNA adducts demonstrated the ability to produce benzo[a]pyrene reactive metabolites. Moreover, in Hep G2 cells, the cytoskeletal protein, tubulin, and the reduced form of glutathione proved to be the cellular targets of copper and zinc toxicity. In response to metal-induced stress in Hep G2 cells, there was a cytoplasmic reorganisation of heat shock protein, Hsp 70. In conclusion, the in vitro systems provide for a rapid evaluation of heterogeneous compounds such as benzo[a]pyrene and heavy metals that differ in toxic potency and mechanisms of action. They could also be used to study the mechanisms of toxic action and to identify specific cellular and molecular targets.

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Section: Introductionmentioning

confidence: 99%

Cellular and Molecular Targets of Benzo[a]pyrene and Metal Toxicity in Xenopus laevis Embryos and in Hep G2 Cells

et al. 1999

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“…However, with the goal of compound ranking in drug development, screening methods employing in vitro acute toxicity studies are an attractive alternative to classical in vivo toxicology. A number of investigations (5,6) have shown a firm relationship between cytotoxicity in vitro and systemic in vivo toxicity, resulting in the concept of basal cytotoxicity, which…”

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Molecular Profiling and Prediction of Toxicity

Schuppe‐Koistinen¹

2001

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The rapid progress in genomics and proteomics technologies creates a unique opportunity for understanding the mechanisms of action and the toxicities of compounds. The application of gene-expression and protein-expression profiling promises to improve the predictive power of safety assessment, resulting in the development of drug candidates with a higher efficacy and a lower toxicity. Additionally, in the later phases of drug development, surrogate markers of treatment efficacy and toxicity can be applied to optimise the monitoring of pre-clinical and clinical studies.

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“…The various elements can then be used in different combinations to model a large number of toxic events. 5 The MEIC programme, 4 and the ECITTS project, 6 address this problem.…”

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In Vitro Test Validation: Should it Obey Laws, Recognise Uncertainty Principles or Follow Scientific Practices?

Walum¹

1992

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My fellow editors of ATLA, Oliver Flint (USA) and Michael Balls (UK), have contributed to the opinions on in vitro test validation in editorials published in the last two issues of the journal. 1 • 2 These editorials have been centred around the recommendations of the Amden Report, 3 Flint critisising what he sees as a lack of emphasis on mechanistic considerations, and Balls restating and reinforcing the conclusions of the Amden Workshop.Flint suggests that there should be one overriding rule for validation: "All tests must have demonstrable mechanistic similarity to the events we wish to study in vivo" (Flint's Law; Balls' denomination), whereas Balls' opinion is that the criteria for validation must be adapted to the type of validation under consideration (Balls' uncertainty principle; my denomination). When one reads the two compositions together, one finds that there is not such a tremendous difference between them. Both Flint and Balls are deeply concerned by questions of how best to develop test procedures, how to validate them correctly and how to formulate a maxim for validation studies. They are certainly both entitled to their beliefs, and I am not going to take sides in any way, other than by explaining some of my own beliefs.Validation should be performed as a research project. Consequently, the purpose of validation is to test one or several hypotheses, formulated on the basis of results obtained from basic cell biological studies, from mechanistic toxicological studies or in toxicity test development. The validity of the results of the project in relation to each hypothesis should then be judged by means of statistical procedures. Some of the ideas investigated in the MEIC-programme 4 may serve as examples of relevant hypotheses:

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Validation of In Vitro Cytotoxicity Tests — Past and Present Strategies

Cited by 13 publications

References 16 publications

Cellular and Molecular Targets of Benzo[a]pyrene and Metal Toxicity in Xenopus laevis Embryos and in Hep G2 Cells

Cellular and Molecular Targets of Benzo[a]pyrene and Metal Toxicity in Xenopus laevis Embryos and in Hep G2 Cells

Molecular Profiling and Prediction of Toxicity

In Vitro Test Validation: Should it Obey Laws, Recognise Uncertainty Principles or Follow Scientific Practices?

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