Toward More Useful In Vitro Toxicity Data with Measured Free Concentrations

2004 ◽  
Vol 38 (23) ◽  
pp. 6263-6270 ◽  
Author(s):  
Minne B. Heringa ◽  
Richard H. M. M. Schreurs ◽  
Frans Busser ◽  
Paul T. Van Der Saag ◽  
Bart Van Der Burg ◽  
...  
Keyword(s):  
In Vitro Toxicity ◽  
Toxicity Data

The point of transition on the dose-effect curve as a reference point in the evaluation of in vitro toxicity data

2012 ◽  
Vol 32 (10) ◽  
pp. 843-849 ◽  
Author(s):  
Salomon Sand ◽  
Joakim Ringblom ◽  
Helen Håkansson ◽  
Mattias Öberg
Keyword(s):  
Reference Point ◽  
Dose Effect ◽  
In Vitro Toxicity ◽  
Toxicity Data ◽  
Effect Curve

scholarly journals Model-based contextualization of in vitro toxicity data quantitatively predicts in vivo drug response in patients

2016 ◽  
Vol 91 (2) ◽  
pp. 865-883 ◽  
Author(s):  
Christoph Thiel ◽  
Henrik Cordes ◽  
Isabel Conde ◽  
José Vicente Castell ◽  
Lars Mathias Blank ◽  
...  
Keyword(s):  
Drug Response ◽  
In Vitro Toxicity ◽  
Toxicity Data ◽  
Model Based

The Necessity of Biokinetic Information in the Interpretation of In Vitro Toxicity Data

2002 ◽  
Vol 30 (2_suppl) ◽  
pp. 85-91 ◽  
Author(s):  
Bas J. Blaauboer
Keyword(s):  
Critical Concentration ◽  
In Vitro Toxicity ◽  
Toxicity Data ◽  
Animal Data ◽  
Hazard And Risk ◽  
Hazard And Risk Assessment ◽  
Critical Site ◽  
Dose Metric

Data derived from in vitro toxicity studies are not directly applicable in an assessment of the toxicity of compounds in intact organisms. The major limitation is the lack of knowledge of biokinetic behaviour in vivo. Since the toxicity of a compound will be determined by the critical concentration (or other dose metric) of the critical compound (or a metabolite thereof) at the critical site of toxic action, biokinetic behaviour must be taken into account. Possibilities of biokinetic modelling on the basis of in vitro and other non-animal data are discussed, and the application of the results in hazard and risk-assessment schedules is considered.

MEIC Evaluation of Acute Systemic Toxicity

1998 ◽  
Vol 26 (1_suppl) ◽  
pp. 93-129 ◽  
Author(s):  
Cecilia Clemedson ◽  
Frank A. Barile ◽  
Barbro Ekwall ◽  
Maria José Gómez-Lechón ◽  
Tony Hall ◽  
...  
Keyword(s):  
Cell Lines ◽  
Primary Cultures ◽  
Toxicity Testing ◽  
Preceding Paper ◽  
In Vitro Toxicity ◽  
Toxicity Data ◽  
Animal Cells ◽  
Basal Cytotoxicity

Results from tests on the first 30 MEIC reference chemicals in 16 different systems are presented as a prerequisite to the subsequent in vitro/in vivo comparisons of acute toxicity data, i.e. the final MEIC evaluation of all test results of the study. The study is a supplement to the previously published results from 68 methods (including methods 45B and 46B [old numbers]) used to test the same set of chemicals. The strategies and methods of the preceding paper were employed to enable a comparative cytotoxicity analysis of the results from these 68 methods and from the 16 new methods to be made. Principal components analysis (PCA) of 82 assays demonstrated a dominating first component which described as much as 83% of the variance in the toxicity data. This remarkable similarity of all toxicity data was the main finding of the present study, and confirmed the results of the previous study with a less-extensive database. Also, the influence on the general variability of results of several key methodological factors was evaluated by analysis of selected sets of data, including linear regression of the results of pairs of methods, which were similar in all respects except for the factor under analysis. This analysis of the same 82 assays as before also confirmed previous results from the 68 assay database: a) the toxicities of a third of the chemicals increased considerably with exposure time; b) in general, cytotoxicity for human cells was well predicted by cytotoxicity tests with animal cells; c) this prediction was poor for two chemicals, i.e. digoxin and malathion; d) prediction of human cytotoxicity by ecotoxicological tests was only fairly good; e) 25 comparisons of similar assays employing different cell lines showed strikingly similar toxicities (mean R2 = 0.86); f) 22 comparisons of similar pairs of assays employing different primary cultures and cell lines also revealed similar toxicities (mean R2 = 0.79); and g) 15 comparisons of similar assays with different growth/viability endpoint measurements demonstrated strikingly similar toxicities (mean R2 = 0.89). Results b, e, f and g must be the main causes of the general similarity of results, while results a, c and d, together with other factors, could explain the 20% dissimilarity. These findings support the basal cytotoxicity concept and may assist in guiding and refining in vitro toxicity testing in the future.

scholarly journals The Use of In Vitro Toxicity Data and Physiologically Based Kinetic Modeling to Predict Dose-Response Curves for In Vivo Developmental Toxicity of Glycol Ethers in Rat and Man

2010 ◽  
Vol 118 (2) ◽  
pp. 470-484 ◽  
Author(s):  
Jochem Louisse ◽  
Esther de Jong ◽  
Johannes J. M. van de Sandt ◽  
Bas J. Blaauboer ◽  
Ruud A. Woutersen ◽  
...  
Keyword(s):  
Kinetic Modeling ◽  
Dose Response ◽  
Developmental Toxicity ◽  
In Vitro Toxicity ◽  
Toxicity Data ◽  
Glycol Ethers ◽  
Response Curves ◽  
Physiologically Based

MEIC Evaluation of Acute Systemic Toxicity

1998 ◽  
Vol 26 (1_suppl) ◽  
pp. 131-183 ◽  
Author(s):  
Cecilia Clemedson ◽  
Marianne Andersson ◽  
Yasunobu Aoki ◽  
Frank A. Barile ◽  
Anna Maria Bassi ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Human Cell ◽  
Protein Denaturation ◽  
Human Cell Line ◽  
Background Information ◽  
In Vitro Toxicity ◽  
Toxicity Data ◽  
Relative Significance

Results from tests on the Multicentre Evaluation of In Vitro Cytotoxicity (MEIC) reference chemicals 31–50 in 67 different in vitro toxicity assays are presented in this paper as a prerequisite to in vitro/in vivo comparisons for all MEIC in vitro toxicity data in forthcoming papers, i.e. the final MEIC evaluation of the relevance of the tests. With the aim of increasing knowledge about the relative significance of some in vitro methodological factors, the strategies and methods of the preceding parts in the MEIC series (Parts II and III) were again employed to enable comparative cytotoxicity analysis of the new in vitro results presented in this paper. A principal components analysis (PCA) of the results from tests of the 20 chemicals in 67 assays demonstrated a dominating first component describing as much as 74% of the variance in the toxicity data, indicating a similar ranking of the cytotoxicities of the chemicals in most of the tests. The influence on the general variability of the results of a few, key methodological factors was also evaluated by using linear regression comparisons of the results of all pairs of methods available in the study, i.e. methods which were similar in all respects except for the factor being analysed. Results from this “random probe” analysis were: a) the cytotoxicities of 11 of the 20 chemicals increased considerably with exposure time (> 10 times over 4–168 hours); b) in general, human cell line toxicity was well predicted by cytotoxicity in animal cells; c) prediction of human cell line toxicity by most ecotoxicological tests was only fairly good; d) 14 comparisons of similar assays with different cell lines showed similar toxicities (mean R2 = 0.83); e) nine comparisons of similar assays employing different primary cultures and cell lines shared similar toxicities (mean R2 = 0.71); and f) 16 comparisons of similar assays with different growth/viability endpoints showed similar toxicities (mean R2 = 0.71). Results b, d, e and f must contribute to the PCA-documented high general similarity of the in vitro toxicity data. Results a and c, together with factors which were not analysed, such as different protocols and inter-laboratory variability of tests, could explain the 26% dissimilarity. To provide background information to the planned final MEIC evaluation of the relevance of the 61 methods in which all 50 chemicals have been tested, an additional PCA was made of the 50 chemical-61 assay in vitro database (from Parts II and III and the present paper). This supplementary PCA demonstrated an 80% similarity of results. Compared with the previous analysis of the tests of the first 30 MEIC reference chemicals (MEIC Part III), the present analysis of the tests of the last 20 MEIC chemicals indicates a somewhat higher variation in the results. Correspondingly, some deviating endpoint measurements and cell line responses were demonstrated by the pairwise comparisons in the present study. As a result, the analysis revealed a high correlation (R2 = 0.73) between the average human cell line toxicity and the results from a new protein denaturation test. These preliminary results suggest that intracellular protein denaturation may be a frequently occurring mechanism in basal cytotoxicity.

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