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

scholarly journals In Vivo and In Vitro Toxicity Evaluation of Polyprenols Extracted from Ginkgo biloba L. Leaves

Molecules ◽  
2015 ◽  
Vol 20 (12) ◽  
pp. 22257-22271 ◽  
Author(s):  
Cheng-Zhang Wang ◽  
Jiao-Jiao Yuan ◽  
Wen-Jun Li ◽  
Hong-Yu Zhang ◽  
Jian-Zhong Ye
Keyword(s):  
Ginkgo Biloba ◽  
In Vitro Toxicity ◽  
Toxicity Evaluation

Integration of in vitro neurotoxicity data with biokinetic modelling for the estimation of in vivo neurotoxicity

2007 ◽  
Vol 26 (4) ◽  
pp. 333-338 ◽  
Author(s):  
Anna Forsby ◽  
Bas Blaauboer
Keyword(s):  
Exposure Period ◽  
Cellular Protein ◽  
In Vitro Toxicity ◽  
Target Tissue ◽  
Receptor Function ◽  
Human Neuroblastoma ◽  
Protein Levels ◽  
Effective Doses

Risk assessment of neurotoxicity is mainly based on in vivo exposure, followed by tests on behaviour, physiology and pathology. In this study, an attempt to estimate lowest observed neurotoxic doses after single or repeated dose exposure was performed. Differentiated human neuroblastoma SH-SY5Y cells were exposed to acrylamide, lindane, parathion, paraoxon, phenytoin, diazepam or caffeine for 72 hours. The effects on protein synthesis and intracellular free Ca2+concentration were studied as physiological endpoints. Voltage operated Ca2 +channel function, acetylcholine receptor function and neurite degenerative effects were investigated as neurospecific endpoints for excitability, cholinergic signal transduction and axonopathy, respectively. The general cytotoxicity, determined as the total cellular protein levels after the 72 hours exposure period, was used for comparison to the specific endpoints and for estimation of acute lethality. The lowest concentration that induced 20% effect (EC 20) obtained for each compound, was used as a surrogate for the lowest neurotoxic level (LOEL) at the target site in vivo. The LOELs were integrated with data on adsorption, distribution, metabolism and excretion of the compounds in physiologically-based biokinetic (PBBK) models of the rat and the lowest observed effective doses (LOEDs) were estimated for the test compounds. A good correlation was observed between the estimated LOEDs and experimental LOEDs found in literature for rat for all test compounds, except for diazepam. However, when using in vitro data from the literature on diazepam's effect on gamma-amino butyric acid (GABA)A receptor function for the estimation of LOED, the correlation between the estimated and experimental LOEDs was improved from a 10 000-fold to a 10-fold difference. Our results indicate that it is possible to estimate LOEDs by integrating in vitro toxicity data as surrogates for lowest observed target tissue levels with PBBK models, provided that some knowledge about toxic mechanisms is known. Human & Experimental Toxicology (2007) 26, 333—338

Drug-induced liver injury classification model based on in vitro human transcriptomics and in vivo rat clinical chemistry data

2014 ◽  
Vol 2 (4) ◽  
pp. 63-70 ◽  
Author(s):  
Danyel Jennen ◽  
Jan Polman ◽  
Mark Bessem ◽  
Maarten Coonen ◽  
Joost van Delft ◽  
...  
Keyword(s):  
Liver Injury ◽  
Clinical Chemistry ◽  
Classification Model ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Chemistry Data ◽  
Model Based ◽  
Injury Classification

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
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