The Prediction of Human Acute Systemic Toxicity by the EDIT/MEIC In Vitro Test Battery: The Importance of Protein Binding and of Partitioning into Lipids

2003 ◽  
Vol 31 (3) ◽  
pp. 245-256 ◽  
Author(s):  
Cecilia Clemedson ◽  
Paul J. Dierickx ◽  
Michael Sjöström
Keyword(s):  
Protein Binding ◽  
Mercuric Chloride ◽  
Culture Medium ◽  
Systemic Toxicity ◽  
Test Battery ◽  
In Vitro Test ◽  
Blood Concentrations ◽  
Uptake Inhibition ◽  
Vitro Test

The aim of the two studies presented in this paper was to further improve the predictability of the original Multicentre Evaluation of In Vitro Cytotoxicity (MEIC) in vitro test battery for acute systemic toxicity. In the first study, whether a protein-free cytotoxicity assay could improve the prediction of human acute systemic toxicity was investigated. The cytotoxicity of 39 MEIC reference chemicals was measured by the neutral red uptake inhibition test after 30 minutes in phosphate-buffered saline (PBS), with hepatoma-derived Fa32 cells. The results were compared with the corresponding values obtained in complete culture medium, including 10% fetal calf serum. Mercuric chloride and hexachlorophene were much more cytotoxic in PBS, as was the case, to a lesser extent, for seven other chemicals. Potassium cyanide and eight other chemicals were less cytotoxic in PBS than in complete culture medium, probably because of poor physiological conditions. The correlation between the cytotoxicity measured in PBS and human acute toxicity was rather low, but became of the same order as for other assays, when mercuric chloride and hexachlorophene were withdrawn from the comparison. In the second study, modelling of human lethal blood concentrations by using the results of the three cell line tests of the original MEIC test battery were complemented by logP (octanol–water partition coefficient) values. The introduction of logP into the modelling did not improve the correlations, but some improvement of both R2 and Q2 was obtained by expanding the logP values with logP2 values. The highest R2 (0.84) and Q2 (0.80) values were obtained for a model in which both experimental and calculated (ambiguous) logP values were used. When only experimental logP values were used, the corresponding values were 0.80 and 0.78. These two studies showed that including protein binding and the partition of chemicals in the MEIC in vitro test battery is important, in order to improve the predictability of the results obtained.

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

2002 ◽  
Vol 30 (3) ◽  
pp. 313-321 ◽  
Author(s):  
Cecilia Clemedson ◽  
Marika Nordin-Andersson ◽  
Henning F. Bjerregaard ◽  
Jørgen Clausen ◽  
Anna Forsby ◽  
...  
Keyword(s):  
Systemic Toxicity ◽  
Target Organ ◽  
Test Battery ◽  
In Vitro Tests ◽  
Good Prediction ◽  
In Vitro Test ◽  
Optimal Test ◽  
Organ Specific ◽  
Vitro Test

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.

Evaluation of an alternative in vitro test battery for detecting reproductive toxicants

2014 ◽  
Vol 48 ◽  
pp. 11
Author(s):  
A.H. Piersma ◽  
S. Bosgra ◽  
M.B.M. van Duursen ◽  
S.A.B. Hermsen ◽  
L.R.A. Jonker ◽  
...  
Keyword(s):  
Test Battery ◽  
In Vitro Test ◽  
Vitro Test ◽  
Reproductive Toxicants

Development of an in vitro test battery for assessing chemical effects on bovine germ cells under the ReProTect umbrella

2008 ◽  
Vol 233 (3) ◽  
pp. 360-370 ◽  
Author(s):  
Giovanna Lazzari ◽  
Irene Tessaro ◽  
Gabriella Crotti ◽  
Cesare Galli ◽  
Sebastian Hoffmann ◽  
...  
Keyword(s):  
Germ Cells ◽  
Test Battery ◽  
In Vitro Test ◽  
Chemical Effects ◽  
Vitro Test

Evaluation of Cytotoxicity of the First Twenty MEIC Chemicals by Using Haemolysis of Human Erythrocytes as an Endpoint

1992 ◽  
Vol 20 (2) ◽  
pp. 226-229
Author(s):  
Boris Isomaa ◽  
Henrik Lilius ◽  
Anne West
Keyword(s):  
Maximum Degree ◽  
Human Lymphocytes ◽  
Rat Hepatocytes ◽  
Haemolytic Activity ◽  
In Vitro Test ◽  
3T3 Cells ◽  
Blood Concentrations ◽  
Vitro Test ◽  
Lethal Blood

The cytotoxicity of the first twenty chemicals on the MEIC list was evaluated by determining the haemolytic activity of the chemicals. All the tested chemicals, except malathion, were haemolytic. With digoxin and sodium fluoride, however, the maximum degree of haemolysis achieved remained less than 50%. The EC10 for the chemicals varied from 0.38mM (digoxin) to 4,830mM (ethylene glycol). Comparing our data for the first ten MEIC chemicals with data obtained with other in vitro test systems, they correlated well with data reported for human lymphocytes (r = 0.93), rat hepatocytes (r = 0.98) and 3T3 cells (r = 0.95). However, in comparison with these tests, the haemolysis assay was less sensitive. The EC10 for the first ten MEIC chemicals correlated rather well (r = 0.84) with human lethal blood concentrations, but the haemolysis assay underestimated the toxicity of most of the chemicals and particularly underestimated the toxicity of digoxin.

Use of an in vitro test battery as a prescreen in the assessment of ocular irritancy

1994 ◽  
Vol 8 (1) ◽  
pp. 75-79 ◽  
Author(s):  
R.W. Lewis ◽  
J.C. McCall ◽  
P.A. Botham
Keyword(s):  
Test Battery ◽  
In Vitro Test ◽  
Vitro Test

The genotoxic activity of glycerol in an in vitro test battery

1988 ◽  
Vol 26 (7) ◽  
pp. 631-635 ◽  
Author(s):  
D.J. Doolittle ◽  
D.A. Lee ◽  
C.K. Lee
Keyword(s):  
Test Battery ◽  
In Vitro Test ◽  
Genotoxic Activity ◽  
Vitro Test
Sign in / Sign up

Export Citation Format

Share Document