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Title: Measuring and modeling of binary mixture effects of pharmaceuticals and nickel on cell viability/cytotoxicity in the human hepatoma derived cell line HepG2

Abstract

The interaction of drugs and non-therapeutic xenobiotics constitutes a central role in human health risk assessment. Still, available data are rare. Two different models have been established to predict mixture toxicity from single dose data, namely, the concentration addition (CA) and independent action (IA) model. However, chemicals can also act synergistic or antagonistic or in dose level deviation, or in a dose ratio dependent deviation. In the present study we used the MIXTOX model (EU project ENV4-CT97-0507), which incorporates these algorithms, to assess effects of the binary mixtures in the human hepatoma cell line HepG2. These cells possess a liver-like enzyme pattern and a variety of xenobiotic-metabolizing enzymes (phases I and II). We tested binary mixtures of the metal nickel, the anti-inflammatory drug diclofenac, and the antibiotic agent irgasan and compared the experimental data to the mathematical models. Cell viability was determined by three different methods the MTT-, AlamarBlue (registered) and NRU assay. The compounds were tested separately and in combinations. We could show that the metal nickel is the dominant component in the mixture, affecting an antagonism at low-dose levels and a synergism at high-dose levels in combination with diclofenac or irgasan, when using the NRU and the AlamarBluemore » assay. The dose-response surface of irgasan and diclofenac indicated a concentration addition. The experimental data could be described by the algorithms with a regression of up to 90%, revealing the HepG2 cell line and the MIXTOX model as valuable tool for risk assessment of binary mixtures for cytotoxic endpoints. However the model failed to predict a specific mode of action, the CYP1A1 enzyme activity.« less

Authors:
 [1];  [1];  [2];  [1]
  1. Helmholtz Centre for Environmental Research - UFZ, Division Health Science, Permoserstr. 15, 04318 Leipzig (Germany)
  2. Universitaet Leipzig, Faculty of Medicine, Environmental Medicine and Hygiene, Liebigstr. 27, 04103 Leipzig (Germany)
Publication Date:
OSTI Identifier:
21344936
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 244; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2010.01.012; PII: S0041-008X(10)00023-2; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALGORITHMS; ANTIBIOTICS; BINARY MIXTURES; BROMIDES; DOSES; DRUGS; ENZYMES; HEPATOMAS; LIVER; MEN; NICKEL; RISK ASSESSMENT; SIMULATION; TOXICITY; ANIMALS; ANTI-INFECTIVE AGENTS; BODY; BROMINE COMPOUNDS; CARCINOMAS; DIGESTIVE SYSTEM; DISEASES; DISPERSIONS; ELEMENTS; GLANDS; HALIDES; HALOGEN COMPOUNDS; MALES; MAMMALS; MAN; MATHEMATICAL LOGIC; METALS; MIXTURES; NEOPLASMS; ORGANIC COMPOUNDS; ORGANS; PRIMATES; PROTEINS; TRANSITION ELEMENTS; VERTEBRATES

Citation Formats

Rudzok, S, Schlink, U, Herbarth, O, and Bauer, M. Measuring and modeling of binary mixture effects of pharmaceuticals and nickel on cell viability/cytotoxicity in the human hepatoma derived cell line HepG2. United States: N. p., 2010. Web. doi:10.1016/j.taap.2010.01.012.
Rudzok, S, Schlink, U, Herbarth, O, & Bauer, M. Measuring and modeling of binary mixture effects of pharmaceuticals and nickel on cell viability/cytotoxicity in the human hepatoma derived cell line HepG2. United States. https://doi.org/10.1016/j.taap.2010.01.012
Rudzok, S, Schlink, U, Herbarth, O, and Bauer, M. 2010. "Measuring and modeling of binary mixture effects of pharmaceuticals and nickel on cell viability/cytotoxicity in the human hepatoma derived cell line HepG2". United States. https://doi.org/10.1016/j.taap.2010.01.012.
@article{osti_21344936,
title = {Measuring and modeling of binary mixture effects of pharmaceuticals and nickel on cell viability/cytotoxicity in the human hepatoma derived cell line HepG2},
author = {Rudzok, S and Schlink, U and Herbarth, O and Bauer, M},
abstractNote = {The interaction of drugs and non-therapeutic xenobiotics constitutes a central role in human health risk assessment. Still, available data are rare. Two different models have been established to predict mixture toxicity from single dose data, namely, the concentration addition (CA) and independent action (IA) model. However, chemicals can also act synergistic or antagonistic or in dose level deviation, or in a dose ratio dependent deviation. In the present study we used the MIXTOX model (EU project ENV4-CT97-0507), which incorporates these algorithms, to assess effects of the binary mixtures in the human hepatoma cell line HepG2. These cells possess a liver-like enzyme pattern and a variety of xenobiotic-metabolizing enzymes (phases I and II). We tested binary mixtures of the metal nickel, the anti-inflammatory drug diclofenac, and the antibiotic agent irgasan and compared the experimental data to the mathematical models. Cell viability was determined by three different methods the MTT-, AlamarBlue (registered) and NRU assay. The compounds were tested separately and in combinations. We could show that the metal nickel is the dominant component in the mixture, affecting an antagonism at low-dose levels and a synergism at high-dose levels in combination with diclofenac or irgasan, when using the NRU and the AlamarBlue assay. The dose-response surface of irgasan and diclofenac indicated a concentration addition. The experimental data could be described by the algorithms with a regression of up to 90%, revealing the HepG2 cell line and the MIXTOX model as valuable tool for risk assessment of binary mixtures for cytotoxic endpoints. However the model failed to predict a specific mode of action, the CYP1A1 enzyme activity.},
doi = {10.1016/j.taap.2010.01.012},
url = {https://www.osti.gov/biblio/21344936}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 244,
place = {United States},
year = {Sat May 01 00:00:00 EDT 2010},
month = {Sat May 01 00:00:00 EDT 2010}
}