Evaluation of Bioanalytical Assays for Toxicity Assessment and Mode of Toxic Action Classification of Reactive Chemicals

Harder, Angela; Escher, Beate I.; Landini, Paolo; Tobler, Nicole B.; Schwarzenbach, René P.

doi:10.1021/es034197h

Cited by 37 publications

(59 citation statements)

References 41 publications

(42 reference statements)

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“…Two representative examples, ACN in the GSH strains and EOX in the DNA strains, are depicted in Figure 1. Generally, our earlier results (25) were quite well reproducible and robust on the EC50 level. However, slight changes in the EC50 values and particularly the slope caused a considerable difference in the mixture predictions.…”

Section: Resultssupporting

confidence: 66%

Mixture Toxicity of Reactive Chemicals by Using Two Bacterial Growth Assays as Indicators of Protein and DNA Damage

Richter

Escher

2005

Environ. Sci. Technol.

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The mixture toxicity of reactive chemicals was investigated with a set of bioanalytical tests that quantify not only the toxic effects but also allow the identification of the preferred target of reactive chemicals in bacterial cells. Softer electrophiles such as acrylates react preferentially with thiol groups in proteins and peptides, and harder electrophiles such as epoxides preferentially attack DNA. In addition, some compounds, e.g., benzyl chloride, have no preference for a biological target and damage both DNA and proteins. A thiophenol was used as a model compound representing nucleophiles. We explored if the paradigms of mixture toxicity also hold true for reactive chemicals. Compounds with the same targets and the same modes of action should act concentration additive in mixtures, and compounds with different modes of action should act according to the concept of independent action. In addition, we investigated the potential for interaction of compounds of mixtures of electrophiles or electrophiles plus nucleophiles, which might lead to synergistic or antagonistic effects. The toxicity of mixtures of electrophiles with a single preferred target was consistent with the prediction for concentration addition. Unfortunately, the predictions for independent action did not differ much from those for concentration addition; therefore it was not possible to differentiate between these two models. Mixtures of two groups with different preferred target sites clearly showed concentration addition. In contrast, mixtures of compounds with multiple targets, i.e., compounds that show nonspecific reactivity toward any biological nucleophile, exhibited effects that lay distinctly between the predictions for concentration addition and independent action. We observed neither synergism (higher toxicity than predicted by concentration addition) nor antagonism (lower toxicity than predicted by independent action) for mixtures of electrophiles. Binary combinations of different electrophiles with the nucleophile 4-chlorothiophenol yielded smaller effects than those expected from the prediction for independent action. The degree of antagonism was correlated with the reaction rate constant of the electrophile with the thiol group of glutathione, which indicates that the interaction between the mixture components occur in the toxicokinetic phase and is purely a result of chemical reactivity between the mixture components. Overall, we conclude that the concepts of mixture toxicity apply not only for baseline toxicity and receptor-mediated mechanisms, as has been shown in a large number of studies, but also for reactive mechanisms of toxicity, provided that one has checked beforehand that no chemical reactions occur between the mixture components.

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Section: Resultssupporting

confidence: 66%

Mixture Toxicity of Reactive Chemicals by Using Two Bacterial Growth Assays as Indicators of Protein and DNA Damage

Richter

Escher

2005

Environ. Sci. Technol.

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“…If a chemical binds irreversibly with some cell constituents, e.g., proteins, its elimination might be hindered. For example, ethylacrylate is a soft electrophile that can react with cystein groups in proteins, which in turn would prevent elimination of the metabolite [59]. Such a reaction could explain the mismatch between the small simulated and large observed internal concentrations during the elimination phase of ethylacrylate ( Fig.…”

Section: Fits Of the Toxicokinetic Modelmentioning

confidence: 99%

Bioaccumulation kinetics of organic xenobiotic pollutants in the freshwater invertebrateGammarus pulexmodeled with prediction intervals

Ashauer

Caravatti

Hintermeister

et al. 2010

Enviro Toxic and Chemistry

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119

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Uptake and elimination rate constants, bioaccumulation factors, and elimination times in the freshwater arthropod Gammarus pulex were measured for 14 organic micropollutants covering a wide range of hydrophobicity (imidacloprid, aldicarb, ethylacrylate, 4,6-dinitro-o-cresol, carbofuran, malathion, 4-nitrobenzyl-chloride, 2,4-dichloroaniline, Sea-Nine, 2,4-dichlorophenol, diazinon, 2,4,5-trichlorophenol, 1,2,3-trichlorobenzene, and hexachlorobenzene; all 14C-labeled). The toxicokinetic parameters were determined by least-square fitting of a one-compartment first-order toxicokinetic model, followed by Markov Chain Monte Carlo parameter estimation. The parameter estimation methods used here account for decreasing aqueous concentrations during the exposure phase or increasing aqueous concentrations during the elimination phase of bioaccumulation experiments. It is not necessary to keep exposure concentrations constant or zero during uptake and elimination, respectively. Neither is it required to achieve steady state during the exposure phase; hence, tests can be shorter. Prediction intervals, which take the between-parameter correlation into account, were calculated for bioaccumulation factors and simulations of internal concentrations under variable exposure. The lipid content of Gammarus pulex was 1.3% of wet weight, consisting of 25% phospholipids and 75% triglycerides. Size-dependent bioaccumulation was observed for eight compounds, although the magnitudes of the relationships were too small to be of practical relevance. Elimination times ranged from 0.45 to 20 d, and bioaccumulation factors ranged from 1.7 to 4,449 L/kg. The identified compounds with unexpectedly long elimination times should be given priority in future studies investigating the biotransformation of these compounds.

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“…The model nucleophiles were deoxyguanosine and glutathione, which served as surrogates for DNA bases and proteins and/or peptides. The reaction rates allowed an estimate of the toxic potency, but also a classification according to the selectivity of the electrophilic reaction (Harder, Escher, Landini, et al 2003; Harder, Escher, Schwarzenbach 2003). Whereas soft electrophiles like acrylates are more reactive with proteins and peptides, hard electrophiles like styrene oxide react with the DNA bases.…”

Section: Classification Of Mechanisms and Modes Of Toxic Actionmentioning

confidence: 99%

Crucial role of mechanisms and modes of toxic action for understanding tissue residue toxicity and internal effect concentrations of organic chemicals

Escher

Ashauer

Dyer

et al. 2010

Integr Envir Assess & Manag

133

109

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This article reviews the mechanistic basis of the tissue residue approach for toxicity assessment (TRA). The tissue residue approach implies that whole-body or organ concentrations (residues) are a better dose metric for describing toxicity to aquatic organisms than is the aqueous concentration typically used in the external medium. Although the benefit of internal concentrations as dose metrics in ecotoxicology has long been recognized, the application of the tissue residue approach remains limited. The main factor responsible for this is the difficulty of measuring internal concentrations. We propose that environmental toxicology can advance if mechanistic considerations are implemented and toxicokinetics and toxicodynamics are explicitly addressed. The variability in ecotoxicological outcomes and species sensitivity is due in part to differences in toxicokinetics, which consist of several processes, including absorption, distribution, metabolism, and excretion (ADME), that influence internal concentrations. Using internal concentrations or tissue residues as the dose metric substantially reduces the variability in toxicity metrics among species and individuals exposed under varying conditions. Total internal concentrations are useful as dose metrics only if they represent a surrogate of the biologically effective dose, the concentration or dose at the target site. If there is no direct proportionality, we advise the implementation of comprehensive toxicokinetic models that include deriving the target dose. Depending on the mechanism of toxicity, the concentration at the target site may or may not be a sufficient descriptor of toxicity. The steady-state concentration of a baseline toxicant associated with the biological membrane is a good descriptor of the toxicodynamics of baseline toxicity. When assessing specific-acting and reactive mechanisms, additional parameters (e.g., reaction rate with the target site and regeneration of the target site) are needed for characterization. For specifically acting compounds, intrinsic potency depends on 1) affinity for, and 2) type of interaction with, a receptor or a target enzyme. These 2 parameters determine the selectivity for the toxic mechanism and the sensitivity, respectively. Implementation of mechanistic information in toxicokinetic-toxicodynamic (TK-TD) models may help explain timedelayed effects, toxicity after pulsed or fluctuating exposure, carryover toxicity after sequential pulses, and mixture toxicity. We believe that this mechanistic understanding of tissue residue toxicity will lead to improved environmental risk assessment. Integr Environ Assess Manag 2011;7:28-49. ß 2010 SETAC

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Evaluation of Bioanalytical Assays for Toxicity Assessment and Mode of Toxic Action Classification of Reactive Chemicals

Cited by 37 publications

References 41 publications

Mixture Toxicity of Reactive Chemicals by Using Two Bacterial Growth Assays as Indicators of Protein and DNA Damage

Mixture Toxicity of Reactive Chemicals by Using Two Bacterial Growth Assays as Indicators of Protein and DNA Damage

Bioaccumulation kinetics of organic xenobiotic pollutants in the freshwater invertebrateGammarus pulexmodeled with prediction intervals

Crucial role of mechanisms and modes of toxic action for understanding tissue residue toxicity and internal effect concentrations of organic chemicals

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