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

Authors

  • Beate I Escher,

    Corresponding author
    1. Department of Environmental Toxicology (Utox), Swiss Federal Institute of Aquatic Science and Technology (Eawag), Überlandstrasse 133, PO Box 611, 8600 Dübendorf, Switzerland
    2. The University of Queensland, National Research Centre for Environmental Toxicology (Entox), Brisbane, Queensland 4108, Australia
    • Department of Environmental Toxicology (Utox), Swiss Federal Institute of Aquatic Science and Technology (Eawag), Überlandstrasse 133, PO Box 611, 8600 Dübendorf, Switzerland.
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  • Roman Ashauer,

    1. Department of Environmental Toxicology (Utox), Swiss Federal Institute of Aquatic Science and Technology (Eawag), Überlandstrasse 133, PO Box 611, 8600 Dübendorf, Switzerland
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  • Scott Dyer,

    1. Procter & Gamble, Cincinnati, Ohio, USA
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  • Joop LM Hermens,

    1. Institute for Risk Assessment Sciences, Utrecht University, The Netherlands
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  • Jong-Hyeon Lee,

    1. NeoEnBiz, Byeoksan Disital Valley, Seoul, South Korea
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  • Heather A Leslie,

    1. Institute for Environmental Studies, Free University of Amsterdam, The Netherlands
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  • Philipp Mayer,

    1. National Environmental Research Institute, Aarhus University, Roskilde, Denmark
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  • James P Meador,

    1. NOAA Fisheries, Northwest Fisheries Science Center, Ecotoxicology and Environmental Fish Health Program, Seattle, Washington, USA
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  • Michael SJ Warne

    1. Centre for Environmental Contaminants Research, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Adelaide, South Australia, Australia
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Abstract

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 time-delayed 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. © 2010 SETAC

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