The crucial role of mechanisms and modes of toxic action for tissue residues of organic chemicals

Escher, Beate I., Ashauer, Roman, Dyer, Scott, Hermens, Joop L. M., Lee, Jong-Hyeon, Leslie, Heather A., Mayer, Philipp, Meador, James P. and Warne, Michael S. J. (2011) The crucial role of mechanisms and modes of toxic action for tissue residues of organic chemicals. Integrated Environmental Assessment and Management, 7 1: 28-49. doi:10.1002/ieam.100

Author Escher, Beate I.
Ashauer, Roman
Dyer, Scott
Hermens, Joop L. M.
Lee, Jong-Hyeon
Leslie, Heather A.
Mayer, Philipp
Meador, James P.
Warne, Michael S. J.
Title The crucial role of mechanisms and modes of toxic action for tissue residues of organic chemicals
Journal name Integrated Environmental Assessment and Management   Check publisher's open access policy
ISSN 1551-3793
Publication date 2011-01
Year available 2010
Sub-type Article (original research)
DOI 10.1002/ieam.100
Volume 7
Issue 1
Start page 28
End page 49
Total pages 22
Place of publication Pensacola, FL, United States
Publisher Society of Environmental Toxicology and Chemistry
Collection year 2012
Language eng
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 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.
Keyword Tissue residue approach
Mechanisms/modes of toxic action
Internal concentration
Body residue
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article first published online: 3 JUN 2010

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
National Research Centre for Environmental Toxicology Publications
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Created: Thu, 22 Mar 2012, 10:20:39 EST by Robyne Anderson on behalf of National Res Centre For Environmental Toxicology