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

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. Integr Environ Assess Manag 2011;7:28-49. ß 2010 SETAC

Uptake and toxicity of polycyclic aromatic hydrocarbons in terrestrial springtails—studying bioconcentration kinetics and linking toxicity to chemical activity

“…Chem. 32,2013compartments of the organism other than the lipids [27,28]. In F. candida, this other compartment is likely the cuticle, which is covered by a hydrophobic waxy layer to reduce evaporative water loss [29].…”

Reduced Life Expectancy Model for Effects of Long Term Exposure on Lethal Toxicity with Fish

“…The ILC 50 is preferred as it is the concentration of toxicant in the organism body at the target site [32–34]. Also it has the advantage that the kinetics effects of the uptake and bioconcentration processes have already been taken into account [3].…”

Measured and Modeled Toxicokinetics in Cultured Fish Cells and Application to In Vitro - In Vivo Toxicity Extrapolation

“…The quantification of the time course of internal concentrations in cells and whole organisms facilitates a better understanding of toxicity and may improve in vitro to in vivo toxicity extrapolation. Finally, following the tissue-residue approach, which proposes the use of tissue or total internal concentrations as the dose metric for characterizing a toxicant's potency [13]–[15], one can derive the hypothesis that, if the chemical acts by the same mode of action in cells and intact animal, the concentrations in an organism that cause toxicity must be similar to the concentrations that cause toxicity in a cell line. Support for this hypothesis was provided by research on surfactants, which elicited toxicity at fish cell residue levels corresponding closely to in vivo residue levels associated with surfactant toxicity [16].…”