Crucial Role of Mechanisms and Modes of Toxic Action for Understanding Tissue Residue Toxicity and Internal Effect Concentrations of Organic Chemicals

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

Chemical Toxicity Correlations For Several Fish Species Based on the Abraham Solvation Parameter Model

Article on chemical toxicity correlations for several fish species based on the Abraham solvation parameter model

Chemical Toxicity Correlations for Several Fish Species Based on the Abraham Solvation Parameter Model

Article on chemical toxicity correlations for several fish species based on the Abraham solvation parameter model

(Q)SARs to Predict Environmental Toxicities: Current Status and Future Needs

The current state of the art of (Quantitative) Structure-Activity Relationships ((Q)SARs) to predict environmental toxicity is assessed along with recommendations to develop these models further. The acute toxicity of compounds acting by the non-polar narcotic mechanism of action can be well predicted, however other approaches, including read-across, may be required for compounds acting by specific mechanisms of action. The chronic toxicity of compounds to environmental species is more difficult to predict from (Q)SARs, with robust data sets and more mechanistic information required. In addition, the toxicity of mixtures is little addressed by (Q)SAR approaches. Developments in environmental toxicology including Adverse Outcome Pathways (AOPs) and omics responses should be utilised to develop better, more mechanistically relevant, (Q)SAR models

Investigation of Critical Body Residues and Modes of Toxic Action Based on Injection and Aquatic Exposure in Fish

The internal concentration represented by the critical body residue (CBR) is an ideal indicator to reflect the intrinsic toxicity of a chemical. Whilst some studies have been performed on CBR, the effect of exposure route on internal toxicity has not been investigated for fish. In this paper, acute toxicity data to fish comprising LC50 and LD50 values were used to investigate CBR. The results showed that exposure route can significantly affect the internal concentration. LD50 and CBR calculated from LC50 and BCF both vary independently of hydrophobicity as expressed by log Kow; conversely, LC50 is related to log Kow. A poor relationship was observed between LC50 and LD50, but the relationship can be improved significantly by introduction of log Kow because log CBR is positively related to log LD50. The parallel relationship of log CBR-log Kow and log LD50-log Kow indicates that LD50 does not reflect the actual internal concentration. The average LD50 is close to the average CBR for less inert and reactive compounds, but greater than the average CBR for baseline compounds. This difference is due to the lipid fraction being the major storage site for most of the baseline compounds. Investigation on the calculated and observed CBRs shows that calculated CBRs are close to observed CBRs for most of compounds. However, systemic deviations of calculated CBRs have been observed for some compounds. The reasons for these systemic deviations may be attributed to BCF, equilibrium time and experimental error of LC50. These factors are important and should be considered in the calculation of CBRs

An Overview of Chemical Mixtures Assessment and Modelling in the Aquatic Environment

The objective of this review is to assess what is known on the effect of mixtures in order todevelop ecological models that incorporate these effects in a coherent way, allowing for a correct description of the effects of exposure in aquatic ecosystems, and to developthresholds for contaminant concentrations that incorporate the knowledge of the effects of chemical mixtures and are not onlybased on a single compound.JRC.H.5-Rural, water and ecosystem resource