A general concept in risk assessment isthat a threshold of exposure exists abovewhich adverse effects are initiated. Toxicityis related to the target-site concentrationor the biologically active... Show moreA general concept in risk assessment isthat a threshold of exposure exists abovewhich adverse effects are initiated. Toxicityis related to the target-site concentrationor the biologically active dose. Although itis often a huge challenge to measure thespecific dose metric of metal toxicity, sig-nificant progress has been obtained toapproach closer to the target-site concen-tration. Such developments are reviewedin the present study. In addition, a generalframework to simulate the subcellularmetal partitioning, which is supposed toaccount for the internal metal sequestra-tion, is developed and applied to variousmetals. The framework allows for delineat-ing mechanisms of internal metal sequestration. Moreover, the specificity in these mechanisms,which varies among metals, species, and exposure conditions, might explain the complicated rela-tionship between the internal concentration and metal toxicity. Attention should be paid to thedata requirements as the high number of unknown parameters might be accompanied by poten-tial uncertainties. In addition, future efforts should focus on linking the concentration of metals insensitive fractions and toxicological effects. Show less
Le, T.T.Y.; Milen, N.; Grabner, D.; Hendriks, A.J.; Peijnenburg, W.J.G.M.; Sures, B. 2022
A toxicokinetic-toxicodynamic model was constructed to delineate the exposure-response causality. The model could be used: to predict metal accumulation considering the influence of water chemistry... Show moreA toxicokinetic-toxicodynamic model was constructed to delineate the exposure-response causality. The model could be used: to predict metal accumulation considering the influence of water chemistry and biotic ligand characteristics; to simulate the dynamics of subcellular partitioning considering metabolism, detoxification, and elimination; and to predict chronic toxicity as represented by biomarker responses from the concentration of metals in the fraction of potentially toxic metal. The model was calibrated with data generated from an experiment in which the Zebra mussel Dreissena polymorpha was exposed to Cu at nominal concentrations of 25 and 50 mu g/L and with varied Na+ concentrations in water up to 4.0 mmol/L for 24 days. Data used in the calibration included physicochemical conditions of the exposure environment, Cu concentrations in subcellular fractions, and oxidative stress-induced responses, i.e. glutathione-S-transferase activity and lipid peroxidation. The model explained the dynamics of subcellular Cu partitioning and the effect mechanism reasonably well. With a low affinity constant for Na+ binding to Cu2+ uptake sites, Na+ had limited influence on Cu2+ uptake at low Na+ concentrations in water. Copper was taken up into the metabolically available pool (MAP) at a largely higher rate than into the cellular debris. Similar Cu concentrations were found in these two fractions at low exposure levels, which could be attributed to sequestration pathways (metabolism, detoxification, and elimination) in the MAP. However, such sequestration was inefficient as shown by similar Cu concentrations in detoxified fractions with increasing exposure level accompanied by the increasing Cu concentration in the MAP. Show less
Le, T.T.Y.; Grabner, D.; Nachev, M.; Garcia, M.R.; Balsa-Canto, E.; Peijnenburg, W.J.G.M.; ... ; Sures, B. 2021
A toxicokinetic-toxicodynamic model based on subcellular metal partitioning is presented for simulating chronic toxicity of copper (Cu) from the estimated concentration in the fraction of... Show moreA toxicokinetic-toxicodynamic model based on subcellular metal partitioning is presented for simulating chronic toxicity of copper (Cu) from the estimated concentration in the fraction of potentially toxic metal (PTM). As such, the model allows for considering the significance of different pathways of metal sequestration in predicting metal toxicity. In the metabolically available pool (MAP), excess metals above the metabolic requirements and the detoxification and elimination capacity form the PTM fraction. The reversibly and irreversibly detoxified fractions were distinguished in the biologically detoxified compartment, while responses of organisms were related to Cu accumulation in the PTM fraction. The model was calibrated using the data on Cu concentrations in subcellular fractions and physiological responses measured by the glutathione S-transferase activity and the lipid peroxidation level during 24-day exposure of the Zebra mussel to Cu at concentrations of 25 and 50 mu g/L and varying Na+ concentrations up to 4.0 mmol/L. The model was capable of explaining dynamics in the subcellular Cu partitioning, e.g. the trade-off between elimination and detoxification as well as the dependence of net accumulation, elimination, detoxification, and metabolism on the exposure level. Increases in the net accumulation rate in the MAP contributed to increased concentrations of Cu in this fraction. Moreover, these results are indicative of ineffective detoxification at high exposure levels and spill-over effects of detoxification. Show less
Le, T.T.Y.; Nachev, M.; Grabner, D.; Garcia, M.R.; Balsa-Canto, E.; Hendriks, A.J.; ... ; Sures, B. 2021
Chronic toxicity of copper (Cu) at sublethal levels is associated with ionoregulatory disturbance and oxidative stress. These factors were considered in a toxicokinetic-toxicodynamic model in the... Show moreChronic toxicity of copper (Cu) at sublethal levels is associated with ionoregulatory disturbance and oxidative stress. These factors were considered in a toxicokinetic-toxicodynamic model in the present study. The ionoregulatory disturbance was evaluated by the activity of the Na+/K+-ATPase enzyme (NKA), while oxidative stress was presented by lipid peroxidation (LPO) and glutathione-S-transferase (GST) activity. NKA activity was related to the binding of Cu2+ and Na+ to NKA. LPO and GST activity were linked with the simulated concentration of unbound Cu. The model was calibrated using previously reported data and empirical data generated when zebra mussels were exposed to Cu. The model clearly demonstrated that Cu might inhibit NKA activity by reducing the number of functional pump sites and the limited Cu-bound NKA turnover rate. An ordinary differential equation was used to describe the relationship between the simulated concentration of unbound Cu and LPO/GST activity. Although this method could not explain the fluctuations in these biomarkers during the experiment, the measurements were within the confidence interval of estimations. Model simulation consistently shows nonsignificant differences in LPO and GST activity at two exposure levels, similar to the empirical observation. Show less
Le, T.T.Y.; Grabner, D.; Nachev, M.; Peijnenburg, W.J.G.M.; Hendriks, A.J.; Sures, B. 2021
