Combining uptake and subcellular partitioning/toxicokinetics and toxicodynamics in modelling Cu2+ toxicity to zebra mussels, taking into account water chemistry

金属对生物体的毒性是由多种因素决定的。环境中的非生物配体可能影响可吸收的金属量。溶解的有机碳可以使金属络合，减少金属与生物体的相互作用。主要阳离子，如Na+和Ca2+，可能与有毒离子竞争结合到生物表面上的位点，影响有毒金属的吸收。生物积累是金属毒性的先决条件，但并不总是可靠的预测因素，这归因于生物体对金属的隔离和解毒能力。因此，亚细胞分裂是金属毒性的另一个决定因素。这些因素已分别以不同的方法加以考虑。环境化学对金属形态的影响以及金属在生物表面的积累已经被包括在生物配体模型中。在生物动力学模型中，金属生物积累被预测为流入和流出的平衡，并与临界身体残留方法中的毒性效应有关。在模拟金属毒性时已考虑到亚细胞分配，但现有方法固有的缺点。例如，基于金属硫蛋白样蛋白诱导的金属暴露评估没有考虑到其他解毒机制。金属的动态亚细胞分配不能通过金属敏感和生物解毒组分中的金属浓度之间的比率来有效地描述。当解毒机制没有被淹没时，亚细胞分配的进一步描述没有考虑金属在敏感组分中的积累，而亚细胞分配和生物反应之间的关系缺乏。斑马贻贝分布广泛、过滤效率高、金属积累能力强，在生物监测中得到了广泛的应用。斑马贻贝中金属亚细胞分配的描述有助于更准确地估计其他水生生物（如鱼类和甲壳类动物）中生物放大的金属。虽然Cu2+对水生生物的生物利用度和毒性已经进行了广泛的研究，但现有的方法仍然存在不确定性，可能与排除上述一些因素有关。本研究旨在建立一个考虑环境条件、生物积累以及斑马贻贝解毒和固铜能力的Cu2+毒性预测模型。提出的模型是摄取动力学和亚细胞分配动力学的结合，同时考虑了环境化学的影响。Cu2+的毒性将与Cu在以金属敏感部分为代表的代谢活跃器官中的积累有关，这将基于摄取，消除和解毒来模拟。

Metal toxicity to organisms is determined by various factors. Abiotic ligands in the environment might affect the amount of metals available for uptake. Dissolved organic carbon may complex metals, reducing the interactions of the metals with organisms. Major cations, e.g. Na+ and Ca2+, might compete with toxic ions for binding to sites on biological surfaces, influencing the uptake of toxic metals. Bioaccumulation is a prerequisite, but not always a reliable predictor of metal toxicity, attributed to the capacity of organisms to sequester and detoxify metals. Therefore, subcellular partitioning is another determinant of metal toxicity. These factors have separately been considered in different approaches. Effects of environmental chemistry on metal speciation as well as accumulation at biological surfaces have been included in the Biotic Ligand Model. Metal bioaccumulation has been predicted as a balance of influxes and effluxes in biodynamic models and related to toxic effects in the Critical Body Residue approach. Subcellular partitioning has been taken into account in modelling metal toxicity, but shortcomings are inherent in available approaches. For instance, the assessment of metal exposure based on the induction of metallothionein-like proteins does not account for other detoxification mechanisms. Dynamic subcellular partitioning of metals cannot effectively be described by a ratio between metal concentrations in the metal-sensitive and biologically detoxified fractions. Further delineation of subcellular partitioning does not consider metal accumulation in sensitive fractions when detoxification mechanisms are not overwhelmed whereas relationships between subcellular partitioning and biological responses are lacking.The zebra mussel Dreissena polymorpha has widely been used in biomonitoring programs, particularly because of its widespread distribution, high filtering efficiency, and high capacity to accumulate metals. The delineation of metal subcellular partitioning in the zebra mussel facilitates more accurate estimates of metals biomagnified in other aquatic organisms like fish and crustaceans. Although bioavailability and toxicity of Cu2+ to aquatic organisms have been extensively investigated, uncertainties are still remaining in available approaches, probably related to the exclusion of some of the factors mentioned above.The proposed research aims at developing a model for predicting Cu2+ toxicity to the zebra mussel, taking into account influence of environmental conditions, bioaccumulation, and the ability of the zebra mussel to detoxify and sequester Cu. The proposed model is a combination of uptake kinetics and subcellular partitioning dynamics while accounting for effects of environmental chemistry. The toxicity of Cu2+ will be related to the accumulation of Cu at the metabolically-active organs represented by the metal-sensitive fraction, which will be simulated based on uptake, elimination, and detoxification.