Given the persistence and toxic potencies of metal contaminants in ecosystems, animals, and human beings, they are considered to be hazardous global pollutants. While the lethality of metal toxicities (e.g., LC₅₀) can significantly vary, even within the same species, the underlying mechanisms are less well-understood. In this study, we developed a subcellular two-compartment toxicokinetic-toxicodynamic (TK-TD) model for zebrafish larvae when exposed to four metals (cadmium, lead, copper, and zinc) to reveal whether differences in metal toxicity (LC₅₀ values) were dominated by the TK or TD processes. Results showed that the subcellular TK and TD parameters of the four metals were significantly different, and the bioconcentration factor (BCF) value of copper was higher than those of the other metals. We also found that the TD parameter internal threshold concentration (C_IT) was significantly positively correlated to the LC₅₀ values (R² = 0.7), suggesting a dominant role of TD processes in metal toxicity. Furthermore, the combined parameter C_IT/BCF for a metal-sensitive fraction (BCF_MSF), which linked exposure to effects through the TK-TD approach, explained up to 89% of the variation in toxicity to the four metals. The present study suggests that the observed variation in toxicity of these four metals was mainly determined by TD processes but that TK processes should not be ignored, especially for copper.

中文翻译：

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毒代动力学和毒理学参数在解释斑马鱼幼虫对四种金属的敏感性中的作用

鉴于金属污染物在生态系统、动物和人类中的持久性和毒性，它们被认为是危险的全球污染物。虽然金属毒性（例如，LC ₅₀）的致死率可能有很大差异，即使在同一物种内，其潜在机制也不太清楚。在这项研究中，我们为斑马鱼幼虫开发了一种亚细胞两室毒代动力学 - 毒代动力学 (TK-TD) 模型，当暴露于四种金属（镉、铅、铜和锌）时，以揭示金属毒性 (LC ₅₀值）由 TK 或 TD 过程主导。结果表明，四种金属的亚细胞TK和TD参数存在显着差异，铜的生物富集因子（BCF）值高于其他金属。我们还发现 TD 参数内部阈值浓度 ( C _IT ) 与 LC ₅₀值显着正相关( R ² = 0.7)，表明 TD 过程在金属毒性中起主导作用。此外，金属敏感部分的组合参数C _IT /BCF (BCF _MSF)，通过 TK-TD 方法将暴露与影响联系起来，解释了四种金属毒性变化的 89%。本研究表明，观察到的这四种金属的毒性变化主要由 TD 过程决定，但不应忽视 TK 过程，尤其是铜。