Tsai Jeng-Wei, Liao Chung-Min
Department of Bioenvironmental Systems Engineering, Ecotoxicological Modeling Center, National Taiwan University, Taipei, Taiwan 10617, Republic of China.
Environ Toxicol. 2006 Feb;21(1):8-21. doi: 10.1002/tox.20150.
We proposed an approach to relate metal toxicity to the concentrations of arsenic (As) in specific target organs of tilapia Oreochromis mossambicus. The relationships among As exposure, uptake, accumulation, and toxicity of tilapia were investigated using kinetic and dynamic modeling. The biouptake rate of waterborne As through the gills of fish was dependent on exposure concentrations, in that the relationship was well described by incorporating Michaelis-Menten type uptake kinetics. The fitted bioaffinity parameter and limiting uptake flux were 3.07 +/- 2.21 microg/mL(-1) (mean +/- SD) and 2.17 +/- 0.38 microg/mL(-1)/d(-1), respectively, suggesting that a low As binding affinity of tilapia gills, yet a relatively high binding capacity was obtained. The toxicity of As was analyzed by determining the lethal exposure concentration associated with a mortality of 50% (LC50) at different integration times. Our results demonstrate that 96-h and incipient LC50s for tilapia are 28.68 (95% CI: 15.98-47.38) and 25.55 microg/mL(-1), respectively. The organ-specific internal residue associated with 50% mortality was estimated by combining the model-predicted toxicokinetic parameters and the area-under-curve (AUC)-based time-integrated concentration toxicity model. A physiologically based toxicokinetic model was constructed to elucidate the principle mechanisms that account for the observed data and to predict the kinetics of As in tilapia under different water exposure scenarios. We employed the Hill equation model to predict the organ-specific dose-response relationships. We used the liver as a surrogate of target sites to assess the As toxicity to tilapia because of its higher sensitivity to As toxic effects. The predicted mortalities never reach 50% when the tilapia were exposed to waterborne As <2 microg/mL(-1). The predicted mortality is, however, slightly higher than the observed values before the 10th day in that the profile reached the 70% maximum mortality, which is comparable to the observed data when the tilapia were exposed to 4 microg/mL(-1). Our results show that a dose-based toxicokinetic and toxicodynamic modeling approach successfully links metal exposure to bioavailability, bioaccumulation, and toxicity, under variable exposure scenarios.
我们提出了一种方法，将金属毒性与罗非鱼（Oreochromis mossambicus）特定靶器官中的砷（As）浓度联系起来。利用动力学和动态模型研究了罗非鱼对砷的暴露、摄取、积累和毒性之间的关系。通过鳃摄取水体中砷的生物摄取率取决于暴露浓度，通过纳入米氏类型摄取动力学能很好地描述这种关系。拟合得到的生物亲和参数和极限摄取通量分别为3.07±2.21微克/毫升⁻¹（平均值±标准差）和2.17±0.38微克/毫升⁻¹/天⁻¹，这表明罗非鱼鳃对砷的结合亲和力较低，但具有相对较高的结合能力。通过确定在不同积分时间下与50%死亡率相关的致死暴露浓度来分析砷的毒性。我们的结果表明，罗非鱼的96小时和初始半数致死浓度（LC50）分别为28.68（95%置信区间：15.98 - 47.38）和25.55微克/毫升⁻¹。通过结合模型预测的毒代动力学参数和基于曲线下面积（AUC）的时间积分浓度毒性模型，估算了与50%死亡率相关的器官特异性内部残留量。构建了一个基于生理学的毒代动力学模型，以阐明解释观测数据的主要机制，并预测在不同水体暴露情景下罗非鱼体内砷的动力学。我们采用希尔方程模型来预测器官特异性剂量 - 反应关系。由于肝脏对砷毒性作用的敏感性较高，我们将其作为靶位点的替代物来评估砷对罗非鱼的毒性。当罗非鱼暴露于水体中砷浓度<2微克/毫升⁻¹时，预测死亡率从未达到50%。然而，在第10天之前预测死亡率略高于观测值，因为该曲线达到了70%的最大死亡率峰值，这与罗非鱼暴露于4微克/毫升⁻¹时的观测数据相当。我们的结果表明，基于剂量的毒代动力学和毒效动力学建模方法在不同暴露情景下成功地将金属暴露与生物有效性、生物积累和毒性联系起来。
