From in vitro hepatic metabolic studies towards human health risk assessment: Two case studies of diuron and carbosulfan

Risk assessment of environmental pollutants is an absolutely essential tool in the overall process of protecting public health. Risk assessment needs reliable scientific information and one source of information is the characterization of metabolic fate and toxicokinetics of environmental pollutants. The aim of in vitro characterization is to produce relevant information on metabolism and interactions to anticipate and ultimately predict what happens in vivo in humans. Because human data is most appropriate to improve human risk assessment, the best option is to rely upon human-derived in vitro models and obtain quantitative toxicokinetics data from in vitro systems for the comparison between species or individuals. In short, based on our studies of pesticide metabolism and interactions, we have used in vitro metabolism data in human and animal hepatic in vitro models and clearance testing data to calculate chemical-specific adjustment factors, instead of fixed uncertainty factors, to be employed as an alternative and more realistic model for human health risk assessment of pesticides and other environmental pollutants.     

镉砷在线蚓中的毒物-毒效动力学过程及定量模拟

为探讨土壤污染物重金属镉(Cd)和类金属砷(As)在陆生生物体内的动态累积及毒性效应过程的差异性和规律性,以线蚓(Enchytraeus crypticus)为研究对象,以Cd和As为目标金属,采用室内试验和模型拟合手段定量描述两者的毒物动力学和毒效动力学过程。结果表明:线蚓体内Cd、As的累积量随着暴露浓度及时间的增加而不断上升并逐渐趋于平衡,Cd、As在暴露期间最大的累积量分别为459.6、32.91 mg·kg~(-1);拟合得到的Cd总吸收速率常数K_u(1.761 mg·kg~(-1)·d~(-1))显著大于As(0.102 mg·kg~(-1)·d~(-1)),Cd总排出速率常数K_e(0.015 d~(-1))小于As(0.287 d~(-1));Cd、As对线蚓的毒性作用随着暴露时间的增加而增强,基于体外暴露浓度计算的半数致死浓度(LC50)随时间的增加而降低,并在暴露约7 d后达到平衡,其最终半数致死浓度(LC_(50∞))分别为0.314、1.253 mmol·L~(-1);进一步基于体内浓度计算其体内半数致死浓度(LC_(50inter)),发现As的LC_(50inter)值基本不受暴露时间的影响,而Cd的LC_(50inter)值随着暴露时间的增加而上升,基于不同暴露时间下体内浓度和毒性数据整体拟合得到总的LC_(50inter)Cd(468.8 mg·kg~(-1)·d~(-1))显著大于LC_(50inter)As(26.65 mg·kg~(-1)·d~(-1))。整体上,Cd和As在线蚓体内的累积和毒性均受到时间的影响;Cd的累积能力显著强于As,基于体外暴露浓度时毒性强度Cd大于As,而体内累积的As则呈现更强的毒性效应;As的体内浓度和其动态毒性效应有很好的相关性(R~2=0.75),而Cd的体内浓度不能很好地预测其毒性(R~2=0.57),说明其体内浓度不能完全代表产生毒性的生物有效浓度。