Hattis D, Shapiro K
Center for Technology, Policy and Industrial Development, Massachusetts Institute of Technology, Cambridge 02139.
Neurotoxicology. 1990 Summer;11(2):219-36.
This case study illustrates how a very simple dynamic modeling approach can extract information of interest for both toxic mechanism research and risk assessment from a series of dose/time/response data. The technique is applicable for effects that are thought to result from damage processes that are reversible, at least at low doses and times of exposure. The data sets analyzed provided information on some specific manifestation of acrylamide neurotoxicity produced by different combinations of acrylamide dose rate and duration of exposure. Assuming that responses occur when a specific amount of axonal damage accumulates, and that the repair of damage depends directly on the amount of damage present, the dose-related change in the time required to produce a specific type of effect can be used to estimate: (1) The rate of repair of the incipient damage - and differences in repair rates for different individuals within species, and among different species, and (2) The dose of acrylamide that would be just barely able to produce each effect in each species, if the experiment were conducted over the animal's entire lifespan. Information of the first type may also be helpful in neurotoxicology research. Specific biomarkers for the main process causing a particular response should be repaired in different locations and in different species with the dynamics that are consistent with the repair rates calculated from the dose vs. time-of-effect data.
本案例研究说明了一种非常简单的动态建模方法如何从一系列剂量/时间/反应数据中提取对毒性机制研究和风险评估都有意义的信息。该技术适用于那些被认为是由至少在低剂量和暴露时间下可逆的损伤过程所导致的效应。所分析的数据集提供了关于丙烯酰胺剂量率和暴露持续时间不同组合所产生的丙烯酰胺神经毒性某些特定表现的信息。假设当特定量的轴突损伤积累时会出现反应，并且损伤的修复直接取决于现存损伤的量，那么产生特定类型效应所需时间的剂量相关变化可用于估计：（1）初始损伤的修复速率——以及物种内不同个体之间和不同物种之间修复速率的差异，（2）如果在动物的整个寿命期内进行实验，每种物种中刚好能够产生每种效应的丙烯酰胺剂量。第一类信息在神经毒理学研究中可能也有帮助。导致特定反应的主要过程的特定生物标志物应以与从剂量与效应时间数据计算出的修复速率一致的动态变化在不同位置和不同物种中得到修复。
