Raffaele K C, Rees C
USEPA, Health and Environmental Review Division, Washington, DC 20460.
Neurotoxicology. 1990 Summer;11(2):237-56.
Dose/response assessment for non-carcinogenic endpoints typically uses the Acceptable Daily Intake (ADI) or Reference Dose (RfD) approach, in which a dose believed to cause no toxic effect is divided by a number of safety or uncertainty factors (e.g., to control for variability and cross-species extrapolation), in order to estimate a dose presumed to have no adverse effects in humans. With the establishment of neurotoxicology testing guidelines, routine use of uncertainty factors to undertake neurotoxicity dose/response assessment procedures is likely. This approach to dose/response assessment has not yet been widely applied to neurotoxicity data. The purpose of this study was to assess the use of uncertainty factors and the assumptions underlying the use of the uncertainty factor method in assessing risk for several known human neurotoxicants. Because of the availability of a large neurotoxicity data base which included human exposure data, parathion, diisopropylfluorophosphate, physostigmine and acrylamide were chosen for this analysis. Literature searches were conducted for both human and animal data. The resulting data were assigned to one of five end point categories: Neurochemistry/neuropathology, physiology/consummatory behavior, sensory/motor, electrophysiology, and learning/memory behavior. No-observed-adverse-effect levels (NOAELs) and/or lowest-observed-adverse-effect levels (LOAELs) were determined when possible for each end point and for several species. Reference doses (RfDs) were calculated and compared across species. A number of issues and critical assumptions were identified.
非致癌终点的剂量/反应评估通常采用每日可接受摄入量（ADI）或参考剂量（RfD）方法，即把认为不会产生毒性作用的剂量除以若干安全或不确定系数（例如，用于控制变异性和跨物种外推），以估算假定对人类无不良影响的剂量。随着神经毒理学测试指南的制定，很可能会常规使用不确定系数来进行神经毒性剂量/反应评估程序。这种剂量/反应评估方法尚未广泛应用于神经毒性数据。本研究的目的是评估不确定系数的使用情况以及在评估几种已知人类神经毒物风险时使用不确定系数方法所依据的假设。由于有一个包含人类暴露数据的大型神经毒性数据库可供使用，因此选择对硫磷、二异丙基氟磷酸酯、毒扁豆碱和丙烯酰胺进行此项分析。对人类和动物数据都进行了文献检索。所得数据被归入五个终点类别之一：神经化学/神经病理学、生理学/摄食行为、感觉/运动、电生理学以及学习/记忆行为。尽可能为每个终点和几个物种确定未观察到不良作用水平（NOAELs）和/或最低观察到不良作用水平（LOAELs）。计算参考剂量（RfDs）并在不同物种间进行比较。确定了一些问题和关键假设。
