Gaylor D W, Slikker W
National Center for Toxicological Research, Jefferson, Arkansas 72079.
Neurotoxicology. 1990 Summer;11(2):211-8.
Regulation of neurotoxicants is generally based on setting allowable doses (exposures) by dividing a no observed adverse effect level (NOAEL) by uncertainty factors that hopefully account for interspecies and intraspecies differences for extrapolations of experimental results obtained in animals to humans. This procedure makes no use of estimates of risk as a function of dose or does it acknowledge any risk at the NOAEL. The purpose of this paper is to illustrate how bioassay data can be used to estimate the risk of neurotoxic effects as a function of dose. In the absence of direct measurements of neurotoxic effects, biomarkers associated with neurotoxic effects can be used as measures of toxicity. In the absence of a definition of an adverse effect, an abnormal level for a measure of toxicity can be established which occurs only in a small fraction of a population which is not exposed to the substance under investigation. Risk is defined as the proportion of a population whose levels of a measure of toxicity equal or exceeds the abnormal level of the measure under study. The procedure is illustrated using data for neurochemical, neurohistological, and behavioral effects of methylenedioxymethamphetamine (MDMA) administered to rats or monkeys. This procedure is more versatile than the NOAEL/uncertainty factor approach since it provides estimates of risk as a function of dose of a potential neurotoxic substance.
神经毒物的监管通常基于设定允许剂量（暴露量），即通过将未观察到有害作用水平（NOAEL）除以不确定系数来实现，这些系数有望考虑到种间和种内差异，以便将在动物身上获得的实验结果外推至人类。该程序未使用风险随剂量变化的估计值，也未承认在NOAEL水平存在任何风险。本文的目的是说明如何利用生物测定数据来估计神经毒性效应风险随剂量的变化情况。在无法直接测量神经毒性效应时，可将与神经毒性效应相关的生物标志物用作毒性指标。在缺乏有害作用定义的情况下，可确定一个毒性指标的异常水平，该水平仅在未接触所研究物质的一小部分人群中出现。风险定义为毒性指标水平等于或超过所研究指标异常水平的人群比例。本文使用给予大鼠或猴子的亚甲基二氧甲基苯丙胺（摇头丸，MDMA）的神经化学、神经组织学和行为效应数据来说明该程序。该程序比NOAEL/不确定系数方法更具通用性，因为它提供了潜在神经毒物风险随剂量变化的估计值。
