Moser V C, Boyes W K
ManTech Environmental Technology Inc., Research Triangle Park, North Carolina 27709.
Fundam Appl Toxicol. 1993 Oct;21(3):277-90. doi: 10.1006/faat.1993.1100.
Strategies for neurotoxicity testing often include initial screening tests, such as a functional observational battery (FOB) and motor activity assessment, followed by detailed characterization studies. In this study, a neurobehavioral screening battery (FOB and motor activity) was used to evaluate the effects of 3-day repeated exposure to 0, 100, 200, or 400 mg/kg/day IDPN. Adult Long-Evans rats (males and females) were tested before dosing and 1, 14, 28, 56, and 91 days after the third dose. IDPN initially produced generalized CNS depression, weakness, and hypothermia. Thereafter, marked hyperactivity, increased excitability, decreased reactivity to visual and auditory stimuli, neuromuscular weakness, equilibrium changes, and a "waltzing syndrome" (vertical and lateral head movements, circling, and retropulsion) emerged and persisted for 3 months. Males were more severely affected than females. Following neurobehavioral testing, the rats were examined for visual function using flash (three intensities) and pattern (three pattern sizes by three contrast levels)-elicited visual evoked potentials (VEPs). IDPN produced changes in pattern- and flash-elicited VEPs, thus verifying predictions made from the screening tests. However, the extent of the VEP changes produced by IDPN was insufficient to account for some of the deficits detected in the FOB, which are dependent on sensory, integrative, and motor functions. Thus, profound neurological effects of IDPN were detected using this screening battery and visual effects were confirmed using VEPs. These effects, following only three doses of IDPN, lasted for at least 3 months and thus may be permanent.
神经毒性测试策略通常包括初始筛选试验，如功能性观察组合（FOB）和运动活动评估，随后进行详细的特征研究。在本研究中，使用神经行为筛选组合（FOB和运动活动）来评估连续3天重复暴露于0、100、200或400mg/kg/天IDPN的影响。成年Long-Evans大鼠（雄性和雌性）在给药前以及第三次给药后的1、14、28、56和91天进行测试。IDPN最初会导致全身中枢神经系统抑制、虚弱和体温过低。此后，出现明显的多动、兴奋性增加、对视觉和听觉刺激的反应性降低、神经肌肉无力、平衡变化以及“华尔兹综合征”（头部垂直和侧向运动、转圈和后推），并持续3个月。雄性比雌性受影响更严重。在神经行为测试后，使用闪光（三种强度）和图形（三种图形大小乘以三种对比度水平）诱发的视觉诱发电位（VEP）对大鼠的视觉功能进行检查。IDPN导致图形和闪光诱发的VEP发生变化，从而验证了筛选试验得出的预测。然而，IDPN产生的VEP变化程度不足以解释FOB中检测到的一些缺陷，这些缺陷取决于感觉、整合和运动功能。因此，使用这种筛选组合检测到了IDPN的严重神经学效应，并使用VEP证实了视觉效应。仅三次剂量的IDPN后，这些效应持续了至少3个月，因此可能是永久性的。
