Mioduszewski R, Manthei J, Way R, Burnett D, Gaviola B, Muse W, Thomson S, Sommerville D, Crosier R
U.S. Army Edgewood Chemical Biological Center, AMSSB-RRT-TT (E3150), 5183 Blackhawk Road, Aberdeen Proving Ground, Maryland 21010-5424, USA.
Toxicol Sci. 2002 Apr;66(2):176-84. doi: 10.1093/toxsci/66.2.176.
Sarin (GB) vapor exposure is associated with both systemic and local toxic effects occurring primarily via the inhalation and ocular routes. The objective of these studies was to develop models for predicting dose-response effects of GB vapor concentrations as a function of exposure duration. Thus, the probability of GB vapor-induced lethality was estimated in rats exposed to various combinations of exposure concentration and duration. Groups of male and female Sprague-Dawley rats were exposed to one of a series of GB vapor concentrations for a single duration (5-360 min) in a whole-body dynamic chamber. The onset of clinical signs and changes in blood cholinesterase activity were measured with each exposure. Separate effective concentrations for lethality in 50% of the exposed population (LC50) and corresponding dose-response slopes were determined for each exposure duration by the Bliss probit method. Contrary to that predicted by Haber's rule, the interaction of LC50 x time (LCT50) values increased with exposure duration (i.e., the CT for 50% lethality in the exposed population and corresponding dose-response slope was not constant over time). A plot of log (LCT50) versus log (exposure time) showed significant curvature. Predictive models derived from multifactor probit analysis of results describing the relationship between exposure conditions and probability of lethality in the rat are discussed. Overall, female rats were more sensitive to GB vapor toxicity than male rats over the range of exposure concentration and duration studied. Miosis was the initial clinical sign noted after the start of GB vapor exposure. Although blood cholinesterase activity was significantly inhibited by GB vapor exposure, poor correlation between cholinesterase inhibition and exposure conditions or cholinesterase inhibition and severity of clinical signs was noted.
沙林（GB）蒸气暴露会导致全身和局部毒性效应，主要通过吸入和眼部途径发生。这些研究的目的是建立模型，以预测GB蒸气浓度的剂量反应效应与暴露持续时间的函数关系。因此，在暴露于不同浓度和持续时间组合的大鼠中估计了GB蒸气诱导致死率的概率。将雄性和雌性Sprague-Dawley大鼠分组，在全身动态舱中暴露于一系列GB蒸气浓度中的一种，持续单一时间（5 - 360分钟）。每次暴露时测量临床症状的出现和血液胆碱酯酶活性的变化。通过布利斯概率单位法为每个暴露持续时间确定50%暴露群体致死的单独有效浓度（LC50）和相应的剂量反应斜率。与哈伯法则预测的相反，LC50×时间（LCT50）值的相互作用随暴露持续时间增加（即，暴露群体中50%致死的CT和相应的剂量反应斜率随时间不是恒定的）。log（LCT50）与log（暴露时间）的关系图显示出明显的曲率。讨论了从多因素概率分析得出的预测模型，该分析描述了大鼠暴露条件与致死概率之间的关系。总体而言，在所研究的暴露浓度和持续时间范围内，雌性大鼠对GB蒸气毒性比雄性大鼠更敏感。瞳孔缩小是GB蒸气暴露开始后注意到的初始临床症状。虽然GB蒸气暴露显著抑制了血液胆碱酯酶活性，但注意到胆碱酯酶抑制与暴露条件之间或胆碱酯酶抑制与临床症状严重程度之间的相关性较差。
