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首页> 外文期刊>Archives of Toxicology >Critical analysis of biomonitoring endpoints for measuring exposure to polymeric diphenyl-methane-4,4'-diisocyanate (MDI) in rats: a comparison of markers of exposure and markers of effect.
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Critical analysis of biomonitoring endpoints for measuring exposure to polymeric diphenyl-methane-4,4'-diisocyanate (MDI) in rats: a comparison of markers of exposure and markers of effect.

机译：关键分析的生物监测终点，以测量在大鼠中暴露于聚合的二苯基甲烷-4,4'-二异氰酸酯（MDI）的暴露：暴露标记和效果标记的比较。

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The object of this study was to compare the relative sensitivity of markers of exposure and effects in the lung of rats exposed to polymeric diphenyl-methane-4,4'-diisocyanate (pMDI) aerosol. Rats were repeatedly exposed to 12.9 mg pMDI/m(3) (6 h/day, 5 days/week for 14 days; exposure was from days 0--17 followed by a post-exposure period to day 35). Markers of exposure were determined in bronchoalveolar lavage (BAL), blood (haemoglobin, plasma proteins), and urine on days 1, 4, 11, 18, 21, 28 and 35. Markers of effects were determined at the same time points and focused on changes in BAL constituents. In BAL, a maximum increase of total protein occurred following the first exposure and levelled off subsequently whilst BAL cell-related endpoints increased in a time-dependent manner. The kinetics of formation and elimination of adducts differed appreciably from one dosimeter to another. Whilst haemoglobin adducts were integrated by the cumulative exposures, the incremental yield of adduct formation appeared to be dependent on pulmonary as well as yet unknown erythrocyte-related factors. Plasma protein adducts attained a plateau after 1 week of exposure. MDI-related metabolite levels in urine did not show any time-dependent changes during the entire exposure period and declined rapidly during the post-exposure period. Thus, the kinetics of the fractional loading and clearance of pulmonary and extrapulmonary dosimeters did not parallel each other, nor was there a clear correlation with the markers of effects. In summary, it is concluded that biomonitoring is a powerful tool for the comparative dosimetry of well-defined exposure regimens. However, especially for irritant agents demonstrating portal-of-entry effects, markers related to 'total body burden' may not necessarily predict the absence or presence of local responses occurring within the target organ, namely the lung. In all compartments, dosimeters related to higher oligomers of MDI demonstrated low bioavailability, i.e. their recovery was appreciably lower than expected.
机译：本研究的目的是比较暴露于聚合二苯基甲烷-4,4'-二异氰酸酯（pMDI）气溶胶的大鼠的暴露标志物和对大鼠肺部影响的相对敏感性。将大鼠反复暴露于12.9 mg pMDI / m（3）（6小时/天，5天/周，共14天;暴露时间为0--17天，然后是暴露后至35天）。在第1、4、11、18、21、28和35天测定支气管肺泡灌洗（BAL），血液（血红蛋白，血浆蛋白）和尿液中的暴露指标。在同一时间点确定影响指标并集中关于BAL成分的变化。在BAL中，总蛋白质最大增加发生在第一次暴露之后，随后趋于平稳，而BAL细胞相关的终点以时间依赖性方式增加。形成和消除加合物的动力学因一个剂量计而异。尽管血红蛋白加合物是通过累积暴露量进行积分的，但加合物形成的增量产量似乎取决于肺以及未知的红细胞相关因素。暴露1周后血浆蛋白加合物达到稳定水平。尿液中与MDI相关的代谢物水平在整个暴露期间没有任何时间依赖性变化，并且在暴露后迅速下降。因此，肺部和肺外剂量计的分数负荷和清除的动力学并不相互平行，也不与作用标志物有明显的相关性。总而言之，可以得出结论，生物监测是用于确定暴露方案的比较剂量测定的强大工具。但是，特别是对于表现出进入门作用的刺激剂，与“全身负担”相关的标记不一定能预测目标器官（即肺）中是否存在局部反应。在所有隔室中，与较高MDI低聚物有关的剂量计均显示出较低的生物利用度，即其回收率明显低于预期。

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