Benson J M, Barr E B, Krone J R
Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87185, USA.
Res Rep Health Eff Inst. 2001 May(102):73-94; discussion 95-109.
The purpose of these studies was to extend previous evaluation of methyl tert-butyl ether (MTBE)* tissue distribution, metabolism, and excretion in rats to include concentrations more relevant to human exposure (4 and 40 ppm) and to determine the effects of coinhalation of the volatile fraction of unleaded gasoline on the tissue distribution, metabolism, and excretion of MTBE. Groups of male F344 rats were exposed nose-only for 4 hours to 4, 40, or 400 ppm 14C-MTBE or to 20 or 200 ppm of the light fraction of unleaded gasoline (LFG) containing 4 or 40 ppm 14C-MTBE, respectively. To evaluate the effects of repeated inhalation of LFG on MTBE tissue distribution, metabolism, and excretion, rats were exposed for 4 hours on each of 7 consecutive days to 20 or 200 ppm LFG with MTBE (4 or 40 ppm) followed on the eighth day by a similar exposure to LFG containing 14C-MTBE. Subgroups of rats were evaluated for respiratory parameters, initial body burdens, rates and routes of excretion, and tissue distribution and elimination. The concentrations of MTBE and its chief metabolite, tert-butyl alcohol (TBA), were measured in blood and kidney immediately after exposure, and the major urinary metabolites-2-hydroxyisobutyric acid (IBA) and 2-methyl-1,2-propanediol (2MePD)-were measured in urine. Inhalation of MTBE alone or as a component of LFG had no concentration-dependent effect on respiratory minute volume. The initial body burdens of MTBE equivalents achieved after 4 hours of exposure to MTBE did not increase linearly with exposure concentration. MTBE equivalents rapidly distributed to all tissues examined, with the largest percentages distributed to liver. The observed initial body burden did not increase linearly between 4 and 400 ppm. At 400 ppm, elimination half-times of MTBE equivalents from liver increased and from lung, kidney, and testes decreased compared with the two smaller doses. Furthermore, at 400 ppm the elimination half-time for volatile organic compounds (VOCs) in breath was significantly shorter and the percentage of the initial body burden of MTBE equivalents eliminated as VOCs in breath increased significantly. These changes probably reflect a saturation of blood with MTBE at 400 ppm and strongly suggest that the uptake and fate of MTBE are notably different at exposure concentrations above and below 400 ppm. Single and repeated coexposure to 20 and 200 ppm LFG with MTBE had opposite effects on the total body burden of MTBE equivalents present at the end of exposures compared with those achieved after 4 and 40 ppm MTBE exposures: 20 ppm LFG increased and 200 ppm LFG significantly decreased the burdens of MTBE equivalents present. The effects of coexposure to LFG on blood levels of MTBE equivalents paralleled the effects on body burden. These differences in overall uptake of MTBE equivalents cannot be attributed to alterations of minute volume. The reason for the increase in overall uptake after 20-ppm LFG exposure is not clear. Decreased MTBE absorption (uptake) after single and repeated coexposure to 200 ppm LFG may be due to a decrease in solubility of MTBE in blood caused by inhalation of other hydrocarbons. Investigations on the blood/air partition coefficient of MTBE in the absence and presence of LFG would be needed to confirm this hypothesis. Single and repeated coexposure to either 20 or 200 ppm LFG significantly decreased the percentage of the initial body burden from MTBE equivalents in tissues, including liver, kidney, and testes, immediately and 72 hours after
这些研究的目的是将先前对甲基叔丁基醚（MTBE）*在大鼠体内的组织分布、代谢和排泄的评估扩展到包括与人类接触更相关的浓度（4和40 ppm），并确定吸入无铅汽油挥发性成分对MTBE组织分布、代谢和排泄的影响。将雄性F344大鼠分组，仅通过鼻吸入暴露4小时，分别暴露于4、40或400 ppm的14C-MTBE，或分别暴露于含4或40 ppm 14C-MTBE的20或200 ppm无铅汽油轻质馏分（LFG）。为了评估重复吸入LFG对MTBE组织分布、代谢和排泄的影响，大鼠连续7天每天暴露4小时于含MTBE（4或40 ppm）的20或200 ppm LFG，然后在第8天进行类似的含14C-MTBE的LFG暴露。对大鼠亚组进行呼吸参数、初始体内负荷、排泄速率和途径以及组织分布和消除的评估。暴露后立即测定血液和肾脏中MTBE及其主要代谢物叔丁醇（TBA）的浓度，并测定尿液中主要的尿代谢物——2-羟基异丁酸（IBA）和2-甲基-1,2-丙二醇（2MePD）。单独吸入MTBE或作为LFG的成分吸入对呼吸分钟量没有浓度依赖性影响。暴露于MTBE 4小时后达到的MTBE当量的初始体内负荷并不随暴露浓度呈线性增加。MTBE当量迅速分布到所有检测组织中，最大比例分布于肝脏。在4至400 ppm之间，观察到的初始体内负荷并非线性增加。在400 ppm时，与两个较低剂量相比，肝脏中MTBE当量的消除半衰期增加，而肺、肾脏和睾丸中的消除半衰期缩短。此外，在400 ppm时，呼出气体中挥发性有机化合物（VOCs）的消除半衰期显著缩短，呼出气体中作为VOCs消除的MTBE当量初始体内负荷百分比显著增加。这些变化可能反映了在400 ppm时血液被MTBE饱和，强烈表明在400 ppm以上和以下的暴露浓度下，MTBE的摄取和归宿明显不同。与4和40 ppm MTBE暴露后相比，单次和重复共同暴露于含MTBE的20和200 ppm LFG对暴露结束时存在的MTBE当量的总体体内负荷有相反影响：20 ppm LFG增加，200 ppm LFG显著降低存在的MTBE当量负荷。共同暴露于LFG对血液中MTBE当量水平的影响与对体内负荷的影响相似。MTBE当量总体摄取的这些差异不能归因于分钟量的改变。20 ppm LFG暴露后总体摄取增加的原因尚不清楚。单次和重复共同暴露于200 ppm LFG后MTBE吸收（摄取）减少可能是由于吸入其他碳氢化合物导致MTBE在血液中的溶解度降低。需要在不存在和存在LFG的情况下对MTBE的血/气分配系数进行研究以证实这一假设。单次和重复共同暴露于20或200 ppm LFG显著降低了暴露后立即和72小时后包括肝脏、肾脏和睾丸在内的组织中MTBE当量初始体内负荷的百分比。
