Hutcheon D E, Arnold J D, ten Hove W, Boyle J
Department of Pharmacology and Toxicology, UMDNJ, New Jersey Medical School, Newark 07103, USA.
J Toxicol Environ Health. 1996 Apr 5;47(5):453-64. doi: 10.1080/009841096161609.
Studies of the toxicology of methyl tertiary butyl ether (MTBE) were reviewed as a possible information base for evaluating the health effects of evaporative emissions from reformulated gasoline (RFG). The major metabolites of the oxidative demethylation of MTBE in vivo were methanol and tertiary butyl alcohol (TBA), whereas formaldehyde and TBA were the principal products of hepatic microsomal oxidation by cytochrome P-450. Pharmacokinetic studies in rats treated with intragastric MTBE in corn oil gave an initial disposition T1/2 for MTBE of 0.32 h. The decline in the serum drug versus time curve for MTBE in rats was accompanied by a progressive increase in serum methanol concentrations to levels more than 50-200 times those of the parent compound. Repeated exposure of MTBE vapor by inhalation in rats resulted in dose-dependent increases in MTBE in the blood, brain, and adipose tissue compartments. Blood concentrations of TBA were also dose dependent and provided an estimate of the total amount of MTBE distributed to peripheral drug metabolizing compartments. Perirenal fat/blood MTBE concentration ratios ranged from 9.7 to 11.6 after 15 wk of intermittent exposure. During an oxyfuels program in Fairbanks, AK, blood levels of occupationally exposed workers were 0.2-31.5 microgram/L MTBE and 1.6 to 72.2 microgram/L TBA with a mean TBA:MTBE blood concentration ratio of 4.2. In patients who received MTBE by percutaneous, transhepatic puncture for the dissolution of cholesterol gallstones, concentrations of MTBE in fat tissue reached 60 and 300 microgram/g at a treatment time when mean blood MTBE was less than 20 microgram/ml. The results of laboratory and clinical studies indicate that metabolites of MTBE may contribute to the nephropathy, neoplasms, and other pathological changes associated with repeated exposure to MTBE in experimental animals. It is concluded that such studies can provide a well-defined database for quantitative safety comparisons and health risk-benefit analyses of MTBE and other oxygenates in RFG.
对甲基叔丁基醚（MTBE）毒理学的研究进行了综述，作为评估重整汽油（RFG）蒸发排放对健康影响的可能信息基础。MTBE在体内氧化脱甲基的主要代谢产物是甲醇和叔丁醇（TBA），而甲醛和TBA是细胞色素P-450介导的肝微粒体氧化的主要产物。用玉米油灌胃给予MTBE的大鼠药代动力学研究得出MTBE的初始处置半衰期为0.32小时。大鼠血清中MTBE药物浓度随时间的下降伴随着血清甲醇浓度的逐渐升高，达到母体化合物浓度的50至200倍以上。大鼠反复吸入MTBE蒸气导致血液、脑和脂肪组织隔室中MTBE剂量依赖性增加。TBA的血液浓度也呈剂量依赖性，并提供了分布到外周药物代谢隔室的MTBE总量的估计值。间歇性暴露15周后，肾周脂肪/血液MTBE浓度比在9.7至11.6之间。在阿拉斯加费尔班克斯的一个含氧燃料项目中，职业暴露工人的血液中MTBE水平为0.2 - 31.5微克/升，TBA水平为1.6至72.2微克/升，TBA与MTBE血液浓度的平均比值为4.2。在通过经皮经肝穿刺接受MTBE以溶解胆固醇胆结石的患者中，在治疗时脂肪组织中MTBE浓度达到60至300微克/克，而此时平均血液MTBE低于20微克/毫升。实验室和临床研究结果表明，MTBE的代谢产物可能导致实验动物中与反复接触MTBE相关的肾病、肿瘤和其他病理变化。结论是，此类研究可为MTBE和RFG中其他含氧化合物的定量安全性比较以及健康风险 - 效益分析提供明确的数据库。
