McGregor Douglas
Toxicity Evaluation Consultants, Aberdour, Scotland, UK.
Crit Rev Toxicol. 2006 Apr;36(4):319-58. doi: 10.1080/10408440600569938.
When methyl tertiary-butyl ether (MTBE) in gasoline was first introduced to reduce vehicle exhaust emissions and comply with the Clean Air Act, in the United States, a pattern of complaints emerged characterised by seven "key symptoms." Later, carefully controlled volunteer studies did not confirm the existence of the specific key symptoms, although one study of self-reported sensitive (SRS) people did suggest that a threshold at about 11-15% MTBE in gasoline may exist for SRSs in total symptom scores. Neurobehavioral and psychophysiological studies on volunteers, including SRSs, found no adverse responses associated with MTBE at likely exposure levels. MTBE is well and rapidly absorbed following oral and inhalation exposures. Cmax values for MTBE are achieved almost immediately after oral dosing and within 2 h of continuous inhalation. It is rapidly eliminated, either by exhalation as unchanged MTBE or by urinary excretion of its less volatile metabolites. Metabolism is more rapid humans than in rats, for both MTBE and tert-butyl alcohol (TBA), its more persistent primary metabolite. The other primary metabolite, formaldehyde, is detoxified at a rate very much greater than its formation from MTBE. MTBE has no specific effects on reproduction or development, or on genetic material. Neurological effects were observed only at very high concentrations. In carcinogenicity studies of MTBE, TBA, and methanol (included as an endogenous precursor of formaldehyde, without the presence of TBA), some increases in tumor incidence have been observed, but consistency of outcome was lacking and even some degree of replication was observed in only three cases, none of which had human relevance: alpha(2u)-globulin nephropathy-related renal tubule cell adenoma in male rats; Leydig-cell adenoma in male rats, but not in mice, which provide the better model of the human disease; and B-cell-derived lymphoma/leukemia of doubtful pathogenesis that arose mainly in lungs of orally dosed female rats. In addition, hepatocellular adenomas were significantly higher in female CD-1 mice and thyroid follicular-cell adenomas were increased in female B6C3F1 mice treated with TBA, but these results lack any independent confirmation, which would have been possible from a number of other studies.
当汽油中的甲基叔丁基醚（MTBE）最初在美国被引入以减少车辆尾气排放并符合《清洁空气法》时，出现了一种以七种“关键症状”为特征的投诉模式。后来，精心控制的志愿者研究并未证实特定关键症状的存在，尽管一项针对自我报告敏感人群（SRS）的研究确实表明，对于SRS人群的总症状评分，汽油中MTBE含量约为11% - 15%时可能存在一个阈值。对包括SRS人群在内的志愿者进行的神经行为和心理生理学研究发现，在可能的暴露水平下，没有发现与MTBE相关的不良反应。口服和吸入暴露后，MTBE能很好且迅速地被吸收。口服给药后几乎立即达到MTBE的Cmax值，连续吸入2小时内也能达到。它能迅速消除，要么以未改变的MTBE形式呼出，要么通过其挥发性较低的代谢产物经尿液排泄。对于MTBE及其更持久的主要代谢产物叔丁醇（TBA），人类的代谢速度比大鼠更快。另一种主要代谢产物甲醛的解毒速度远大于其由MTBE形成的速度。MTBE对生殖、发育或遗传物质没有特定影响。仅在非常高的浓度下才观察到神经学效应。在MTBE、TBA和甲醇（作为甲醛的内源性前体包括在内，不存在TBA）的致癌性研究中，观察到一些肿瘤发生率有所增加，但结果缺乏一致性，甚至仅在三个案例中观察到一定程度的重复，且这些案例均与人类无关：雄性大鼠中与α(2u)-球蛋白肾病相关的肾小管细胞腺瘤；雄性大鼠中的睾丸间质细胞瘤，但在小鼠中未出现，而小鼠是更适合人类疾病的模型；以及主要出现在口服给药雌性大鼠肺部的、发病机制存疑的B细胞源性淋巴瘤/白血病。此外，用TBA处理的雌性CD - 1小鼠中肝细胞腺瘤显著增多，雌性B6C3F1小鼠中甲状腺滤泡细胞腺瘤增多，但这些结果缺乏任何独立验证，而其他多项研究本可以做到这一点。
