Dermal, oral, and inhalation pharmacokinetics of methyl tertiary butyl ether (MTBE) in human volunteers.

Methyl tertiary butyl ether (MTBE), a gasoline additive used to increase octane and reduce carbon monoxide emissions and ozone precursors, has contaminated drinking water and can lead to exposure by oral, inhalation, and dermal routes. To determine its dermal, oral, and inhalation kinetics, 14 volunteers were exposed to 51.3 microg/ml MTBE dermally in tap water for 1 h, drank 2.8 mg MTBE in 250 ml Gatorade(R), and inhaled 3.1 ppm. MTBE for 1 h. Blood and exhaled breath samples were then obtained. Blood MTBE peaked between 15 and 30 min following oral exposure, at the end of inhalation exposure, and ~5 min after dermal exposure. Elimination by each route was described well by a three-compartment model (Rsq >0.9). The Akaike Information Criterion for the three-compartment model was smaller than the two-compartment model, supporting it over the two-compartment model. One metabolite, tertiary butyl alcohol (TBA), measured in blood slowly increased and plateaued, but it did not return to the pre-exposure baseline at the 24-h follow-up. TBA is very water-soluble and has a blood:air partition ratio of 462, reducing elimination by exhalation. Oral exposure resulted in a significantly greater MTBE metabolism into TBA than by other routes based on a greater blood TBA:MTBE AUC ratio, implying significant first-pass metabolism. The slower TBA elimination may make it a better biomarker of MTBE exposure, though one must consider the exposure route when estimating MTBE exposure from TBA because of first-pass metabolism. Most subjects had a baseline blood TBA of 1-3 ppb. Because TBA is found in consumer products and can be used as a fuel additive, it is not a definitive marker of MTBE exposure. These data provide the risk assessment process of pharmacokinetic information relevant to the media through which most exposures occur-air and drinking water.     

Disturbance of zinc and glucose homeostasis by methyl tert-butyl ether (MTBE); evidence for type 2 diabetes

1.?The prevalence of diabetes and the other metabolic disorders has noticeably increased worldwide. A causal link between increasing risk of type 2 diabetes and exposure to environmental pollutants has been reported.

2.?We hypothesized that exposure to methyl tert-butyl ether (MTBE), an oxygenate additive to gasoline would hinder zinc and glucose homeostasis in rats.

3.?Male Sprague–Dawley rats received MTBE in drinking water for 90 days. At the end of the treatment, pancreas and blood samples were collected for biochemical and molecular examinations. Expression of four candidate genes, including Insulin1, Insulin2, MT1A, SLC30A8 by Real-Time Quantitative PCR (Q-PCR) as well as biochemical parameters, including fasting blood glucose (FBS), triglycerides (TG), cholesterol (CHO), low-density lipoprotein (LDL), high-density lipoprotein (HDL), copper (Cu²⁺) and calcium (Ca²⁺) levels as well as High-sensitive C-reactive protein were assessed as endpoints.

4.?This study suggested that MTBE exposure can be associated with disruption in zinc homeostasis and glucose tolerance.     

Methyl-tertiary-butyl-ether (MTBE) misclassified

Methyl-tertiary-butyl-ether (MTBE) was introduced into motor fuels in 1992 to reduce carbon monoxide automotive emissions in areas where the National Ambient Air Quality Standards for CO were exceeded. At a meeting of the National Toxicology Program's Board of Scientific Counselors (2-3 December 1998), data were presented showing that exposure to MTBE caused increased incidence of liver tumors, renal adenomas, carcinomas and interstitial cell adenomas of the testes in male, and lymphomas and leukemia in female CD1 mice [National Toxicology Program, 1998]. Despite this evidence, the NTP Board defeated a motion to list MTBE as "Reasonably anticipated to be a human carcinogen" by a vote of 6 to 5. This decision directly contravenes rules and procedures previously established by NTP for assessing carcinogenicity of chemical compounds. Good public health policy dictates that the NTP Board conduct another review of MTBE with proper consideration of the criteria that have been established for listing agents as carcinogens. Millions of Americans who are exposed daily to this chemical deserve an unbiased evaluation of carcinogenic agents being introduced into the environment.     

甲基叔丁基醚无铅汽油肾脏毒性的实验研究

目的：了解甲基叔丁基醚（MTBE）无铅汽油对肾脏的毒性及毒作用机制。方法：昆明种小鼠经呼吸道静式染毒，MTBE无铅汽油22．9、11．4及2．3g/m^3每天一次，连续2h，共22d亚急性染毒。日立－7150型全自动生化仪检测血清中尿素氮（BUN）、肌酐（Cr）含量；肾组织均浆中丙二醛（MDA）和超氧化物歧化酶（SOD）含量分别用荧光法，邻苯三酚自氧化固定时间法测定；电镜观察肾皮质区超微结构的变化，结果：22.9g/m^3染毒组雌性小鼠血清中BUN含量与阴性对照组间比较差异有显著性（P＜0．05）；电镜观察到22.9g/m^3染色毒对照组雌雄性小鼠的肾小球基底膜，肾小管细胞线粒体及绒毛均未见显著异常改变。结论：MTBE无铅汽油对肾小球的滤过功能有一定的影响，雌性小鼠可能更为敏感。     

Alterations in endocrine responses in male Sprague-Dawley rats following oral administration of methyl tert-butyl ether.

Methyl tert-butyl ether (MTBE) is an oxygenated fuel additive used to decrease carbon monoxide emissions during combustion. MTBE is a nongenotoxic chemical that induces Leydig cell tumors (LCT) in male rats. The mechanism of MTBE-induced LCT is not known; however, LCT induced by other nongenotoxic chemicals have been associated with the disruption of the hypothalamus-pituitary-testicular (HPT) axis. The objective of this study was to determine whether MTBE functions as an endocrine-active compound by affecting levels of specific hormones involved in the maintenance of the HPT axis. Nine-week-old male Sprague-Dawley rats were administered MTBE by gavage at 0, 250, 500, 1000, or 1500 mg MTBE/kg/day for 15 or 28 consecutive days and sacrificed 1 h following the last dose. Relative testis weights were increased only in high-dose animals treated for 28 days, and no testicular lesions were observed at any dose level. Adrenal gland, liver, and kidney weights were also increased. Histologic changes included protein droplet nephropathy of the kidney and centrilobular hypertrophy of the liver. Interstitial fluid and serum testosterone levels as well as serum prolactin levels were decreased only in animals treated with 1500 mg MTBE/kg/day for 15 days. At 28 days, serum triiodothyronine (T3) was significantly decreased at 1000 and 1500 mg MTBE/kg/day compared to control animals, and a decrease in serum luteinizing hormone and dihydrotestosterone was observed at 1500 mg MTBE/kg/day. These results indicate that MTBE causes mild perturbations in T3 and prolactin; however, the changes in testosterone and LH levels did not fit the pattern caused by known Leydig cell tumorigens.     

Epidemiology, toxicokinetics, and health effects of methyltert-butyl ether (MTBE)

This paper reviews the published information assessing the kinetics and potential for adverse health effects related to exposure to the fuel oxygenate, methyltert-butyl ether (MTBE). Data were obtained from previously published reports, using human data where possible. If human data were not available, animal studies were cited. The kinetic profile of MTBE in humans is similar for ingestion and inhalation. The concentrations of MTBE to which the general public is expected to be exposed are orders of magnitude below concentrations that have caused adverse health effects in animals. Controlled human studies have not replicated early epidemiology studies that suggested, but did not confirm, a possible association between MTBE exposure and nonspecific health complaints.     

无铅汽油新型添加剂甲基叔丁基醚的致突变性研究

目的；研究甲基叔丁基醚（MTBE）的致突变性及遗传毒性。方法：采用Ames试验检测MTBE的遗传毒性，并用单细胞凝胶电泳法检测国产MTBE大鼠经口亚慢性染毒后血液有核细胞的DNA的损伤状况。结果：Ames试验（TA98和TA100菌株）中，在加与不加S9的情况下，MTBE均未表现出明显的致突变性。染毒大鼠血液有核细胞DNA的断裂损伤也较对照组未见统计学差异。结论：本研究结果未发现MTBE对受试系统有致突变性。     

Toxicity of methyl tertiary‐butyl ether (MTBE) following exposure of Wistar Rats for 13 weeks or one year via drinking water

Thirteen‐week and one‐year toxicity studies of methyl tertiary‐butyl ether (MTBE) administered in drinking water to Wistar rats were conducted. Male and female rats were exposed to MTBE in drinking water at 0.5, 3, 7.5 and 15 mg ml^?1 for 13 weeks and at 0.5, 3 and 7.5 (males) or 0.5, 3 and 15 mg ml^?1 (females) for 1 year. Body weights were reduced only in males following 13 weeks of exposure. Reduced water consumption and urine output were observed in males and females exposed to MTBE. Kidney cell replication and α_2u‐globulin levels in males were increased at 1 and 4 weeks of MTBE exposure and tubular cell regeneration was increased in male kidneys exposed to MTBE concentrations of 7.5 mg ml^?1 or greater for 13 weeks. Wet weights of male kidneys were increased following 13 weeks, 6 months and 1 year of exposure to MTBE concentrations of 7.5 mg ml^?1 or greater. Kidney wet weights were increased in females at MTBE concentrations of 15 mg ml^?1 for 13 weeks. Tertiary‐butyl alcohol blood levels increased linearly with dose in males and females following 1 year of exposure. Chronic progressive nephropathy (CPN), of minimal to mild severity, increased in males, but not females, with 1 year of MTBE exposure. In summary, exposure of Wistar rats to MTBE in the drinking water resulted in minimal exposure‐related effects including limited renal changes in male rats suggestive of α_2u‐globulin nephropathy following 13 weeks of exposure and an exacerbation of CPN in males at the end of 1 year of exposure. Copyright © 2011 John Wiley & Sons, Ltd.     

Study on correlation of computed tomographic classification of a gallstone with its dissolution using methyl tert-butyl ether(MTBE) in vitro

Severalnonsurgicaltherapiesoncholelithiasishavebeenwidelyusedinclinicalpractice.Whethertheywouldsucceedornotdependsonselectionofpatients.CTisthemostfrequentlyusedmethodforcaseselection.Itmaypredictaccuratelythechemicalpropertiesandstructuralfeaturesofagallstone.Nevertheless,therearefewstudiesinChinaoncorrelationbetweenCTanddissolutionofstoneswithmethyltert--butylether(MTBE).MATERIALSANDMETHODSCTscanningofgallstonesinvitroForty--fivecasesof90stones(twoforeachcase)wereobtainedatsurge…     

自制复方溶石剂的体外溶石作用及毒性的初步研究

目的 评价自制复方溶石剂的体外溶石效果和毒性作用。方法 用甲基叔丁醚(MT—BE)作用对照,在体外对胆固醇、混合性、胆色素性结石进行溶石实验以及在20只兔胆囊内灌注溶石剂后观察血生化和各脏器的病理改变。结果 自制复方溶石剂对胆固醇、混合性、胆色素性结石的溶石比例分别达到97．20％、88．43％、82．69％;毒性比MTBE小。结论 自制复方溶石剂是一种相对低毒、安全、对大多数胆道结石有良好效果的直接溶石剂。