Methyl Tertiary Butyl Ether Vapor Research Articles

Experimental Exposure to Methyltertiary-Butyl Ether

Methyltertiary-butyl ether (MTBE) is widely used in gasoline as an oxygenate and octane enhancer. Acute effects, such as headache, nausea, and nasal and ocular irritation, have been associated with the exposure to gasoline containing MTBE. The aim of this study was to assess acute health effects up to the Swedish occupational exposure limit value, both with objective methods and a questionnaire. Ten healthy male volunteers were exposed to MTBE vapor for 2 h at three levels (5, 25, and 50 ppm), during light physical work (50 W). All subjects rated the degree of irritative symptoms, discomfort, and CNS effects before, during, and after all three exposure occasions using a questionnaire. Answers were given on a 100-mm visual analog scale, graded from “not at all” to “almost unbearable.” Ocular (redness, tear film break-up time, self-reported tear film break-up time, conjunctival epithelial damage, and blinking frequency) and nasal (mouth and nasal peak expiratory flow, acoustic rhinometry, biochemical inflammatory markers, and cells in nasal lavage) measurements were performed mainly at the highest exposure level. The ratings of solvent smell increased dramatically (ratings up to 50% of the scale) as the volunteers entered the chamber and declined slowly with time (p< 0.05, repeated-measures ANOVA). All other questions were rated from “not at all” to “hardly at all” (0–10% of the scale) with no significant relation to exposure. The eye measurements showed no effects of MTBE exposure. Blockage index, a measure of nasal airway resistance calculated from the peak expiratory flows, increased significantly after exposure; however, the effect was not related to exposure level. In addition, a nonsignificant tendency of decreased nasal volume was seen in the acoustic rhinometry measurements, but with no clear dose–effect relationship. In conclusion, our study suggests no or minimal acute effects of MTBE vapor upon short-term exposure at relatively high levels.

Experimental Exposure to Methyltertiary-Butyl Ether

Methyltertiary-butyl ether (MTBE) is widely used in gasoline as an oxygenate and octane enhancer. The aim of this study was to evaluate the uptake, distribution, metabolism, and elimination of MTBE in humans. Ten healthy male volunteers were exposed to MTBE vapor (5, 25, and 50 ppm) on three different occasions during 2 h of light physical exercise (50 W). MTBE and the metabolitetertiary-butyl alcohol (TBA) were monitored in exhaled air, blood, and urine. Blood and urine were collected at selected time intervals, during and up to 3 days after the exposure, and analyzed by head space gas chromatography. MTBE in exhaled air was collected with sorbent sample tubes and subsequently analyzed by gas chromatography. The respiratory uptake of MTBE was rather low (42–49%), and the respiratory exhalation was high (32–47%). A relatively low metabolic blood clearance (0.34–0.52 L/h/kg) was seen compared to many other solvents. The kinetic profile of MTBE in blood could be described by four phases, and the average half-lives were 1 min, 10 min, 1.5 h, and 19 h. The post-exposure decay curve of MTBE in urine was separated into two linear phases, with average half-lives of 20 min and 3 h. The average post-exposure half-lives of TBA in blood and urine were 10 and 8.2 h, respectively. The urinary excretion of MTBE and TBA was less than 1% of the absorbed dose, indicating further metabolism of TBA, other routes of metabolism, or excretion. The kinetics of MTBE and TBA were linear up to the highest exposure level of 50 ppm. We suggest that TBA in blood or urine is a more appropriate biological exposure marker for MTBE than the parent ether itself.

Assessment of Occupational Methyl Tertiary Butyl Ether Vapor Exposures to Petroleum Refinery and Transport Loading Rack Facility Employees

Abstract The use of oxygenated gasoline is required for metropolitan areas which exceed the carbon monoxide nonattainment standard as specified by the Clean Air Act Amendments of 1990. Many petroleum refineries blend methyl tertiary butyl ether (MTBE) with gasoline to make oxygenated fuel, which burns cleaner and reduces carbon monoxide emissions from motor vehicle exhaust. MTBE has a low acute toxicity ranking and is only mildly irritating to the eyes and skin. Excessive acute vapor inhalation causes depression of the central nervous system. Limited animal data indicate that MTBE may increase the risk of cancer, although this has not been adequately addressed. This assessment was conducted to monitor airborne MTBE occupational exposure to petroleum refinery and transport loading rack facility employees at one location. The 47 time-weighted average (TWA) and short-term exposure limit (STEL) personal air samples collected did not exceed the American Industrial Hygiene Association workplace environmental exposure level of 100 ppm for an 8-hour TWA. The 38 personal STEL samples collected ranged from <0.896 to 35.012 ppm with a geometric mean of 2.44 ppm. The nine personal TWA samples ranged from <0.042 to 1.750 ppm with a geometric mean of 0.58 ppm. This study found that minimal occupational exposures to MTBE occurred when fugitive emissions from operating equipment were limited, leaks and spills during product transfer were minimized, and mechanical equipment was thoroughly depressurized and purged before allowing the equipment to be repaired.

Methyl tertiary butyl ether-induced endocrine alterations in mice are not mediated through the estrogen receptor.

Chronic exposure to methyl tertiary butyl ether (MTBE) altered the rodent tumor incidence of endocrine-sensitive tissues and decreased the incidence of estrogen-dependent uterine cystic hyperplasia in mice. To test the hypothesis that changes in the incidence of tumors in female B6C3F1 mice after MTBE exposure are secondary to endocrine alterations, we exposed female mice to the carcinogenic dose of MTBE vapor (8000 ppm) for 3 or 21 days or 4 or 8 months under conditions similar to a previous 2-year bioassay. MTBE exposure significantly decreased body weight gain and ovary and pituitary weight at 4 and 8 months and uterine weight at all time points. After 8 months of exposure, MTBE significantly increased the length of the estrous cycle by increasing the mean number of days in both the estrus and the nonestrus stages. Histological evaluation of H&E-stained tissues showed a decrease in the number of uterine glands after subchronic MTBE exposure. DNA synthesis, as measured by the incorporation of 5-bromo-2'-deoxyuridine (BrdU), was decreased in uterine glandular and luminal epithelial cells after MTBE exposure for 3 or 21 days or 4 or 8 months. MTBE exposure decreased the number of epithelial layers in the cervix and vagina at all time points. DNA synthesis was decreased in cervical and vaginal epithelium after 21 days of MTBE. Decreased zona reticularis of adrenal glands was found after 4 and 8 months of MTBE exposure without changes in BrdU incorporation. MTBE did not competitively bind to estrogen receptor. MTBE exposure did not alter serum estrogen levels or alter the location or intensity of estrogen receptor immunoreactivity in the uterus, cervix, and vagina. These data indicate that while MTBE exposure causes multiple endocrine-related tissue and cellular responses, these effects are not mediated through the estrogen receptor.

Quantitative relationship between transforming growth factor-alpha and hepatic focal phenotype and progression in female mouse liver.

Modulations in the positive hepatocyte growth factor, transforming growth factor-alpha (TGF-alpha) and its receptor epidermal growth factor receptor (EGFR), occur in rat and human liver tumors. The purpose of this study was to determine if TGF-alpha and EGFR are altered in basophilic and acidophilic preneoplastic and neoplastic liver lesions generated in DEN-initiated mice exposed to a variety of hepatocarcinogens. Female B6C3F1 mice were initiated with N-nitrosodiethylamine (DEN) and treated with hepatocarcinogenic concentrations of unleaded gasoline vapor (2,000 ppm), methyl tertiary butyl ether vapor (7,814 ppm), phenobarbital (500 ppm, diet), or chlordane (25 ppm, diet). Hepatic foci and tumors were identified and evaluated immunohistochemically with antibodies for TGF-alpha and EGFR. In all treatment groups, basophilic hepatic foci were negative for TGF-alpha immunoreactivity (554/564, 98%). In contrast, regardless of treatment, acidophilic hepatic foci were immunoreactive for TGF-alpha (107/108, 99%). There was no significant difference in mean hepatic labeling index as measured by the incorporation of 5-bromo-2'-deoxyuridine between foci immunoreactive and nonimmunoreactive for TGF-alpha. The incidence of immunoreactivity for TGF-alpha increased in hepatocellular tumors that were predominantly of the basophilic phenotype. Of basophilic hepatocellular adenomas, 16/81 (20%) were immunoreactive for TGF-alpha, while 17/29 (59%) of hepatocellular carcinomas stained positive for TGF-alpha. A similar increased incidence of EGFR immunoreactivity was found in basophilic hepatocellular adenomas (17/67, 25%) and carcinomas (19/28, 68%) relative to basophilic foci (11/367, 3%), suggesting an autocrine mechanism for the development of mouse liver tumors. The increased incidence of TGF-alpha immunoreactivity in basophilic liver tumors suggests that TGF-alpha is a marker of tumor progression in mouse liver. Furthermore, TGF-alpha modulations were dependent on phenotype rather than treatment, indicating inherent differences in the expression of TGF-alpha in basophilic and acidophilic hepatic lesions.

Oncogenicity studies of inhaled methyl tertiary-butyl ether (MTBE) in CD-1 mice and F-344 rats.

Oncogenicity studies of methyl tertiary-butyl ether (MTBE) vapor were conducted in CD-1 mice and Fischer 344 rats. Fifty animals of each sex per species per group were exposed for 6 h a day, 5 days per week to 0 (control), 400, 3000 and 8000 ppm MTBE vapor in air for 18 months (mice) and 24 months (rats). Both species showed reversible central nervous system depression at 8000 ppm for the first week of exposure, which continued for mice for the study duration. For the 8000 ppm mice, reduced body weight gain and early mortality prior to terminal euthanasia were exposure related. In the males, these deaths appear to be due to exacerbation of uropathy or dysuria, which occurs spontaneously in this strain. Increases in absolute and relative liver (both sexes) and kidney weight (males only) were seen at 3000 and 8000 ppm and decreases in brain and spleen weights were also noted (the latter decreases were without microscopic lesions and occurred at 8000 ppm only). An increase in hepatocellular hypertrophy occurred in both sexes at the two highest concentrations. The only neoplastic lesion found in this study in mice was an increased incidence of hepatocellular adenomas in females at the 8000 ppm exposure. In a follow-up study, a statistically significant elevation of cell proliferation in female mouse liver has been shown to occur following 5 days, but not 28 days, of exposure to 8000 ppm MTBE, suggesting that MTBE induces mitogenesis. For male rats, early euthanasia was required at week 82 and week 97 for the 8000 and 3000 ppm groups, respectively, due to excessive mortality from a severe progressive nephrosis. The end stage of this process appeared earlier in the male rats of all MTBE exposure groups; the incidence of this lesion and mortality for exposed females was comparable to control females. No exposure-related changes in hematological parameters were observed for any group at any time point, but a decrease in corticosterone levels was seen for male rats from the 8000 ppm group. Absolute and relative kidney and liver weight increases occurred in 3000 and 8000 ppm exposure groups, but the liver weight change was not accompanied by histopathological change. At study termination, increases in the incidence and severity of a chronic nephropathy in males from all exposure groups and in females exposed to 3000 and 8000 ppm was associated with secondary lesions of hyperplasia of the parathyroid and mineralization of tissues. Renal tubular cell tumors were increased in male rats exposed to 3000 and 8000 ppm. This may be associated with an accumulation of protein (stainable by Mallory's Heidenhain) in kidney tubular epithelial cells after 4 weeks of exposure. An increased incidence of interstitial cell adenomas of the testes was seen in males exposed to 3000 and 8000 ppm but was believed to be an artefact of an unusually low control incidence and not considered to be exposure related. Based on the above effects, the no-observed-effect level (NOEL) for chronic toxicity is 400 ppm, and the NOEL for carcinogenic effects is 3000 ppm (mice) and 400 ppm (rats).

Two-generation reproductive toxicity study of methyl tertiary-butyl ether (MTBE) in rats.

A two-generation reproductive toxicity study of methyl tertiary-butyl ether (MTBE) was conducted in Sprague-Dawley rats. Twenty-five rats of each sex (F0) were exposed by inhalation to 0, 400, 3000 or 8000 ppm MTBE vapor, 6 h a day for 10 weeks prior to mating. Parental animals were then mated within groups for up to 3 weeks. Parental females were exposed during mating, gestation and lactation (starting on day 5); parental males were exposed during mating through delivery of their last litter sired. The F1 adults were selected from the F1 litters and were exposed beginning on postnatal day 28 for at least 8 weeks before mating to produce F2 litters. During exposures to 3000 and 8000 ppm MTBE, group observations included hypoactivity and lack of startle reflex in parental animals from both generations. Parental animals at 8000 ppm were also ataxic. During the pre-mating period, body weights of the 8000 ppm males from both generations and the F1 females were significantly reduced compared to control animals. Transient body weight reduction was also observed in the 3000 ppm F1 males and females during the pre-mating period. Lactational body weights were increased in the 8000 ppm females from both generations. In the F1 generation, increased liver weights were noted in the 3000 and 8000 ppm animals for both sexes, although histopathological examination revealed no treatment-related effects. There were no treatment-related reproductive effects noted in any of the parameters measured in this study. Offspring survival was equivalent among treated and control groups from both generations, and there were no remarkable post-mortem findings. There was, however, a significant increase in dead F2 pups in the 8000 ppm group on postnatal day 4. The F1 litters at 3000 and 8000 ppm had lowered body weights from postnatal days 14-21 and 14-28, respectively. The F2 generation of pups at 3000 and 8000 ppm also exhibited lowered body weights from postnatal days 14-28 and 7-28, respectively. Body weight gains in both the F1 and F2 litters were also reduced for the corresponding time intervals. Thus, exposure to MTBE vapor produced no reproductive toxicity to two generations of Sprague-Dawley rats even in the presence of parental toxicity at 3000 and 8000 ppm. Postnatal toxicity was observed in the offspring of both generations, but only in the presence of maternal toxicity. The no-observed-effect level (NOEL) for both parental and postnatal toxicity is 400 ppm, and the NOEL for reproductive toxicity is at least 8000 ppm.

Disposition, metabolism, and toxicity of methyl tertiary butyl ether, an oxygenate for reformulated gasoline.

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.

Toxicokinetics and acute effects of MTBE and ETBE in male volunteers

Methyl tertiary butyl ether (MTBE) is widely used in gasoline as an oxygenator and octane enhancer. There is also an interest in using the ethyl tertiary butyl (ETBE) and methyl tertiary amyl (TAME) ethers. We measured the blood, water, and olive oil/air partition coefficients in vitro of MTBE, ETBE, TAME and tertiary butyl alcohol (TBA), a metabolite of MTBE and ETBE. The results indicate similar uptake and distribution behavior for the three ethers and a slight affinity for fatty tissues. The partition coefficients of TBA indicate that this metabolite is not excreted via the lungs to any great extent and that it is preferentially distributed in body water. Further, we exposed 10 healthy male volunteers to MTBE vapor at 5, 25 and 50 ppm for 2 h during light physical exercise. Uptake and disposition were studied by measuring MTBE and TBA in inhaled and exhaled air, blood and urine. Low uptake, high post-exposure exhalation, and low blood clearance indicate slow metabolism of MTBE relative to many other solvents. A low recovery of TBA in urine (below 1% of uptake) indicates further metabolism of TBA. The concentration of MTBE and TBA in blood was proportional to exposure level suggesting linear kinetics up to 50 ppm. The half life of 7–10 h in blood and urine indicates that TBA would be more suitable than the parent compound as a biomarker for MTBE exposure. Subjective ratings (discomfort, irritative symptoms, CNS effects) and eye (redness, tear film break-up time, conjunctival damage, blinking frequency) and nose (peak expiratory flow, acoustic rhinometry, inflammatory markers in nasal lavage) measurements indicated no or minimal effects of MTBE.

Health effects of oxygenated fuels.

The use of oxygenated fuels is anticipated to increase over the next decades. This paper reviews the toxicological and exposure information for methyl tertiary-butyl ether (MTBE), a fuel additive, and methanol, a replacement fuel, and discusses the possible health consequences of exposure of the general public to these compounds. For MTBE, the health effects information available is derived almost exclusively from rodent studies, and the exposure data are limited to a few measurements at some service stations. Based on these data, it appears unlikely that the normal population is at high risk of exposure to MTBE vapor. However, in the absence of health and pharmacokinetic data in humans or in nonhuman primates, this conclusion is not strongly supported. Similarly, there are a number of uncertainties to take into consideration in estimating human risk from the use of methanol as a fuel. Although methanol may be toxic to humans at concentrations that overwhelm certain enzymes involved in methanol metabolism, the data available provide little evidence to indicate that exposure to methanol vapors from the use of methanol as a motor vehicle fuel will result in adverse health effects. The uncertainties in this conclusion are based on the lack of information on dose-response relationship at reasonable, projected exposure levels and of studies examining end points of concern in sensitive species. In developing a quantitative risk assessment, more needs to be known about health effects in primates or humans and the range of exposure expected for the general public for both compounds.