Mutagenicity evaluation of methyl tertiary- butyl ether in multiple tissues of transgenic rats following whole body inhalation exposure.

Methyl tertiary-butyl ether (MTBE) is used as a component of motor vehicle fuel to enhance combustion efficiency and to reduce emissions of carbon monoxide and nitrogen oxides. Although MTBE was largely negative in the in vitro and in vivo genotoxicity studies, isolated reports of positive findings along with the observation of tumors in the rat cancer bioassays raised concern for its in vivo mutagenic potential. To investigate this, transgenic male Big Blue Fischer 344 rats were exposed to 0 (negative control), 400, 1000, and 3000 ppm MTBE via whole body inhalation for 28 consecutive days, 6 h/day. Mutant frequencies (MF) at the cII locus of the transgene in the nasal epithelium (portal of entry tissue), liver (site of primary metabolism), bone marrow (rapidly proliferating tissue), and kidney (tumor target) were analyzed (5 rats/exposure group) following a 3-day post-exposure manifestation period. MTBE did not induce a mutagenic response in any of the tissues investigated. The adequacy of the experimental conditions to detect induced mutations was confirmed by utilizing tissue samples from animals treated with the known mutagen ethyl nitrosourea. These data provide support to the conclusion that MTBE is not an in vivo mutagen and male rat kidney tumors are not likely the result of a mutagenic mode of action.

Gollapudi BB ，Rushton EK 《-》

Investigation of the potential mutagenicity of ethyl tertiary-butyl ether in the tumor target tissue using transgenic Big Blue Fischer 344 rats following whole body inhalation exposure.

Ethyl tertiary-butyl ether (ETBE) is a fuel oxygenate used for the efficiency of motor vehicle fuels and their octane ratings. ETBE has been reported to induce liver adenomas in male rats in a 2-year bioassay at the highest inhalation concentration tested of 5000 ppm. To investigate the potential mutagenicity of ETBE in the liver, male Big Blue Fischer 344 rats were exposed for 28 consecutive days (6 h/day) to 0, 500, 1500, and 5000 ppm ETBE. The treated rats were sacrificed 3 days post-exposure and the frequencies of cII mutants were evaluated in the liver and bone marrow tissues. The mutant frequency (MF) of the liver in the negative control group was 36.3 × 10-6 and this value was not significantly different in ETBE-exposed animals (39.4, 37.3, and 45.9 × 10-6 in 500, 1500, and 5000 ppm groups, respectively). In the bone marrow, the mean MF in the negative control was 32.9 × 10-6 which was not different from the means of the exposed groups (33.8, 22.6, and 32.0 × 10-6 for groups exposed to 500, 1500 and 5000 ppm, respectively). These data, along with consistent negative response reported in the literature for other apical genotoxicity endpoints informs that mutagenicity is not likely the initial key event in the mode of action for ETBE-induced hepatocarcinogenesis in the rat.

Gollapudi BB ，Rushton EK 《-》

Physiologically based pharmacokinetic rat model for methyl tertiary-butyl ether; comparison of selected dose metrics following various MTBE exposure scenarios used for toxicity and carcinogenicity evaluation.

There are a number of cancer and toxicity studies that have been carried out to assess hazard from methyl tertiary-butyl ether (MTBE) exposure via inhalation and oral administration. MTBE has been detected in surface as well as ground water supplies which emphasized the need to assess the risk from exposure via drinking water contamination. This model can now be used to evaluate route-to-route extrapolation issues concerning MTBE exposures but also as a means of comparing potential dose metrics that may provide insight to differences in biological responses observed in rats following different routes of MTBE exposure. Recently an updated rat physiologically based pharmacokinetic (PBPK) model was published that relied on a description of MTBE and its metabolite tertiary-butyl alcohol (TBA) binding to alpha 2u-globulin, a male rat-specific protein. This model was used to predict concentrations of MTBE and TBA in the kidney, a target tissue in the male rat. The objective of this study was to use this model to evaluate the dosimetry of MTBE and TBA in rats following different exposure scenarios, used to evaluate the toxicity and carcinogenicity of MTBE, and compare various dose metrics under these different conditions. Model simulations suggested that although inhalation and drinking water exposures show a similar pattern of MTBE and TBA exposure in the blood and kidney (i.e. concentration-time profiles), the total blood and kidney levels following exposure of MTBE to 7.5mg/ml MTBE in the drinking water for 90 days is in the same range as administration of an oral dose of 1000 mg/kg MTBE. Evaluation of the dose metrics also supports that a high oral bolus dose (i.e. 1000 mg/kg MTBE) results in a greater percentage of the dose exhaled as MTBE with a lower percent metabolized to TBA as compared to dose of MTBE that is delivered over a longer period of time as in the case of drinking water.

Borghoff SJ ，Parkinson H ，Leavens TL 《-》

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

Bird MG ，Burleigh-Flayer HD ，Chun JS ，Douglas JF ，Kneiss JJ ，Andrews LS ... -  《JOURNAL OF APPLIED TOXICOLOGY》

Methyl tert-butyl ether causes alpha2u-globulin nephropathy and enhanced renal cell proliferation in male Fischer-344 rats.

Prescott-Mathews JS ，Wolf DC ，Wong BA ，Borghoff SJ ... -  《TOXICOLOGY AND APPLIED PHARMACOLOGY》