Interagency Assessment of Potential Health Risks
Associated with Oxygenated Gasoline

A. Purpose

The use of oxygenated gasoline was mandated under the Clean Air Act Amendments of 1990 in areas that did not meet the federal ambient air standard for carbon monoxide (CO), an air pollutant associated with potential health risks. CO interferes with the body's ability to utilize oxygen by combining with hemoglobin, which then prevents it from transporting oxygen efficiently to organs of the body. Persons with chronic heart disease are at particular risk for adverse health effects of CO, but other groups, including the elderly, pregnant women, infants, and persons with anemia or cardiopulmonary disease, are also likely to be at increased risk due to CO exposure. Motor vehicle emissions are the primary source of ambient CO levels in most areas. The Clean Air Act requires at least a 2.7% oxygen content for gasoline sold in CO nonattainment areas. Gasoline containing 2.7% oxygen (by weight) is typically achieved by the addition of 15% methyl tertiary butyl ether (MTBE) or 7.5% ethanol (by volume). The higher oxygen content of oxygenated gasoline compared to conventional gasoline is intended to lead to a more complete combustion of the gasoline and therefore to reduced tailpipe emissions of CO. In addition, oxygenates usually displace aromatics in gasoline, such as benzene, toluene and xylene, which are a source of octane. These aromatics have been targeted for reduction in the reformulated gasoline program.

Soon after the oxygenated gasoline program was introduced nationally in the winter of 1992-1993, anecdotal reports of acute health symptoms were received by health authorities in various areas of the country. Such health concerns had not been anticipated but have subsequently focused attention on the possible health risks associated with using oxygenated gasoline. The purpose of this interagency assessment of the potential health risks of oxygenated gasoline is to explore the question of whether evidence from recent health studies of oxygenated gasoline or oxygenates, especially MTBE, and acute illness warrants a reconsideration by EPA of potential health risks of the oxygenated gasoline program during the coming winter months. This assessment is being prepared for the Office of Science and Technology Policy, under the auspices of the Interagency Oxygenated Fuels Assessment Steering Committee. The potential health benefits of the oxygenated program are not addressed in this assessment; such benefits will be considered in the more comprehensive interagency assessment of oxygenated fuels that is currently under way.

A team of scientists from three Federal agencies, the Centers for Disease Control and Prevention (CDC), the National Institute for Environmental Health Sciences (NIEHS), and the Environmental Protection Agency (EPA) was assembled to complete this evaluation. Members of this team were chosen by members of the Interagency Steering Committee or their designates on the basis of the members' expertise in different scientific disciplines and knowledge about issues related to oxygenated gasoline.

B. Scope

This assessment focuses on exposures that occur through inhalation; ingestion of oxygenates from contaminated water supplies may also be important but was considered beyond the scope of this assessment. The data base on ethanol is extensive, but it pertains primarily to ingestion, not inhalation. A full consideration of the relevance of the literature regarding the health effects of ethanol by ingestion to exposure by inhalation from evaporative and combustion mixtures of ethanol in gasoline also was considered beyond the scope of this assessment.

This assessment also attempts to identify areas where the scientific data base is particularly limited. It should also be noted that most of the information available on the health effects of MTBE pertains to MTBE alone rather than the mixture of MTBE and gasoline. This assessment does not attempt to assess the risks or benefits of MTBE-oxygenated gasoline in relation to conventional gasoline.

In addition, a more comprehensive review of the fundamental basis and efficacy of the Environmental Protection Agency's winter oxygenated gasoline program is currently being conducted by a combination of technical and scientific experts from across several Federal agencies, under the coordination of the National Science and Technology Council's Committee on Environment and Natural Resources. This more comprehensive review will consider not only health effects, but also air quality benefits, fuel economy and engine performance, ground water and drinking water quality, and an economic analysis of benefits. In addition, an independent review of the health effects of the use of oxygenates in gasoline is currently being conducted by the Health Effects Institute (HEI) and a panel of experts, in response to a request from the EPA. It is expected that the HEI review will be the core of the health effects section of the more comprehensive interagency review.

A. Air Quality

Various studies (e.g., Stump et al., 1989, 1990, 1992, 1994; Auto/Oil Air Quality Improvement Research Program 1990, 1991a,b,c; Carter et al., 1991; Kiskis et al., 1989; Reuter et al., 1992) have examined the impact of oxygenates on evaporative and combustion emissions from vehicles. For example, one study (Reuter et al., 1992) of 20 vehicles (1989 models with three-way catalysts) showed that, at 24°C, there was a trend for MTBE to cause a net reduction in the total mass of toxic combustion emissions. In general, emissions of benzene tended to decrease and emissions of formaldehyde tended to increase; 1,3-butadiene was not substantially altered when MTBE was added. However, more testing is needed with different types of vehicles under a variety of conditions (especially lower and higher temperatures) to characterize fully the overall changes in evaporative and combustion emissions associated with oxygenate usage.

Although some models for relating emissions data to ambient air quality are available, these changes in emissions cannot be quantitatively extrapolated to estimate with acceptable precision their impact on the air quality of a city. Moreover, ambient air measurements may provide only a rough (and sometimes misleading) guide to personal exposure levels that a population might encounter during hour-to-hour and day-to-day activities.

Little is known about the atmospheric transport and transformation of the complex mixtures associated with the use of oxygenated fuels or the possible significance of human exposure to these fuels. For example, tertiary butyl formate is a photochemical-transformation product of MTBE, as is formaldehyde (Tuazon et al., 1991). The possibility of increased human exposures to such substances as a result of using oxygenated fuel has not yet been evaluated. Ambient and microenvironmental air monitoring is needed to determine the levels of these and other possibly significant by-products of oxygenated fuels.

1. Ambient air measurements

Zweidinger (1993) analyzed air samples collected over 8-hour periods in Fairbanks, Alaska; Stamford, Connecticut; and Albany, New York for aldehydes, MTBE, and other volatile organic compounds (VOCs) in conjunction with investigations by CDC (1993a,b,c). The Fairbanks samples were collected by the State of Alaska during three time periods: time period 1 (December 1 through 12, 1992) occurred immediately before the phase out of 15% MTBE in gasoline, and 25 VOC and 35 aldehyde samples were obtained; time period 2 occurred during the phase-out itself (December 18 through 22, 1992), and 31 VOC and 26 aldehyde samples were obtained; and time period 3 occurred after the phase-out of MTBE-oxygenated fuels (February 2 through March 5, 1993) during which 73 samples each of VOCs and aldehydes were obtained. On the basis of the analysis of gasoline samples collected in Fairbanks during time periods 2 and 3, the percentage of MTBE in gasoline decreased from 8.5% to 1% for unleaded regular gasoline and from 14.7% to 5.6% for premium gasoline. The Stamford samples were collected by EPA Region 1 from April 13 through 14, 1993; 30 samples each of VOCs and aldehydes were collected. These samples were obtained in Stamford because the city represented another part of the country where MTBE-oxygenated gasoline was also sold. The Albany samples were collected from May 5 through May 27, 1993, by the New York State Department of Health; 20 samples each of VOCs and aldehydes were collected. Albany represented an area of the country where MTBE was not used as an oxygenate but was present only as an octane enhancer in gasoline. The Fairbanks time-period 1 VOC samples were analyzed by the Oregon Graduate Center, and the Desert Research Institute analyzed the aldehyde samples. All other ambient samples were analyzed by EPA's Atmospheric Research and Exposure Assessment Laboratory.

The samples from each city consisted of samples taken at roadside intersections, the pump islands of gas stations, garage service bays, and in residential neighborhoods. Samples of indoor air and from background sites were also collected. Samples of indoor air and of air from service bay or background sites were not collected in Albany, and no air samples from service bays were collected in Fairbanks during time period 2. In addition, air samples from the interiors of commercial vehicles in Fairbanks were collected early during time periods 1 and 3. Significant differences in ambient temperature and other meteorological conditions existed among the cities where samples were collected. Relatively few samples were collected in a given area, and the samples were collected over a few days only. Therefore, the data cannot be used to describe the air quality quantitatively in any of these cities. Rather, the data can be used to estimate approximate ranges of air quality in the locations sampled.

The highest average concentrations of MTBE (0.345 parts per million [ppm], or 1.28 mg/m³), benzene (0.629 mg/m³), total nonmethane organic carbon (80.5 ppm C), and formaldehyde (0.038 mg/m³) were found in garage service bays. One of the highest average concentrations for a single compound was found to be 1,1,1-trichloroethane (methyl chloroform), which exceeded 38.0 mg/m³ in service bays (Fairbanks, time period 3). Aside from the service bays, gas stations showed next highest concentrations of MTBE (Fairbanks: 0.05 ppm, or 0.194 mg/m³, time period 1; 0.037 ppm or 0.134 mg/m³, time period 2; and 0.006 ppm, or 0.020 mg/m³, time period 3). MTBE concentrations in Stamford gas stations were the lowest (0.004 ppm or 0.013 mg/m³) but were likely the result of sampler location (the Albany average was 0.024 ppm, or 0.086 mg/m³). Whereas the air samplers in Fairbanks and Albany were located on the pump islands, the samplers in Stamford were located at least 15 feet from the islands. In Fairbanks, indoor and outdoor MTBE concentrations were similar and averaged about 0.007 ppm (0.025 mg/m³) for the samples from time period 2, falling to 0.001 ppm (0.0037 mg/m³) in time period 3, with the exception of one home where the average indoor value was 0.02 ppm (0.072 mg/m³). This home had an attached garage, and air samples taken there showed elevated levels of benzene (0.138 mg/m³) and other compounds associated with gasoline. Indoor MTBE concentrations in Stamford averaged 0.0006 ppm (0.002 mg/m³). MTBE concentrations measured inside vehicles in Fairbanks averaged 0.007 ppm (0.024 mg/m³) during time period 1 (not including one sample of 0.067 ppm or 0.241 mg/m³) and averaged 0.005 ppm (0.019 mg/m³) during time period 3 (not including one sample of 0.035 ppm or 0.127 mg/m³).

Formaldehyde concentrations were higher indoors (0.012 to 0.034 mg/m³) than outdoors (0.0025 to 0.025 mg/m³), which is generally the case, and levels appeared typical of those seen in indoor air studies. Benzene levels were higher in Fairbanks (average roadside levels were 0.026 mg/m³ for December and 0.042 mg/m³ during time period 3) than in the other cities (Stamford, 0.003 mg/m³ Albany, 0.0014 mg/m³). A related report by Gordian et al. (1995) noted that the gasoline used in Alaska has the highest concentration of benzene (~ 5%) of any state in the nation; the report also stated that, during this same period in Fairbanks, formaldehyde and benzene levels in indoor and ambient air samples were higher after MTBE was removed from gasoline. However, these findings do not establish a causal relationship between decreased MTBE levels in gasoline and increased formaldehyde and benzene levels in the air.

In response to complaints by residents of Milwaukee, Wisconsin, regarding reformulated gasoline (2.0% oxygen content), the State of Wisconsin (Anderson et al., 1995) recently measured air concentrations of MTBE and other compounds (ETBE, benzene, ethyl benzene, xylenes, toluene). Levels of MTBE were less than 0.001 ppm at most of the sites sampled, including at the North Campus of the University of Wisconsin-Milwaukee where 24-hour and 2-hour samples were obtained at various intersections and gasoline stations. The highest ambient air concentrations of MTBE were obtained at two gasoline stations and a civic center parking ramp (0.00243, 0.00458, and 0.00205 ppm, respectively). The highest value was found at a station without a stage II vapor-recovery system.

2. Air concentrations in vehicle-related microenvironments

The Environmental and Occupational Health Sciences Institute (EOHSI) and the Research Triangle Institute (RTI) completed a study of field measurements of MTBE concentrations inside automobiles during an approximately 1-hour commute and during refueling (Lioy et al., 1993, 1994). Field measurements were collected during April 1993 in Middlesex County, New Jersey, at two stations with full service and stage II vapor-recovery systems; in Westchester County, New York, at three stations with self service and stage II vapor-recovery systems; and in Fairfield County, Connecticut, at five stations with self service and no stage II vapor-recovery system. One new-model automobile (a 1992 Corsica) and one older model automobile, either a 1985 Caprice or a 1986 Monte Carlo, were assigned to each commuter route. The samples were collected from the interior of the front passenger side of the automobile. The number of samples per automobile ranged from 14 to 20 for the commute and from 3 to 5 for the fill-up.

The driver's window was open during the fill-up. The time to complete the fill-up was about 2 minutes, and the total time at the gas station was 5 to 10 minutes. In addition to the measurements taken inside the automobile, a few measurements were collected near the breathing zone of the person refueling the gas tank.

Concentrations of MTBE measured in the cabin interior during the 1-hour commute had a geometric mean of 0.006 ppm (0.021 mg/m³), with a range of 0.001 ppm (0.004 mg/m³) to 0.16 ppm (0.58 mg/m³). The commuter runs in Connecticut had higher geometric mean concentrations (0.007 ppm or 0.023 mg/m³) than those in New Jersey (0.005 ppm or 0.016 mg/m³). One vehicle, the 1987 Caprice, had somewhat higher levels than the other vehicles; inside the older-model automobiles, concentrations were higher, probably reflecting differences in the design and deterioration of the older-model vehicles.

Concentrations during a 5-minute refueling at a self-service station averaged in excess of 0.3 ppm (1 mg/m³) and ranged from about 0.01 ppm to 4.1 ppm (0.036 to 14.7 mg/m³), with the highest values measured in the breathing zone of a person refueling at a station with no stage II vapor-recovery system. Measurements taken inside the cars during refueling generally ranged from 0.01 to 0.1 ppm (0.036 to 0.36 mg/m³) for stations both with and without stage II vapor-recovery systems.

International Technologies Inc. completed a set of field measurements of MTBE concentrations in the personal breathing zone (PBZ) during fill-up, at the pump island, and around the property line of gas stations (Johnson, 1993). This study was done in conjunction with the above EOHSI/RTI study that was conducted at the same 10 gas stations. All concentrations measured for this study, even those for intermittent exposures in the personal breathing zone, were from a 4-hour continuous sample. Average fence-line concentrations, which are typically taken at the apparent property line, ranged from 0.005 to 0.065 ppm (0.018 to 0.234 mg/m³) MTBE (Johnson, 1993). The highest fence-line concentrations ranged from 0.1 to 0.139 ppm (0.36 to 0.5 mg/m³) MTBE. The highest breathing-zone and pump-island concentrations ranged from 0.194 to 2.5 ppm (0.7 to 9 mg/m³) MTBE. Further discussion of this study and other exposure measurements among service station attendants is included in the next section on occupational exposures.

As should be expected, these 4-hour breathing-zone concentrations described above were lower than those reported by the Clayton Environmental Consultant study (Clayton Environmental Consultants, 1991), which collected samples only during the fill-up period (approximately 2 minutes). In the Clayton study, mean MTBE concentrations in the breathing zone for oxygenated fuels containing 12% to 13% MTBE were 3.6 ppm (13 mg/m³), with vapor recovery, and 8.3 ppm (30 mg/m³), without vapor recovery. The absolute range among these MTBE concentrations was 0.089 to 38 ppm (0.32 to 137 mg/m³). Although several stations were monitored, the highest and lowest measurements were made at one station, illustrating the variability of breathing zone exposures. Indeed, a wide range of air concentrations within the breathing zone can be expected. Ambient air concentrations measured at a gas station will be highly dependent on wind speed and direction. In addition, breathing-zone concentrations can be dramatically influenced by one's position in relation to wind direction. Any spilling of fuel while the tank is being filled also can dramatically increase the inhaled concentration.

Personal breathing zone (PBZ) measurements obtained in conjunction with the Wisconsin study of reformulated gasoline (2.0% oxygen content) ranged from 0.070 to 2.93 ppm for MTBE, 0.050 to 0.100 ppm for ETBE, and 0.050 to 0.150 ppm for benzene (Anderson et al., 1995). These samples were collected approximately 1 meter from the fuel nozzle over 15-minute periods. The highest air concentrations of MTBE were measured at a station lacking a Phase II vapor recovery system. In some cases, the concentrations were higher for MTBE at a station using ETBE-oxygenated fuel and were likely due to vapors from the previous fill-up escaping during the refueling. Thus, it may be difficult to ascertain the particular oxygenate to which people are exposed under real-world conditions.

B. Human Exposure Estimates for MTBE

The data on air quality and microenvironments (e.g., at gas pumps, inside cars, in personal garages) are too limited to provide a distribution of MTBE levels for the general population. These data, however, may be used to roughly estimate reasonable worst-case potential exposures, based on certain assumed activity patterns and approximate microenvironmental concentrations. Because of the interest in MTBE, the present evaluation focuses on this compound, even though any potential health effects might result from complex pollutant mixtures of which MTBE is only one component.

Acute as well as long-term exposures are of importance in evaluating potential health risks of oxyfuels. Table 1 illustrates two hypothetical types of people with varying activity patterns and oxyfuel exposure potentials. The concentrations and activity patterns were previously used by Huber (1993) for estimating MTBE exposures and were based on a variety of population-activity studies and microenvironmental measurements of MTBE as described above. Exposure (ppm^.hr) is a function of concentration (ppm) and time (hr). The concentrations in Table 1 are based on measurement averages that were rounded up to the next order of magnitude so as to provide inherent conservatism (i.e., overestimation) in the exposure estimates. The two estimates in Table 1 reflect different assumptions about the microenvironmental concentrations and activity patterns represented. For example, the concentrations of MTBE during refueling in Scenarios I and II differ by an order of magnitude. Scenarios I and II each represent hypothetical persons who visit a gasoline station 1.5 times per week, commute an average of 10 hour/week, visit an auto repair shop four times per year for 15 minutes per visit, and spend about 57 hours per week in an office or public building. However, scenario I assumes that the person lives in a house without an attached garage and does not reside near or spend time around a highway or in the vicinity of a filling station.

Hypothetical person II differs from person I in that the individual lives in a house with an attached garage and spends time outside in the vicinity of a gasoline station or heavily used highway. The higher concentrations of MTBE in the residential garage and home assume evaporative emissions from the vehicle in the garage or a small gasoline spill with the garage door closed. Hypothetical person II represents a "reasonable worst case" scenario (Huber, 1993). More extreme cases are conceivable, but they would probably reflect differences in the occurrence or in the duration of activities rather than reflecting higher average concentrations of MTBE in the microenvironments considered. For example, a person who visits a gasoline station every day to refuel his or her car and who works 40 hours per week outside near a highway or other source of high MTBE levels would not likely be exposed to higher concentrations of MTBE within those microenvironments, but that person's overall exposure might be higher than that of hypothetical person II because of the greater cumulative duration of his or her exposure. Currently it is not possible to state what percentages of the general population might be represented by hypothetical persons I and II, but the term "reasonable worst case" is meant to imply that few individuals would be exposed at higher levels. It is not meant to imply a "high average" exposure. The average exposure for the entire exposed population would be expected to be somewhat lower than hypothetical person I and much lower than hypothetical person II.

Time-weighted average exposure levels may be estimated for the oxyfuel season itself or for an entire year, assuming that the oxyfuel season is limited to a few months in an area that is not required to use reformulated gasoline. During the oxyfuel season, the time-weighted average MTBE exposure of a hypothetical person would be one-half the sum of that person's exposure levels divided by one-half the number of hours in a year e.g. (159/2 ÷ 8760/2 = 0.018 ppm for person I, or 309/2 ÷ 8760/2 = 0.0345 ppm for person II). To calculate an annual time-weighted average exposure, an allowance is made for the assumed use of 1.5% MTBE in nonoxygenated gasoline. This assumption may be a high estimate of the average amount of MTBE in nonoxygenated gasoline because of the relatively limited use of premium (high-octane) fuels containing MTBE. Nevertheless, assuming 1.5% MTBE (which is 1/10 of the 15% MTBE concentration typical of oxygenated gasoline) during the non-oxyfuel season and assuming a 6-month oxyfuel season, the annual time-weighted average MTBE exposure level for hypothetical person I would be [(159/8760)*(6/12)] + (0.1*[(159/8760)*(6/12)]) = 0.010 ppm. The annual time-weighted average MTBE exposure level of hypothetical person II would be 0.019 ppm. For a 4-month oxyfuel season, the annual time-weighted average levels would be 0.007 ppm for person I and 0.014 ppm for person II. If reformulated gasoline containing 10% MTBE by volume were used during the remainder of the year, the annual time-weighted average exposure for a 6-month oxyfuel season would be 0.015 ppm for person I and 0.029 ppm for person II.

It can be assumed that a gasoline fill-up scenario, although brief, would result in the highest acute-exposure concentrations. The highest human exposure is expected when one is near evaporative emissions. Thus, exposure would be greatest when handling gasoline. The highest reported MTBE concentration measured at a filling station was 38 ppm (137 mg/m³), although levels as low as 0.089 ppm (0.32 mg/m³) were also measured at the same station, illustrating the variability in fill-up exposures (Clayton Environmental Consultants, 1991). A more typical worst-case scenario for the MTBE concentration in the breathing zone during fill-up would be 10 ppm (36 mg/m³) MTBE for a few minutes (Johnson, 1993; Lioy et al., 1993, 1994; Clayton Environmental Consultants, 1991). However, higher concentrations are possible, especially in the event of an accidental spill.

For purposes of comparison with the 1-hour human experimental exposure studies (at 1.4 and 1.7 ppm [5 and 6 mg/m³]), discussed below, 1-hour time-weighted average concentrations of MTBE were calculated for two exposure scenarios by using high concentration data. The first scenario assumed highest measured values and involved a 2-minute fill-up (38 ppm or 137 mg/m³), a 30-minute commute associated with a fill-up (0.5 ppm or 1.8 mg/m³), and a 28-minute commute (0.076 ppm or 0.275 mg/m³); the average MTBE concentration was 1.56 ppm (5.6 mg/m³) MTBE. The second scenario used the MTBE levels in Table 1. Scenario 2 assumed a 2-minute fill-up (10 ppm or 36 mg/m³), 2 minutes in a personal garage (1 ppm or 3.6 mg/m³), a 30-minute commute (0.1 ppm or 0.36 mg/m³), 10 minutes in a public garage (0.5 ppm or 1.8 mg/m³), and 16 minutes in a public building (0.01 ppm or 0.036 mg/m³); the average concentration was 0.5 ppm (1.8 mg/m³) MTBE.

In summary, selected hypothetical scenarios suggest that the annual time-weighted average daily personal exposure level for a "reasonable worst case" motorist in the general (nonoccupational) population might be on the order of 0.019 ppm MTBE. This level is not simply a "high average" exposure. The annual time-weighted average exposure levels for most people would be somewhat lower, perhaps closer to the estimate of 0.010 ppm MTBE for hypothetical person I, or even an order of magnitude lower than 0.010 ppm, in view of the rounding up of the data on which the estimates were based. In addition, long-term exposure levels are likely to be lower than those found during short-term measurements. That is, hypothetical person II is unlikely to have consistently high exposure levels from day to day, and the trend over a year or a lifetime would be for exposure levels to regress toward the mean. Thus, in estimating health risks in relation to these exposure estimates, it is important to consider the likely period of exposure over which health effects could be induced. For example, a 4 or 6-month oxyfuel season might in itself pose little risk with respect to lifetime cancer risk but could be of significance with respect to potential effects due to acute exposures. Two illustrative acute-exposure estimates for different scenarios yield averages of 0.5 ppm and 1.56 ppm, reflecting in part the highly variable air concentrations that have been measured at gasoline stations. It must be emphasized that these exposure values are not based on, and make no predictions regarding, the nature of population-exposure distributions. Personal exposure data for probabilistic samples are needed before an exposure assessment for MTBE can provide an adequate characterization of population exposures for health risk assessment purposes.

^a Concentrations are based on measurement averages that were rounded up to the next order of magnitude.

C. Occupational Exposure - MTBE

Since 1990, occupational exposure to MTBE has been assessed under a variety of conditions and for various purposes, most notably in support of evaluations of health complaints associated with exposures. The realm of occupational exposures to MTBE involving gasoline includes exposures to the pure compound during manufacture and transport (for subsequent blending) and exposure to gasoline mixtures during blending, transport, distribution, and sale. Other tangential occupational exposures have been evaluated in jobs where at least a portion of a work shift is spent near an MTBE-blended gasoline source; the most common source is the automobile.

1. Service station attendants

Undoubtedly, the largest occupational group with a significant potential exposure to MTBE is service station attendants. The number of retail automotive service stations has been estimated at 150,000 to 210,000 (ENVIRON, 1990). Even with self service, fuel dispensing undoubtedly continues to be an important source of occupational exposure to MTBE, although no data were available on the number of attendants exposed to reformulated or oxygenated fuels containing MTBE.

In 1990, at the request of the American Petroleum Institute (API), the National Institute for Occupational Safety and Health (NIOSH) evaluated exposure to the gasoline components MTBE, benzene, toluene, and xylene at six retail automotive service stations (NIOSH, 1993a). To reflect MTBE's multiple uses and the range of potential exposures, two facilities were selected to represent its ubiquitous use as an octane enhancer (generally blended at less than 1% of the fuel); two facilities were selected to represent requirements to use MTBE in oxygenated fuel (blended at 12-15 liquid volume percent [LV%] of the fuel), and two with stage II-type vapor-recovery systems were selected to determine the relative effectiveness of these engineering controls.

Of 16 PBZ samples collected from attendants working at stations that sold gasoline with less than 1% MTBE, 15 were below the lowest detectable concentration (LDC) of 0.02 ppm. The one sample above the LDC was reported at 0.16 ppm. At stations using at least 12% MTBE blends, 41 PBZ samples ranged from 0.03 to 3.89 ppm, averaging 0.54. At stations equipped with stage II vapor recovery systems, 15 of the 48 PBZ samples had detectable levels (above the LDC), ranging from 0.02 to 0.73 ppm, averaging 0.18 ppm. Sampling and analysis for MTBE was by the NIOSH Method 1615 (Palassis, 1993). Benzene exposures among this same population averaged approximately 0.07 ppm.

The study included an assessment of factors, such as climatic conditions and work practices, affecting the extent of exposure. Statistical analysis, using step-wise linear regression, indicated that MTBE exposures were most affected by wind velocity, followed by the amount of fuel dispensed by the attendant. The report also noted that benzene exposures were not significantly affected by the amount of MTBE in the fuel.

In 1994, NIOSH conducted a follow-up study to assess short-term, or "peak," exposures among attendants (Cook, 1995). Two service stations in New Jersey were selected, and direct-reading real-time measurements for total hydrocarbons, as a surrogate for peak MTBE exposures, were made in attendants' breathing zones, as were long-term, full-shift determinations of MTBE exposures. A video-monitoring overlay technique was used to determine the predominant sources of peak exposures. Twenty-one of the full-shift samples taken from the PBZs of the station attendants who were evaluated for MTBE exposure ranged from 0.08 to 1.27 ppm, with a geometric mean (GM) of 0.38 ppm. Total hydrocarbon exposures averaged 1.89 ppm, with peaks as high as 327 ppm. NIOSH is currently assessing the magnitude of associated MTBE peak exposures.

Service station attendants' exposures were again assessed by NIOSH (NIOSH, 1993b) as part of a larger effort in support of a CDC epidemiologic investigation of public health complaints reportedly associated with exposure to MTBE in Fairbanks, Alaska. Two samples were obtained from attendants at service stations using MTBE as an octane enhancer (approximately 1% MTBE). The use of MTBE as an oxygenated-fuel had previously been discontinued after reports surfaced of ill health effects associated with its use. MTBE concentrations were reported at 0.03 ppm (the LDC) and 0.15 ppm; both results were within the range of exposure concentrations determined from the previous NIOSH study.

In 1993, in support of an EPA solicitation for MTBE exposure data, the API contracted for a service station study with ITAir Quality Services (API, 1994) at 10 service stations in the northeastern United States. In addition to measuring MTBE, ITAQS measured benzene, toluene, ethyl benzene, xylene, formaldehyde, and carbon monoxide in attendant and customer breathing zones, near the pump islands, and at perimeter locations. For comparison of sampling or analytical methods, attendant exposures were measured using both charcoal-tube samplers and canisters. Service stations with and without vapor-recovery systems were included in the assessment. The MTBE content of the gasoline ranged from 13.4 to 15.7 LV% at all stations monitored. Of the eight, 4-hour, side-by-side charcoal tube or canister samples collected at vapor-recovery stations, seven were above the analytical detection limit for MTBE (detection limit not specified), ranging from 0.084 to 0.558 ppm and averaging (geometric mean) 0.33 ppm. Two 8-hour PBZ charcoal-tube samples collected at stations without vapor-recovery systems had MTBE concentrations of 0.554 and 1.191 ppm, respectively.

In 1994, the API contracted with NATLSCO for an evaluation of exposure to oxygenated fuel components among attendants and mechanics at sixteen service stations in four geographical areas (API, 1995). For comparison purposes, sampling was conducted during the winter (February - April) oxyfuel season, and summer (July - August) non-oxyfuel season. During the winter, MTBE was present in the fuel of the stations in approximate amounts ranging from 10-17 wt%. During the summer, no oxygenates were detected above the 0.1 wt% analytical limit of detection.

During the "winter phase", 51 long-term (generally greater than six hours) PBZ samples for MTBE ranged from 0.03 to 0.5 ppm, with a geometric mean of 0.2 ppm. Fifty-nine short-term (generally 15 - 20 minutes) PBZ samples ranged from 0.32 - 2.1 ppm, with a geometric mean of 0.6 ppm. During the "summer phase", 53 long-term PBZ samples ranged from 0.03 - 0.42 ppm, with a geometric mean of 0.08. Sixty-one short-term samples ranged from 0.19 - 0.33 ppm, averaging 0.31 ppm. The author notes that summary statistics (range and means) include non-detected results; they were assigned their LDC value and included in range and GM computations. This conservative approach yields overestimates of actual average exposures.

In 1992, the API surveyed member companies to obtain MTBE occupational exposure data (API, 1994). Of the samples collected at service stations, MTBE concentrations of 13 full-shift samples ranged from 0.09 to 34 ppm, averaging 0.77 ppm (geometric mean). The author noted that, in addition to fuel attendants, samples were collected from mechanics, weights and measures inspectors, and people repairing fuel pumps.

2. Auto mechanics

As with service station attendants, auto mechanics and auto technicians represent a large population with potential for significant exposure to gasoline. In the API 16 service station study (API, 1995a), 86 long-term (generally greater than six hours), PBZ samples for MTBE ranged from 0.02 to 2.6 ppm, averaging (geometric mean) 0.12 ppm for the "winter phase", and from 0.02 to 0.18 ppm, averaging 0.03 ppm during the "summer phase". Short-term samples (n=88) ranged up to 32 ppm, with winter and summer geometric mean exposures of 1.04 and 0.42 ppm, respectively. As with the attendant sample results, these data include non-detectable values, which overestimates the average exposures.

In the Fairbanks study (NIOSH, 1993b), 17 of 26 PBZ samples from auto mechanics were above the LDC for MTBE (0.03 ppm). Results ranged from less than 0.03 to 0.45 ppm, averaging 0.06 ppm (geometric mean). As previously mentioned, at the time of the NIOSH investigation, MTBE use as an oxygenate had been discontinued; its use was only as an octane enhancer (generally less than 1% MTBE/gasoline blend).

In a similar study in Stamford, Connecticut, (NIOSH, 1993c), 23 of 28 PBZ samples collected from auto mechanics were above the LDC, ranging from less than 0.03 to 12.04 ppm, averaging 0.11 ppm. The MTBE content of five bulk gasoline samples collected from the area ranged from 13 to 17 LV%.

In a third NIOSH study supporting a CDC epidemiologic investigation in Albany, New York, an area not using oxygenated gasoline (NIOSH, 1993d), three of eight PBZ samples from mechanics were above the LDC, ranging from less than 0.03 to 0.14 ppm and averaging 0.03 (geometric mean). The MTBE content of the gasoline was reported to be in concentrations of up to 10%.

3. Other occupational MTBE exposures related to gasoline

In the three NIOSH evaluations of MTBE exposure in support of CDC epidemiologic investigations (NIOSH 1993b, NIOSH 1993c, NIOSH 1993d), researchers evaluated occupations in which people had significant exposure to motor vehicles and traffic (but not gasoline) in an effort to determine the extent of exposure to MTBE. These occupations included 1) service station cashiers or managers, 2) service advisors, 3) parking meter attendants, 4) animal control personnel, 5) truck drivers, and 6) taxi drivers. Of the 26 PBZ samples collected from people in these occupations in Fairbanks, Stamford, and Albany, only one sample, reported at 0.10 ppm from a service station manager, was above the LDC for MTBE. From these same investigations in Fairbanks and Stamford, exposure to MTBE by commuters was assessed. Commuters were defined as people whose occupations required them to spend a significant amount of their time driving. None of 14 PBZ samples from commuters was above the 0.03 ppm LDC. The last major category assessed in these studies was parking lot attendants. Of six PBZ samples from people in this group, one was reported at 0.10 ppm, which is above the LDC for MTBE.

4. Other industry exposure assessments

From a survey of 17 member company's occupational exposure data for MTBE, the API published summary statistics for PBZ long-term and short-term samples (API, 1995b), see Table 2. Although additional environmental data were presented in the API report, the data in Table 2 represent samples for which the sampling time was known/available. As expected, due to the numerous contributors, sampling and analyses varied between the OSHA Method 7, NIOSH method 1615, and in-house, industry-developed methods.

In summary:

• The time-weighted average MTBE exposures of service station attendants ranged up to approximately 4 ppm, averaging below 1 ppm.
• The time-weighted average MTBE exposures for auto mechanics ranged up to 12 ppm, averaging below 0.1 ppm.
• Time-weighted average MTBE exposure related to automobiles (fuel containing MTBE) ranged up to 0.1 ppm (only one of 26 samples was above the 0.03 ppm LDC).
• Time-weighted average exposure to MTBE associated with its manufacture/distribution may range up to approximately 700 ppm (transport of pure MTBE; condition not specified). The geometric mean for this category was 0.30 ppm. The highest geometric mean for any category was 1.73 ppm (blending pure MTBE).

D. Metabolism, Disposition, and Toxicokinetics of MTBE in Animals

The major metabolic pathway of MTBE in both animals and humans is its oxidative demethylation, which leads to the formation of t-butyl alcohol (TBA) and formaldehyde. There is evidence that oxidative demethylation of MTBE is catalyzed by the cytochrome P450 enzymes (Brady et al., 1990). TBA was identified in the blood and expired air of rats which received ¹⁴C-MTBE (radiolabeled at the central butyl carbon) by oral, intravenous, dermal, or inhalation exposure (Bio-Research Laboratories Report # 38843; Exxon 1988). Secondary metabolism of TBA results in the formation of 2-methyl-1,2-propanediol, which is further metabolized to (alpha-hydroxy isobutyric acid (Bio-Research Reports # 38843-38844, 1990). Both metabolites were identified in the urine of rats which received ¹⁴C-MTBE (Bio-Research Report # 38843-38844, 1990). In vitro studies with rat liver microsomes also indicated that TBA may undergo oxidative demethylation to produce formaldehyde (Cederbaum and Cohen, 1980). A negligible portion of the administered MTBE dose (1% or less) to the rats was converted to ¹⁴C0₂ (Table 3).

In another study (API 1984), significantly larger amounts of ¹⁴C0₂ (ca. 7.0% of dose) were reported to have been expired after intraperitoneal administration of 232 mg ¹⁴C-MTBE/kg (radiolabeled at the methyl and the central butyl carbons). Formaldehyde was not reported in rats which received ¹⁴C-MTBE by oral, intravenous, dermal, or inhalation exposure (Bio-Research Laboratories Reports # 38842-38845, 1990). However, it was reported that ¹⁴C-formic acid accounted for most of the MTBE metabolites which were excreted in the urine and feces (approximately 3 and 1 % of dose, respectively) of rats that received 232 mg ¹⁴C-MTBE/kg by intraperitoneal administration (API, 1984).

In vitro metabolism studies revealed that incubating MTBE (5 mM) with rat hepatic microsomes resulted in the formation of relatively equimolar amounts of TBA and formaldehyde (Brady et al., 1990). Additional evidence for formaldehyde formation from MTBE was reported in studies which investigated the in vitro metabolism of TBA using rat hepatic microsomes (Cederbaum and Cohen, 1980). Results of these studies showed that oxidative demethylation of TBA by rat microsomes resulted in the formation of formaldehyde.

The disposition and toxicokinetics of ¹⁴C-MTBE and its major metabolite, TBA, were compared in mature adult male and female F344 rats after oral, intravenous, inhalation, and dermal exposure (Bio-Research Laboratories Reports #38842-45, 1990). ¹⁴C-MTBE (radiolabeled at the central butyl carbon) was administered to groups of rats in a dosing vehicle of 0.9% saline at a single dose of 40 mg/kg body weight using gavage, intravenous, or dermal (occluded application) routes. A higher dose of 400 mg/kg body weight was similarly administered to rats using oral or dermal application. A summary of the disposition of MTBE is presented in Table 3.

The major routes of MTBE elimination after oral, intravenous, intraperitoneal or dermal exposure were via the lungs as expired organic volatiles and via the kidneys as urinary metabolites (Table 3). Quantitative analysis of charcoal-trapped expired organic volatiles showed that the unchanged parent compound accounted for most of the organic volatiles exhaled by these rats. The portions of MTBE dose expired as unchanged parent compound and TBA were relatively higher after oral compared to intravenous exposure (Table 3). Elimination of MTBE via the lungs was also demonstrated in earlier studies conducted after MTBE was administered to Fischer rats orally or intravenously (Exxon, 1988). Additionally, exhalation of unchanged MTBE via the lungs was reported in mice as the major elimination pathway of MTBE after intraperitoneal administration at 50, 100, and 500 mg/kg (Yoshikawa et al., 1994). Pulmonary elimination of parent MTBE in mice ranged from 23% to 69% of the administered dose (Yoshikawa et al., 1994). In a study where MTBE was administered to CD rats intraperitoneally, a surprising 91-92% of the dose was eliminated in the expired air as parent MTBE (Table 3).

TBA exhalation accounted for 3% or less of the administered dose after all 3 routes of administration (Table 3). Two urinary metabolites, 2-methyl-1,2-propanediol and (alpha-hydroxy isobutyric acid, were identified in rats which received MTBE (Bio-Research Laboratories Reports #38843-38844, 1990). These 2 metabolites are most likely formed as a result of secondary metabolism of TBA. Fecal elimination of MTBE-derived radioactivity was minimal and accounted for approximately 1% of the administered dose regardless of the route of administration (Table 3).

The toxicokinetic parameters of MTBE and TBA depend on the dose and route of administration (Table 4). While the half-life (t_1/2) of MTBE ranged from 0.45 to 0.62 hour after the low oral and intravenous dose, it ranged from 0.79 to 0.93 hour after administration of the high doses (Table 4). On the other hand, the t_1/2 of MTBE after intraperitoneal and dermal application varied from 0.8-1.0 and 0.9-2.3 hours, respectively (Table 4). The t_1/2 of inhaled MTBE was unaffected by dose or repetitive exposure to MTBE and ranged from 0.51-0.63 hour (Table 4). Maximum plasma concentration (C_max) was higher among males than females after oral administration of MTBE (Table 4), and the difference was statistically significant only after intravenous administration. The total plasma clearance (CL) of MTBE was relatively similar in all animals receiving similar doses of MTBE regardless of the route of administration and ranged from 273 to 481 ml/hr. TBA, the main metabolite of MTBE, was detected in the expired air; however, products of TBA's secondary metabolism (2-methyl-1,2-propanediol and alpha-hydroxy isobutyric acid) were detected in the urine (Bio-Research Laboratories Report #38843, 1990).

In another study, MTBE metabolism and toxicokinetics were investigated in F344 rats of both sexes using a 6-hour single exposure to 400 ppm (calculated doses in males and females are 215 and 293 mg/kg, respectively) or 8000 ppm (the calculated doses in males and females were 4220 and 5840 mg/kg, respectively) using nose-only inhalation (Bio-Research Reports Laboratories #38844-38845, 1990). Using the same route of exposure, the toxicokinetics of MTBE was also investigated using repeat 6-hour daily exposure to 400 ppm (calculated doses in males and females were 245 and 344 mg/kg, respectively) after 14 days of 6-hour daily exposures to unlabeled MTBE (Bio-Research Laboratories Reports #38844-38845, 1990).

In contrast with routes of elimination when ¹⁴C-MTBE was administered orally, dermally, intravenously, or intraperitoneally, the main route of post exposure elimination of MTBE-derived radioactivity after nose-only inhalation was in the urine; the second major route of elimination was exhalation of organic volatiles (Table 3). However, the percentage of dose eliminated via each of the 2 routes (lungs and the kidneys) may actually be different since exhalation of MTBE and TBA during the 6-hour exposure to MTBE was not accounted for in these studies. Minimal changes in the disposition of MTBE were observed after repeat nose-only inhalation exposure to 400 ppm. In both exposure regimens, approximately 60-70% of the dose was eliminated in the urine compared to 15-20 % of the dose exhaled in the expired air. Furthermore, the ratio of MTBE/TBA exhaled in the expired air was lower in animals which received MTBE via nose-only inhalation compared to oral, intravenous, or dermal exposure (Table 3). Significant changes in the disposition of MTBE were observed after exposure to 8000 ppm. A decline in the portion of the dose eliminated in the urine in association with an increase in the exhalation of MTBE was observed (Table 3). In addition, the ratio of MTBE/TBA exhalation increased after exposure to 8000 ppm as a result of increased exhalation of unchanged MTBE (Table 3). Further, significant differences in the AUCs of the 2 doses were observed (Table 4).

In summary, studies of the metabolism, disposition, and toxicokinetics of MTBE in animals demonstrated that:

• MTBE was rapidly absorbed into the circulation from all sites of administration and distributed to all major rat tissues. Maximum blood concentrations of MTBE were rapidly achieved (15 minutes after oral administration vs. 4-6 hours after dermal application). Metabolism and elimination of MTBE and its metabolites also proceed rapidly regardless of the route of administration.

• Absorption of dermally applied MTBE was somewhat limited and slower than absorption after other routes. The relative bioavailabilty of dermally applied MTBE was approximately 20% and 40% at the high and low doses, respectively. It is likely that dermal absorption of MTBE may be limited by the high volatility of MTBE.

• Elimination of MTBE and its metabolites occurred mainly via the lungs and the kidneys. Exhaled organic compounds comprised MTBE and TBA and the ratio of the two components was dose and route dependent. Clearance of unchanged MTBE via the lungs is likely to be a function of blood/air partition coefficient and appears to be directly proportional to the Cmax of MTBE achieved. A small portion of the administered dose was eliminated as CO₂. A negligible portion of the dose was eliminated in the feces.

• Urinary elimination of MTBE-derived radioactivity was also dose- and route-dependent and two urinary metabolites, 2-methyl-1,2-propanediol and (alpha-hydroxy isobutyric acid, were identified in the urine of rats which received MTBE. These 2 metabolites are most likely formed via the secondary metabolism of TBA. MTBE metabolism to formaldehyde was demonstrated in vitro using rat liver microsomes (Brady et al., 1990). However, there is little evidence for the formation of formaldehyde in vivo. One study reported the elimination of small amounts of formic acid in the urine and feces of rats that received MTBE by intraperitoneal administration (API 1984).

• From the available experimental evidence, it is proposed that MTBE undergoes oxidative demethylation via the cytochrome P450 enzymes to yield TBA and formaldehyde. TBA may be eliminated unchanged in the expired air or may undergo secondary metabolism resulting in the formation of 2-methyl-1,2-propanediol and (alpha-hydroxy isobutyric acid; both are eliminated in the urine. In vitro evidence also suggested that TBA may undergo oxidative demethylation to produce to formaldehyde. Identification of CO₂ in the expired air of MTBE-treated rats is indicative that a portion of the administered MTBE dose was subjected to complete oxidation. It is likely that complete oxidation of MTBE to CO₂ may proceed via the formaldehyde intermediate.

• Since MTBE metabolism is catalyzed by the cytochrome P450 enzymes, concurrent exposure to other environmental chemicals (e.g. gasoline emission combustion product, cigarette smoke) which are known to affect this enzyme system may also alter MTBE metabolism and its potential toxicity or carcinogenicity.

• Although human studies showed that exposure to MTBE, similar to animal studies, leads to the appearance of TBA in blood, no reports of MTBE metabolism to formaldehyde in humans is currently available. However, there is no reason to believe that humans would metabolize MTBE in a qualitatively different manner than animals. In order to assess the contribution of MTBE metabolites to its overall toxicity, it is essential to fully investigate the qualitative and quantitative behavior of MTBE kinetics in both humans and animals. Determination of the rates of metabolism as well as the internal dose of MTBE, and its main metabolites (TBA and formaldehyde) will be critical for understanding the mechanisms of MTBE-induced toxicity. Further, this data will be essential for extrapolation from animals to humans and for more accurate assessment of the potential health risks to humans from exposure to MTBE.

• Differences in the disposition and toxicokinetics parameters of MTBE after various doses administered by the same route and differences after the same dose administered via various routes suggested that there is a potential for the saturation of MTBE metabolizing enzymes at high exposure levels and after bolus administration of MTBE.

• Studies on the disposition and toxicokinetics of MTBE in experimental animals after oral, intravenous, dermal, intraperitoneal, and inhalation exposures suggested that neither MTBE nor any of its metabolites has the potential for bioaccumulation in animals.

• Some evidence of gender differences in the disposition and toxicokinetics of MTBE is evident from some of the data presented in Tables 3 and 4. However, the differences were not consistent and therefore the biological significance of such differences remains to be established.

C_max = maximum plasma concentration; AUC = area under the curve; T_1/2 = half life; CL = total clearance; NA = data not available.

E. Biological Measurements in Humans

1. Controlled human exposure studies

To date, three controlled human exposure studies on MTBE have been conducted. These three studies had similar designs and were aimed at evaluating internal dose levels resulting from known controlled exposure and the pharmacokinetics of uptake and decay.

In 1993, EPA and CDC collaborated to examine the internal dose concentrations of MTBE and its metabolite TBA resulting from exposing one male and one female volunteer for 1 hour to a 1.39 ppm MTBE concentration in a controlled environmental chamber (Gerrity et al., 1993; Prah et al., 1994; Buckley et al., 1995). MTBE and TBA levels in blood and urine and MTBE in the breath of these two subjects were determined both during the exposure phase and for 8 hours after the subjects were removed from the exposure. These subjects had significantly different body mass - the male weighed 102.5 kg and the female weighed 66.5 kg.

In both subjects, blood MTBE levels showed a rapid increase during the exposure phase but did not reach a steady-state plateau after 1 hour. Once the subjects were removed from the chamber, the blood MTBE levels decreased rapidly indicating that mo st of the internal dose quickly leaves the body, but in one subject these levels did not return to pre-exposure levels even after 7 hours. TBA levels in blood also rose quickly after the exposure began, but there was a much longer plateau period that extended over the entire 7-hour evaluation. Breath measurements on these subjects did not return to baseline after 7 hours in either case (Buckley et al., 1995).

MTBE levels measured in urine were of similar concentration and followed a similar course to blood MTBE concentrations with a rapid rise and decay. TBA levels in urine increased to a plateau, which remained constant for a number of hours, but the rise in these levels appeared to be delayed for blood TBA. Levels of MTBE in the breath also showed a similar response to levels in blood and urine with a rapid increase upon the initiation of exposure. The rate of increase slowed with time, but did not reach a plateau during this 1-hour exposure period. Thus, these results show that there is a rapid equilibration among blood, breath, and urine levels of MTBE. The metabolism of MTBE to TBA is a rapid process, and even though a large portion of MTBE is exha led unchanged, a fraction is metabolized to form TBA. Excretion of unmetabolized MTBE should also be considered as a significant elimination mechanism since the urine levels of this compound rapidly increase upon exposure.

The MTBE blood level reached after a 1-hour exposure to 1.39 ppm MTBE in air for the male subject was 8.2 ug/L and for the female subject, 14.1 ug/L. Thus, the response of MTBE blood levels was 1.7 times higher in the second subject than in the first. The breath levels in the second subject were also much higher than in the first subject. After 1 hour, MTBE levels in the breath were 43.0 ug/L in the first subject and 69.5 ug/L in the second, so that the second subject's breath MTBE level was 1.6 times higher than the first subject's breath MTBE level. This figure is in agreement with the blood results. These limited findings suggest a dependence of the internal dose of MTBE on body mass that differed in the two subjects by a ratio of 1.5. In contrast, the level of TBA in blood was similar for these subjects, reaching maximum levels of 9.5 ug/L and 10.4 ug/L.

Evaluation of the blood and breath MTBE concentrations after removal from exposure indicates that the decay process over time is multiexponential. Fitting the blood and breath to a three-exponential model yields residence times of 10.5 minutes, 75.1 minutes and 31 hours; and 3.3 minutes, 33 minutes and 8 hours, respectively. Because of the limited number of samples taken during the decay period, there is a wide uncertainty in these residence times, but the presence of a multiexponential decay is clear. This finding explains how MTBE can be eliminated rapidly from the body immediately after exposure stops and still not return to baseline 7 hours after the subjects were removed from exposure to MTBE. Previous studies have discovered this same finding with other VOCs (Pellizzari et al., 1992). In these previous studies, the long-term exponential decay was given as evidence of the deposition of VOCs into deeper body stores, most likely in adipose tissue. The determination of a long-term exponential decay for MTBE concentration suggests that, upon exposure, a significant portion of this compound also deposits in deeper body stores. The studies performed by the EPA and CDC cited earlier were limited to short-term exposures to people who had been exposed recently to MTBE. A slowly eliminated component suggests that, with repeated exposures, the internal dose of MTBE in the body may remain elevated over a long time period. There will be short-term spikes in the internal dose of MTBE as each exposure occurs, but this compound will give a steady-state level that depends on the frequency of exposure events and the exposure levels during these events. Pre-exposure levels of MTBE will be indicative of long-term exposure integration, and samples taken immediately after or during exposure will show short-term levels. The slow excretion of TBA suggests that this compound will accumulate even more than MTBE, so that a substantial internal dose level of TBA may result even when exposure to MTBE occurs at lower levels or less often.

In 1993, investigators at Yale University (Cain et al., 1993) measured blood MTBE and TBA levels in four subjects before, during, and after 1 hour of exposure to 1.7 ppm of MTBE. Measurements were made for 90 minutes after the end of exposure. This study also showed a rapid rise of MTBE blood concentrations during the exposure period with failure to reach equilibrium after 1 hour. MTBE concentrations reached an average of 17.1 ug/L after 1 hour and decayed after the subjects were removed from the exposure. The rate of decay appears to be slower than that reported in the EPA/CDC study in which the half-life was reported to be approximately 40 minutes; however, after 90 minutes, the MTBE levels were still a factor of 9 above the pre-exposure level. Peak MTBE blood concentrations were equivalent to the second EPA/CDC subject after differences in exposure level are taken into account.

Swedish researchers (Nihlen et al., 1994; Johanson et al., 1995) have performed a series of controlled chamber MTBE-exposure experiments at concentrations that were significantly higher than those described in the first two studies and that lasted for 2 hours. They measured levels of MTBE and TBA in blood, urine, inhaled air, and exhaled air during and after exposure of 10 healthy male volunteers to 5, 25, and finally, 50 ppm MTBE vapor during light physical exercise. They monitored blood levels for 24 hours (48 hours at 50 ppm) after the cessation of exposure. Low uptake, high post-exposure exhalation, and low blood clearance indicated the slow metabolism of MTBE.

Blood concentrations of MTBE reached a maximum concentration of approximately 1.2, 6.5, and 12.5 uM, which are equivalent to 106, 570, and 1100 ug/L for the 5, 25, and 50 ppm MTBE exposures. These levels are approximately twice those expected from the previous studies. The differences can be explained at least in part by the longer exposure time and by the subjects' light exercise during exposure. The pharmacokinetics of MTBE in blood was determined to require a three-exponential fit of the data with half-lives of 10 minutes, 1.5 hours, and 19 hours. These results are in good agreement with the EPA/CDC results and support the indication that, although most of the blood concentration of MTBE is quickly eliminated, long-term elevated levels of MTBE may occur with repeated exposure. The area under the concentration curves of blood MTBE and blood TBA were linearly related to the MTBE exposure level, suggesting that the toxicokinetics are linear up to at least 50 ppm. In contrast to MTBE however, blood TBA continued to increase during the 2-hour MTBE exposure, then leveled off and started to decline about 6 hours later. The post-exposure half-life of TBA in blood was 10 hours.

The study by Nihlen et al. 1994 also found detectable levels of MTBE and TBA in urine as did the EPA/CDC study. Less than 1% of the absorbed dose of MTBE was excreted as TBA in urine within 24 hours; this finding may indicate further metabolism of TBA in humans as has been shown in rats (Bio-Research Laboratories Report #38845, 1990). Urinary MTBE levels decreased rapidly after exposure ended, and TBA concentrations changed during the uptake and elimination phases with a rapid increase, long plateau phase, and a half-life of 7-9 hours. The presence of MTBE and TBA in urine and the longer half-life of MTBE in urine compared to blood suggest that urine may be a useful matrix for determining internal-dose levels of MTBE and TBA. Since people are more likely to be willing to give a urine specimen than a blood sample, it is probable that subject participation would increase. However, since urinary volume output is variable, a single measurement of TBA or MTBE may not be as meaningful as a similar measurement in blood. Use of MTBE or TBA in urine must be fully investigated before this matrix can be accepted as a sensitive measure of MTBE exposure.

2. Epidemiologic field studies

a. Fairbanks, Alaska

For workers in Phase 1, the median pre-shift concentration of MTBE in blood was 1.15 ug/L (range 0.1 - 27.8 ug/L), with an increase to a median post-shift concentration of 1.80 ug/L (range 0.2 - 37.0 ug/L). This difference was statistically significant. Among workers in Phase 2, median pre-shift MTBE levels were 0.21 ug/L (range < 0.05 - 4.35 ug/L) and the median postshift concentration was 0.25 ug/L (range < 0.05 - 1.44 ug/L). The results show that blood MTBE levels increased during the work-shift while MTBE was being used as a fuel oxygenate, and blood levels were lower after the cessation of the oxygenated fuels program.

In Phase 1, the blood MTBE levels among commuters changed from 0.18 ug/L before they commuted to 0.83 ug/L afterward. In Phase 2, the blood MTBE levels before the commute (0.09 ug/L) and after the commute (0.10 ug/L) were not significantly different (t-test). Since many people commute to work each day, the increase in MTBE internal dose levels among commuters suggests that a large proportion of the public in locations where MTBE is present in gasoline receive a measurable exposure to this compound.

It is significant that blood MTBE levels were not below detection limits for either workers or commuters before the work shift or morning commute (the period of MTBE exposure). The median blood MTBE level in 15 participants in the Third National Health and Nutrition Examination Survey was below the detection limit of 0.05 ug/L (Ashley, 1993). Elevated levels measured before exposure support the results of controlled human exposure studies because they suggest that MTBE levels in the body have not returned to baseline even after 16 hours. Thus, daily exposures may yield elevated levels for a time much longer than the estimated half-life.

In the Fairbanks study, there was a significant correlation between the difference between pre- and post-shift blood MTBE levels among workers and in workplace air concentrations. For these workers, the median air concentration of MTBE was 0.1 ppm and blood levels showed a statistically significant mean difference between pre- and post-exposure samples of 0.65 ug/L. Among some of the workers whose exposure was greater, air levels of 0.55 ug/L yielded a difference between pre- and post-exposure samples of 10 ug/L. This finding is in agreement with the EPA/CDC controlled-chamber exposure study in which air levels of 1.4 ppm MTBE in the chamber yielded 11 ug/L MTBE in the blood. For the workers, the internal dose levels of MTBE were higher, since the workers were exposed for 8 hours rather than 1 hour as in the controlled exposure studies. Blood levels do not increase linearly as time increases, because the internal dose levels begin to plateau after about 1 hour. Thus, the internal dose levels of MTBE are a function of both exposure time and exposure concentration and not just their product as exposure is normally defined.

b. Stamford, Connecticut

The measurements of blood MTBE levels among car-repair workers in Stamford, Connecticut, is in excellent agreement with the levels found among the workers in Fairbanks. Thus, this segment of the population receives a substantial MTBE exposure even in a region of the country that does not have Alaska's extreme conditions. Internal dose levels of MTBE among commuters were lower than those found in Fairbanks. This difference may be due to the differences in driving habits during the periods when these studies occurred. The first phase of the Fairbanks investigation took place during the winter when commuters are more likely to not open their car windows, thus reducing the free flow of fresh air into the vehicle. In the Stamford study, samples were collected at the beginning of spring, when ventilation through the vehicle may have reduced the extent of exposure. Since the oxygenated fuels program is chiefly in effect during the winter months, the weather may have had a significant effect on the extent of exposure of commuters.

3. Summary: Biological exposures in humans

Studies in humans of MTBE metabolism suggest that, with repeated exposures, levels of both MTBE and TBA may be elevated in biological fluids for a time much longer than the half-life with TBA doing so to a larger extent as a result of the longer residence times for this metabolite. Exposure will be integrated over a period of days for MTBE and possibly longer for TBA when repeat exposure to MTBE occurs. Thus, there will be repeated spikes in the internal dose immediately after exposure followed by a steady-state level between exposure events.

By carefully timing sample collection with exposure events, it is possible to evaluate exposure and to gain insight into the duration of either short-term or long-term MTBE levels. Internal-dose concentrations found among workers and commuters indicate that both highly exposed populations and the commuting public experienced increases in internal-dose levels of MTBE when the oxygenated fuels program was in effect.

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