National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency,
* Research Triangle Park, North Carolina 27711, and
Washington, DC 20460
Received December 1, 2000; accepted February 1, 2001
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ABSTRACT |
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Key Words: MTBE; methyl tertiary butyl ether; risk assessment; health effects; inhalation; water contamination; odor; taste; animal models; review; public policy.
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INTRODUCTION |
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Health Risks of MTBE |
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In 1991, EPA used the data available from these studies to derive an inhalation reference concentration (RfC). The RfC is defined as an estimate (with uncertainty spanning about an order of magnitude) of a continuous inhalation exposure level for the human population (including sensitive subpopulations) that is likely to be without appreciable risk of deleterious non-cancer effects during a lifetime. After additional data on the effects of chronic exposures became available in late 1992, the initial RfC of 0.5 mg/m3 was revised to 3 mg/m3, based on findings of increased liver and kidney weights and increased severity of spontaneous renal lesions in female rats, as well as increased prostration in females and swollen periocular tissue in male and female rats (IRIS, 1993). When this value of 3 mg/m3 was compared with "worst case" chronic inhalation exposure scenarios, yielding time-weighted average exposure levels of less than 0.2 mg/m3 MTBE, it appeared unlikely that the general population would be at appreciable risk of non-cancer health effects from MTBE (U.S. EPA, 1993U.S. EPA, 1994
). Subsequent reviews and assessments by other organizations (Health Effects Institute, 1996
; Interagency Oxygenated Fuels Assessment Steering Committee, 1997
; NRC, 1996
) have been consistent with this conclusion.
Other questions about the health risks of MTBE have been more contentious, particularly with respect to the potential for acute health effects and for carcinogenicity from longer-term exposure. The issue of acute health effects arose soon after the introduction of the oxygenated gasoline program in the fall of 1992. Complaints of headache, nausea, eye and nose irritation, and other symptoms began to be reported in Fairbanks, Alaska and some other locales where the new oxygenated winter fuel was being used. In response, several studies were initiated to investigate the basis for such symptom reports. Some of these studies were conducted in communities where people were likely to be exposed to oxygenated gasoline (e.g., Mohr et al., 1994; White et al., 1995), and some were performed under controlled experimental inhalation conditions with either human volunteers or laboratory animals (e.g., Cain et al., 1996; Johanson et al., 1995; Prah et al., 1994; Tepper et al., 1994). Although the presence of the additive or one of its metabolites, tertiary butanol (TBA), could confirm exposure to MTBE in blood, an association between exposure indicators and symptoms or signs could not be clearly established. In short, no basis could be determined for the acute symptoms that had been reported, but the possibility that some individuals were especially sensitive to MTBE could not be ruled out.
Subsequent attempts to investigate self-described sensitive individuals under controlled laboratory conditions have met with mixed success. Even recruiting complainants for participation in controlled-exposure studies has been difficult (Fiedler et al., 2000; Prah, personal communication). Fiedler et al. (2000) have reported the only study to date that has evaluated the responses of self-reported sensitive (SRS) subjects under controlled conditions. Twelve SRS subjects were compared with 19 control subjects under four exposure conditions: clean air, gasoline alone, gasoline with 11%-vol MTBE, and gasoline with 15%-vol MTBE. The two concentrations of MTBE corresponded to the levels that have typically been used in winter fuels for CO control (15%-vol) and in reformulated gasoline for ozone control (11%-vol), with the exposure concentrations approximating documented exposures during refueling. Compared with control subjects, the SRS subjects reported significantly more symptoms of all types (including some not previously associated with complaints about MTBE) under all conditions, including clean air. Other than these subjective responses, the SRS and control subjects did not differ on neurobehavioral or physiological endpoints or in their ratings of the odors of the exposure conditions. However, the SRS subjects did report significantly more symptoms (but no other objective response measure) when exposed to 15%-vol MTBE-gasoline than to clean air or, for that matter, 11%-vol MTBE-gasoline. Thus, it can be argued that SRS subjects were indeed shown to be more "sensitive" to 15%-vol MTBE-gasoline and that this differential symptom response was not mediated by their ability to discriminate the different conditions by odor. On the other hand, it can also be argued that the lack of difference in symptom reports between 11%-vol MTBE-gasoline and gasoline alone (or even clean air) shows there may be "no problem," even for these SRS individuals, with MTBE-oxygenated reformulated gasoline, which constitutes the vast majority of the current U.S. usage of MTBE. But generalizing from such a small sample of subjects is problematic, so it is not likely that the debate on acute health effects can be resolved on the basis of this study.
The cancer risk of MTBE is also still unresolved. Three long-term studies have been conducted with laboratory rodents, two by inhalation in rats and mice (Bird et al., 1997) and one by gavage in rats (Belpoggi et al., 1995
, 1998
). The inhalation study showed an increased incidence of testicular interstitial cell adenomas and renal tubular cell tumors in male Fischer 344 rats at 10,800 and 28,800 mg/m3. An increased incidence of hepatocellular adenomas was observed in female CD-1 mice at 28,800 mg/m3. In Sprague Dawley rats given MTBE in olive oil by gavage at 0, 250, or 1000 mg/kg bw, females had an increased incidence of lymphomas and leukemia, and males had an increased incidence of testicular interstitial cell adenomas. In addition, two major metabolites of MTBE, namely TBA and formaldehyde, have shown evidence of carcinogenicity (Cirvello et al., 1995
; IRIS, 1991).
These findings have been the ongoing subject of extensive evaluation and debate. To illustrate briefly the type of issues in contention, the finding of kidney tumors observed in male rats exposed to MTBE by inhalation (Bird et al., 1997) has been questioned as to the relevance to human cancer risk because of the role the male rat-specific protein alpha-2u-globulin (
-2u) has been found to play in inducing kidney tumors in male rats. Borghoff and her colleagues (Borghoff et al., 1996
; Borghoff and Williams, 2000
; Poet and Borghoff, 1997
; Prescott-Matthews et al., 1997) have amassed several lines of evidence that
-2u mediates the formation of male rat kidney tumors from MTBE. However, the relationship between MTBE-induced
-2u accumulation and renal cell proliferation is not fully understood, because the proliferative response is disproportional to the relatively weak
-2u response to MTBE. This disproportion leaves open the possibility that some other non-species-specific mode of action could also figure into the induction of male rat kidney tumors. Expert advisory groups have had mixed judgments on human cancer risk based on this and other evidence of MTBE-induced tumors in laboratory rodents. Some evaluations (e.g., California EPA, 1999; Interagency Oxygenated Fuels Assessment Steering Committee, 1997; U.S. EPA, 1994) have concluded that MTBE could pose a possible or potential cancer risk to humans, whereas other public health bodies (e.g., IARC, 1998; U.S. Department of Health and Human Services, 2000; World Health Organization, 1998) have concluded that there is not enough information to classify MTBE with regard to human carcinogenicity under their classification schemes. The U.S. EPA plans to formally evaluate carcinogenicity and other health issues for its Integrated Risk Information System (IRIS) and to update, if necessary, the Agency's consensus opinion on MTBE health hazards and potential risks.
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Sensory Characteristics |
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The State of California has both a primary, health-based standard for MTBE and a secondary standard based on taste and odor properties. The primary standard is 13 µg/l, and the secondary standard is 5 µg/l (California EPA, 1999). The fact that the California primary standard is higher than the secondary standard reflects a view that available health effects information does not suggest that MTBE is likely to pose as much of a risk to public health as an offense to the senses or sensibilities (see also U.S. EPA, 1997). This is not to say that a foul odor or taste is necessarily any less "real" than a health risk. Confronted with an unusual taste or odor, people may understandably be fearful that their water is tainted. They might also go to some expense or effort to treat the water, replace it, or otherwise avoid using it. These public welfare issues are recognized as a valid basis for setting secondary MCLs to protect the odor or appearance of water, as EPA has done for several substances, including copper, iron, sulfates, and zinc, and is considering doing for MTBE.
Although published and anecdotal reports frequently describe the taste and odor of MTBE in strongly aversive terms, a statistically representative sampling of population responses to the taste and odor of MTBE in water has not been reported. The sensory threshold studies that have been conducted to date on MTBE have, for the most part, been conducted with small numbers of experienced or trained individuals as a panel of subjects. The results of such studies may be useful for public water suppliers to determine a level of contamination at which their clients might detect or object to the presence of MTBE in their water. However, such data are not likely to be representative of the range of sensitivities and reactions present in the population as a whole, which is known to include a substantial number of hyposmic and anosmic individuals. Thus, the general population is likely to be described by a distribution that includes not only individuals with very low thresholds but those who have little or no sense of taste or smell. Apart from the minimum concentration for detection or recognition, other dimensions of odor or taste include the intensity, character, and hedonic quality of the experience (U.S. EPA, 1992b). Limited data suggest a range of responses to MTBE in these dimensions as well: along with descriptors such as bitter, nasty, and solvent- or plastic-like, the terms "sweet" and "vanilla-like" have sometimes been applied to MTBE in drinking water (Dale et al., 1997
; Young et al., 1996
). Moreover, Dale et al. (1997) reported that a panel of four trained analysts, when presented with samples of MTBE in odor-free water at concentrations of approximately 2, 5, 20, 50, 100 µg/l and higher, could detect MTBE at levels as low as 25 µg/l, but did not consider the intensity of the sensory experience "objectionable" until a concentration of approximately 50 µg/l for taste or 90100 µg/l for odor was reached.
The implications of such varied reactions are interesting. One implication is pertinent to the notion that MTBE acts as an "early warning" signal that water is contaminated with gasoline and thus serves to reduce or avert human exposure to harmful gasoline constituents such as benzene. This supposed early warning benefit is sometimes offered as a defense of MTBE, but the argument is not very compelling when one considers the broad range of sensory acuity (or lack thereof) in a normal population. Even individuals with average sensory abilities might regularly ingest MTBE-contaminated water for many reasons, including the fact that substances such as disinfection chemicals could mask the taste or odor (Shen et al., 1997a).
When individuals or groups of persons seem to differ considerably in their sensitivity or reaction to a stimulus, such divergence may reflect more than variability in physiological response. Dalton (1996) has shown that cognitive factors can significantly influence the perception of an odor. In one experiment, subjects were given the information that a substance was either (1) a natural extract reported to have positive effects on mood and health (positive condition), (2) an industrial solvent reported to cause problems with health and cognition (negative condition), or (3) a standard odorant approved for olfactory research (neutral condition). The subjects' ratings of the intensity of the odor varied according to the type of information they were provided before the exposure. The positive group showed a typical pattern of adaptation in which intensity ratings declined over time, whereas, the negative group showed an initial adaptation that reversed after a few minutes and was replaced by increasing intensity ratings, i.e., sensitization to the odor. The neutral group was intermediate in response. In addition, spontaneous reports of headache, lethargy, dizziness, and irritation were registered by 11 of the 15 subjects in the negative group and 2 of 15 in the neutral group, but by none in the positive group.
The importance of odor and contextual information is also suggested by the results of a study conducted in response to adverse public reaction to RFG when it was first introduced in Milwaukee (Anderson et al., 1995). Residents of three areas were randomly surveyed by telephone: Milwaukee, where about 50% of the RFG was oxygenated with MTBE; Chicago, which had RFG from the same distribution network as Milwaukee; and other areas of Wisconsin, where RFG was not required. Reports of symptoms previously associated with oxygenated gasoline (headache, dizziness, nausea), as well as unrelated symptoms (backache, fever), were significantly higher among Milwaukee respondents (23%) than among those in either Chicago or non-RFG areas of Wisconsin (6% each). Having had a cold or the flu was the strongest predictor of reporting symptoms attributed to RFG among Milwaukee respondents, but not among Chicago or Wisconsin respondents; yet all three areas had similar rates of colds and flu that season. Another key factor associated with the higher prevalence of symptom reporting was awareness of RFG, which was greater in Milwaukee, due in part to substantial local media coverage of RFG issues. Respondents who indicated that they had purchased RFG were also more likely to report "unusual smells" from the gasoline than those who said they had not purchased RFG or did not know what type of fuel they had bought. Thus, it appears that "many symptoms reported by Milwaukee residents may have actually been due to colds or flu and not RFG exposure," and that "knowledge about RFG, including "...potential negative effects ..., may have heightened perception of current health status and resulted in the assumption that any health symptoms experienced were unusual and attributable to gasoline exposure" (Anderson et al., 1995
).
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Lessons Learned |
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Without necessarily concluding that MTBE is a public health threat, some commentators have nonetheless asserted that this additive should have been evaluated much more thoroughly before being introduced on such a wide scale into the U.S. fuel supply (Goldstein and Erdal, 1999). As it applies to the first introduction of MTBE in the late 1970s, when toxicity information on MTBE was extremely limited, the criticism seems quite apropos. Indeed, it was several years later before EPA issued a rule, as mandated by section 211(b) of the Clean Air Act, to require toxicity testing of fuels and fuel additives (Federal Register, 1994
). Nevertheless, by late 1992when the first federally mandated oxygenated fuel program began and MTBE usage increased considerablya substantial amount of toxicity data had in fact been obtained under the TSCA enforceable consent agreement between EPA and MTBE manufacturers. These studies have since been published as several articles in a supplement to the Journal of Applied Toxicology, 17(S1): S164, 1997).
One could argue that there were clues in the available data from the TSCA testing and other sources that were not heeded. Given the types of neurobehavioral effects (ataxia, hypoactivity, and other signs of reversible CNS depression) observed in laboratory rodents exposed to high (>10,000 mg/m3) concentrations of MTBE, and given the history of human experience with other ethers (e.g., diethyl ether, at one time used as a general anesthetic), would not one expect the types of symptoms (headache, eye and nose irritation, nausea, dizziness, lethargy) that some people reported after the introduction of oxygenated fuels? One problem with this observation is that, despite some qualitatively similar CNS depressant effects, such effects had been observed in rodents (and perhaps surgery patients) only at exposure levels several orders of magnitude higher than were thought likely to occur in general population exposures. Even the no-observed-effect levels (288014,400 mg/m3) for these types of effects were orders of magnitude higher than observed environmental levels. Moreover, there had been little indication of adverse public reaction to MTBE-oxygenated gasoline in smaller scale fuel programs such as the ones in Denver and Phoenix during the late 1980s (U.S. EPA, 1993).
However, rodents might not be considered an adequate model for the type of effects some people experienced. After all, "rats don't retch," so how would their reactions predict nausea in humans? Still, at least one attempt to discover evidence of respiratory irritancy, using a standard testing method for mice, showed little indication that MTBE vapor was relatively irritating (Tepper et al., 1994); moreover, inhalation testing with human volunteers showed little evidence of an irritancy effect (Cain et al., 1996
; Johanson et al., 1995
; Prah et al., 1994
). Perhaps the testing should have been done with a mixture of gasoline and MTBE, not MTBE alone? Yet epidemiologic studies (Mohr et al., 1994
; White et al., 1995
) did not confirm a significant incidence of health symptoms in individuals exposed to real-world mixtures of gasoline and MTBE. Nevertheless, if the segment of the population that experiences symptoms is relatively small, such studies would probably not have enough power to detect the effects. But the study of self-reported sensitive individuals described above (Fiedler et al., 2000
), while substantiating the existence of individuals who are relatively more sensitive to 15%-vol MTBE-gasoline, does not corroborate the symptoms attributed to RFG with 11%-vol MTBE.
After all of these "on-the-one-hand" and "on-the-other" points have been laid out, one comes down to the basic conundrum of how much testing should have been done to anticipate the kind and prevalence of symptoms that surfaced with the oxygenated gasoline programs. If the percentage of physiologically sensitive individuals in the general population is quite small, it seems unlikely that even much more extensive animal toxicity testing would have predicted the extent or severity of their reactions. Despite substantial efforts directed at investigating acute-symptom reports (Fiedler et al., 2000; U.S. EPA, 1995
), the basis for these complaints has yet to be adequately elucidated. Given this current state of the science, one must question whether the course of events, as they unfolded in the 1990s, would have been altered even if the TSCA testing had been completed in the mid-1970s (before any use of MTBE), or even if the more extensive animal and human testing performed in the 1990s had been performed earlier.
None of this discussion is meant to imply that it makes no difference whether a substance to which several million people are daily exposed is adequately evaluated before its widespread use. Clearly, it is important, and the authority to require such testing under Section 211(b) of the Clean Air Act is evidence of the importance that Congress attached to such evaluation. However, the limits of such testing for detecting the types of problems that have arisen with MTBE should be seen as a cautionary note for toxicologists and risk assessors: do not be overly confident in the ability of standard toxicity testing to predict or avert health issues in the general population. Actually, in this case, the limitations of the tests themselves may not have been the primary problem; rather, the attempt to focus the testing in a manner that seemed rational and efficient at the time ended up missing or being unable to address the concerns that subsequently emerged. Whereas the TSCA testing program was directed at the inhalation toxicity of MTBE vapors alone, when public concerns surfaced about oxygenated gasoline it became obvious that more information was needed on the mixture of MTBE and gasoline (U.S. EPA, 1996). Then, as concerns arose about groundwater contamination and possible drinking water exposure to MTBE, attention turned back to neat MTBEbut by the oral route, not by inhalation (U.S. EPA, 1998
).
Among the many paradoxes surrounding MTBE, one of the most obvious is that something that was intended to improve environmental quality has ended up being widely viewed as an environmental threat (Greenbaum, et al. 1999). Possibly the most valuable lesson to be gained from the MTBE experience may be the importance of obtaining a comprehensive understanding of the many and varied risks and benefits potentially offered by any given fuel option. This should entail a consideration of all facets of the life cycle of a fuel or additive, including the environmental fate of any emissions or releases, because the by-products of a chemical may be of greater toxicological or environmental significance than the parent compound itself. Moreover, the potential for exposure of human populations and ecosystems needs to be understood in terms of multi-media, multi-pathway cumulative exposures. Finally, no fuel option exists in a vacuum. It is not simply a question of whether MTBE is "good" or "bad," but whether its trade-offs are better or worse than the trade-offs presented by the alternative(s), e.g., conventional gasoline or RFG containing a different oxygenate or, possibly, no oxygenate at all (Franklin et al., 2000
).
Ironically, several years ago the U.S. EPA laid out a strategy for obtaining comprehensive information on the risks and benefits of fuels and additives, including MTBE. Among other things, the strategy called for research to "assess the impact of reformulated gasolines on the potential for groundwater contamination and resultant pollutant exposure," and to "characterize the impacts of oxygenates on the fate and transport of fuel components" (U.S. EPA, 1992a). Had these prescient statements been heeded more closely by industry or government, perhaps some of the paradoxes of MTBE would not have developed.
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ACKNOWLEDGMENTS |
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NOTES |
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1 To whom correspondence should be addressed at NCEA/ORD (MD-52), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711. Fax: (919) 541-0245. E-mail: Davis.Jmichael{at}epa.gov.
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REFERENCES |
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Angle, C. R. (1991). If the tap water smells foul, think MTBE. JAMA 266, 29852986.
Belpoggi, F., Soffritti, M., and Maltoni, C. (1995). Methyl-tertiary-butyl ether (MTBE)a gasoline additivecauses testicular and lymphohaematopoeitic cancers in rats. Toxicol. Ind. Health 11, 119149.[ISI][Medline]
Belpoggi, F., Soffritti, M., and Maltoni, C. (1998). Pathological characterization of testicular tumours and lymphomas-leukaemias, and of their precursors observed in Sprague-Dawley rats exposed to methyl-tertiary-butyl-ether (MTBE). Eur. J. Oncol. 3, 201206.
Bird, M. G., Burleigh-Flayer, H. D., Chun, J. S., Douglas, J. F., Kneiss, J. J., and Andrews, L. S. (1997). Oncogenicity studies of inhaled methyl tertiary-butyl ether (MTBE) in CD-1 mice and F-344 rats. J. Appl. Toxicol. 17(Suppl. 1), S4555.[ISI][Medline]
Borghoff, S. J., Murphy, J. E., and Medinsky, M. A. (1996). Development of a physiologically based pharmacokinetic model for methyl tertiary-butyl ether and tertiary-butanol in male Fischer-344 rats. Fundam. Appl. Toxicol. 30, 264275.[ISI][Medline]
Borghoff, S. J., and Williams, T. M. (2000). Species-specific tumor responses following exposure to methyl tert-butyl ether. CIIT Activities 20(2), 19 (available at http://www.ciit.org/ACTIVITIES/activ.html). Accessed March 22, 2001.
Cain, W. S., Leaderer, B. P., Ginsberg, G. L., Andrews, L. S., Cometto-Muniz, J. E., Gent, J. F., Buck, M., Berglund, L. G., Mohsenin, V., Monahan, E., and Kjaergaard, S. (1996). Acute exposure to low-level methyl-tertiary-butyl ether (MTBE): human reactions and pharmacokinetic response. Inhal. Toxicol. 8, 2148.[ISI]
California EPA (1999). Public health goal for methyl tertiary butyl ether (MTBE) in drinking water. Office of Environmental Health Hazard Assessment, Sacramento, CA. Available at: www.oehha.ca.gov/water/phg/allphgs. html. Accessed March 22, 2001.
Cirvello, J. D., Radovsky, A., Heath, J. E., Farnell, D. R., and Lindamood, C., III (1995). Toxicity and carcinogenicity of t-butyl alcohol in rats and mice following chronic exposure in drinking water. Toxicol. Ind. Health 11, 151165.[ISI][Medline]
Dale, M. S., Moylan, M. S., Koch, B., and Davis, M. K. (1997). MTBE: Taste-and-odor threshold determinations using the flavor profile method. Presented at Water Quality Technology Conference of the American Water Works Association, November, Denver, CO. Metropolitan Water District of Southern California, La Verne, CA.
Dalton, P. (1996). Odor perception and beliefs about risk. Chem. Senses 21, 447458.[Abstract]
Duffy, J. S., Del Pup, J. A., and Kneiss, J. J. (1992). Toxicological evaluation of methyl tertiary butyl ether (MTBE): testing performed under TSCA consent agreement. J. Soil Contam. 1, 2937.
Federal Register (2000). Methyl tertiary butyl ether (MTBE); advance notice of intent to initiate rulemaking under the toxic substances control act to eliminate or limit the use of MTBE as a fuel additive in gasoline; advance notice of proposed rulemaking. Federal Register 65, 1609316109.
Federal Register (1994). Fuels and fuel additives: Registration regulations. Federal Register 59, 3304233142.
Fiedler, N., Kelly-McNeil, K., Mohr, S., Lehrer, P., Opiekun, R. E., Lee, C.-W., Wainman, T., Hamer, R., Weisel, C., Edelberg, R., and Lioy, P. J. (2000). Controlled human exposure to methyl tertiary butyl ether in gasoline: Symptoms, psychophysiologic and neurobehavioral responses of self-reported sensitive persons. Environ. Health Perspect. 108, 753763.[ISI][Medline]
Franklin, P. M., Koshland, C. P., Lucas, D., and Sawyer, R. F. (2000). Clearing the air: Using scientific information to regulate reformulated fuels. Environ. Sci. Technol. 34, 38573863.[ISI]
Goldstein, B. D., and Erdal, S. (1999). Exposure to methyl tert-butyl ether in oxygenated fuels: What are the health policy lessons? Epidemiology 10, O473O473.
Greenbaum, D., et al. Achieving Clean Air and Clean Water. The Report of the Blue Ribbon Panel on Oxygenates in Gasoline. September 1999. Available at: http://www.epa.gov/otaq/consumer/fuels/oxypanel/blueribb.htm. Accessed March 22, 2001.
Health Effects Institute (1996). The potential health effects of oxygenates added to gasoline: A review of the current literature, a special report of the Institute's Oxygenates Evaluation Committee. Cambridge, MA: Health Effects Institute, Oxygenates Evaluation Committee executive summary. Available at: http://www.healtheffects.org/Pubs/oxysum.htm. Accessed March 22, 2001.
IARC (1999). Methyl tert-butyl ether (Group 3); Summary of Data Reported and Evaluation. In Some Chemicals that Cause Tumors of the Kidney or Urinary Bladder in Rodents and Some Other Substances, Vol. 73, p. 339. International Agency for Research on Cancer, Lyon, France. Available at: http://193.51.164-11/htdocs/monographs/Vol73/73-13.html. Accessed March 22, 2001.
Interagency Oxygenated Fuels Assessment Steering Committee (1997). Interagency assessment of oxygenated fuels. National Science and Technology Council, Committee on Environment and Natural Resources and Office of Science and Technology Policy. Washington, DC. Available at: http://www.epa.gov/otaq/fuels.htm#oxy. Accessed March 22, 2001.
IRIS, Integrated Risk Information System (1993). Reference concentration for MTBE. Cincinnati, OH: U.S. Environmental Protection Agency, Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office. Available at: http://www.epa.gov/ngispgm3/iris/. Accessed March 22, 2001.
IRIS, Integrated Risk Information System (1991). Carcinogenicity assessment for formaldehyde. Cincinnati, OH: U.S. Environmental Protection Agency, Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office. Available at: http://www.epa.gov/ngispgm3/iris/. Accessed March 22, 2001.
Johanson, G., Nihlen, A., and Lof, A. (1995). Toxicokinetics and acute effects of MTBE and ETBE in male volunteers. Toxicol. Lett. 82/83, 713718.
Malcolm Pirnie, Incorporated (1998). Taste and odor properties of methyl tertiary-butyl ether and implications for setting a secondary maximum contaminant level. Report no. 3195001007, Oxygenated Fuels Association, Inc., Arlington, VA.
Mohr, S. N., Fiedler, N., Weisel, C., and Kelly-McNeil, K. (1994). Health effects of MTBE among New Jersey garage workers. Inhalation Toxicol. 6, 553562.[ISI]
NRC (1996). Committee on Toxicological and Performance Aspects of Oxygenated and Reformulated Motor Vehicle Fuels. Toxicological and performance aspects of oxygenated motor vehicle fuels. National Academy Press, Washington, DC.
Poet, T. S., and Borghoff, S. J. (1997). In vitro uptake of methyl tert-butyl ether in male rat kidney: Use of a two-compartment model to describe protein interactions. Toxicol. Appl. Pharmacol. 145, 340348.[ISI][Medline]
Prah, J. D., Goldstein, G. M., Devlin, R., Otto, D., Ashley, D., House, D., Cohen, K. L., and Gerrity, T. (1994). Sensory, symptomatic, inflammatory, and ocular responses to, and the metabolism of, methyl tertiary butyl ether in a controlled human exposure experiment. Inhalation Toxicol. 6, 521538.[ISI]
Prescott-Mathews, J. S., Wolf, D. C., Wong, B. A., and Borghoff, S. J. (1997). Methyl tert-butyl ether causes alpha 2u-globulin nephropathy and enhanced renal cell proliferation in male Fischer-344 rats. Toxicol. Appl. Pharmacol. 143, 301314.[ISI][Medline]
Shen, Y., Yoo, L., Bergen, M., Navia, A., Fitzsimmons, S., and Wehner, M. (1997a). Effect of residual chlorine on the threshold odor concentrations of MTBE in drinking water. Presented at: Proceedings of the 1997 Water Quality Technology Conference, November, Denver CO. American Water Works Association, Denver, CO.
Shen, Y. F., Yoo, L. J., Fitzsimmons, S. R., and Yamamoto, M. K. (1997b). Threshold odor concentrations of MTBE and other fuel oxygenates. In Preprints of Papers Presented at the 213th American Chemical Society National Meeting in San Francisco, CA, Vol. 37, pp. 407409. ACS Division of Environmental Chemistry.
Tepper, J. S., Jackson, M. C., McGee, J. K., Costa, D. L., and Graham, J. A. (1994). Estimation of respiratory irritancy from inhaled methyl tertiary butyl ether in mice. Inhalation Toxicol. 6, 563569.[ISI]
U.S. Department of Health and Human Services (2000). National Toxicology Program, Ninth report on carcinogens. Public Health Service, Washington, DC. Available at: http://ehis.niehs.nih.gov/roc/toc9.html. Accessed March 22, 2001.
U.S. EPA (1992a). Alternative fuels research strategy. Office of Research and Development, report no. EPA/600/AP-92/002. Washington, DC. Available at: http://www.epa.gov/ncea/oxygenates/oxystrat.htm. Accessed March 22, 2001.
U.S. EPA (1992b). Reference guide to odor thresholds for hazardous air pollutants listed in the Clean Air Act Amendments of 1990. Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC. Report no. EPA-600/R-92/047.
U.S. EPA (1993). Assessment of potential risks of gasoline oxygenated with methyl tertiary butyl ether (MTBE). Office of Research and Development, report no. EPA/600/R-93/206. Washington, DC. Available at: http:// www.epa.gov/ncea/oxygenates/gas-mtbe.htm. Accessed March 22, 2001.
U.S. EPA (1994). Health risk perspectives on fuel oxygenates, report no. EPA 600/R-94/217. Office of Research and Development, Washington, DC. Available at: http://www.epa.gov/ncea/oxygenates/risk-oxy.htm. Accessed March 22, 2001.
U.S. EPA (1995). Proceedings of the conference on MTBE and other oxygenates: A research update. July 1993. National Center for Environmental Assessment, Falls Church, VA. Report no. 600/R-95/134. Available at: http://www.epa.gov/ncea/oxygenates/confmtbe.htm. Accessed March 22, 2001.
U.S. EPA (1996). Oxyfuels information needs. Research Triangle Park, NC: National Center for Environmental Assessment, report no. EPA/600/R-96/069. Available at: http://www.epa.gov/ncea/oxygenates/oxyfuels.htm. Accessed March 22, 2001.
U.S. EPA (1997). Drinking water advisory: Consumer acceptability advice and health effects analysis on methyl tertiary-butyl ether (MTBE), report no. EPA-822-F-97008. Office of Water, Washington, DC. Available at: http://www.epa.gov/ost/drinking/mtbe.html). Accessed March 22, 2001.
U.S. EPA (1998). Oxygenates in water: Critical information and research needs. Washington, DC: Office of Research and Development; report no. EPA/600/R-98/048. Available at: http://www.epa.gov/ncea/oxygenates/oxyneeds.htm. Accessed March 22, 2001.
U.S. EPA. (2000). Methyl tertiary butyl ether (MTBE), http://www.epa.gov/mtbe/gas.htm. Accessed March 22, 2001.
Vetrano, K. M. (1993). Final report to ARCO Chemical Company on the odor and taste threshold studies performed with methyl tertiary-butyl ether (MTBE) and ethyl tertiary-butyl ether (ETBE). TRC Environmental Corporation, Windsor, CT.
White, M. C., Johnson, C. A., Ashley, D. L., Buchta, T. M., and Pelletier, D. J. (1995). Exposure to methyl tertiary-butyl ether from oxygenated gasoline in Stamford, Connecticut. Arch. Environ. Health 50, 183189.[ISI][Medline]
World Health Organization (1998). Methyl tertiary-butyl ether. Environmental Health Criteria 206. World Health Organization, Geneva, Switzerland.
Young, W. F., Horth, H., Crane, R., Ogden, T., and Arnott, M. (1996) Taste and odour threshold concentrations of potential potable water contaminants. Water Res. 30, 331340.[ISI]