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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels (1996)

Chapter: 5 POTENTIAL HEALTH EFFECTS OF OXYGENATES

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Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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5
POTENTIAL HEALTH EFFECTS OF OXYGENATES

In evaluating the potential adverse health effects of oxygenated fuels, the committee was charged with reviewing three reports and providing critique regarding scientific credibility, comprehensiveness, and internal consistency of the data presented. In addition, as part of its charge, the committee was to identify priorities for research to fill data gaps. The reports to be reviewed included the Health Effects Institute's Oxygenates Evaluation Committee's report The Potential Health Effects of Oxygenates Added to Gasoline: A Review of the Current Literature (February 1996), the HEI report; the National Science and Technology Council Committee on Environment and Natural Resources and Interagency Oxygenated Fuels Assessment Steering Committee Report Interagency Assessment of Potential Health Risks Associated with Oxygenated Gasoline (February 1996), the OSTP report; and a memorandum from the Centers for Disease Control and Prevention signed by Richard J. Jackson and directed to the Interagency Oxygenated Fuels Assessment Steering Committee dated March 12, 1996, the CDC white paper, which compared and contrasted the other two reports.

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×

Both the HEI report and the OSTP report relied upon published, peer-reviewed literature; unpublished reports from a number of sources, including industry, government agencies, and scientists; and personal communications. The National Research Council's Committee on Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels was not provided with the original sources of data from which the review reports were written, so a full and complete critique of scientific credibility, comprehensiveness, and internal consistency of the data is not possible.

METABOLISM, DISPOSITION, AND TOXICOKINETICS

DATA REVIEWED IN THE HEI AND OSTP REPORTS

The HEI report reviews what is known about the metabolism, disposition, and toxicokinetics of MTBE and ethanol in both animals and humans. Some recent data on the disposition of ethyltertiary-butyl ether (ETBE) in animals are also reviewed. The report states that there is essentially no information available on the disposition, metabolism, or toxicokinetics of other proposed oxygenates. As is summarized in the report, following absorption, the major pathways for elimination of MTBE are exhalation and oxidative demethylation to form tert-butyl alcohol (TBA) and formaldehyde. MTBE metabolism displays saturation kinetics. TBA appears to have a longer half-life in the body than MTBE, and thus TBA in blood may be a better biologic marker of exposure than MTBE blood levels. Formaldehyde has a very short half-life in the body. Thus, its potential increase in blood after exposure to MTBE has not been studied. Differences between MTBE levels and the ratio of MTBE to TBA in blood following chamber and field studies were noted, and it was postulated that this could be due to differences in sampling times.

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×

With respect to ethanol, HEI concludes that at the expected levels of exposure to ethanol in oxygenated fuels, the incremental blood levels of ethanol are predicted to be insignificant compared with endogenous blood levels. It is also unlikely that the fetus would be affected by this insignificant increment.

COMMITTEE CRITIQUE

There do not appear to be any major differences between the HEI and the OSTP report in regard to disposition, metabolism, and toxicokinetics of MTBE, and the committee is in basic agreement with the review and evaluation of the data presented, with the following exception.

Although the disposition of inhaled and orally administered radiolabeled MTBE in animals is reviewed in the HEI report, there is no definitive discussion of the amount absorbed into the systemic circulation following either route of exposure. However, it is stated that the data available from studies in which human volunteers were exposed to MTBE in chambers "suggest that less than half of the MTBE administered (32% to 42%) is absorbed after inhalation" and that this is consistent with the animal studies.

For purposes of extrapolating health-effects data from animals to humans, knowing the percentage absorbed following inhalation and ingestion for both animals and humans would be very useful. The final report needs to address whether this information is available from the studies already conducted, or if more studies are needed to obtain this information.

CONCLUSIONS

The committee is in basic agreement with the review and evaluation of the data presented in the HEI and OSTP reports. No major

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×

differences between the HEI and OSTP reports were noted with regard to the metabolism, disposition, and toxicokinetics of MTBE. The committee does note that the final report should address whether or not available animal studies address the percentage absorption following inhalation and oral exposures. This information would be useful when extrapolating health-effects data from animals to humans. The committee also concludes that it is essential that the actual exposure to MTBE be better quantified in any future epidemiological studies designed to evaluate the possible acute effects of inhaling MTBE. It is essential that the kinetics of MTBE and TBA in blood be established so that they can be used as biologic markers of exposure. In this regard, it would also be useful if measurements of formate (the metabolized product of formaldehyde exposure) from inhalation of MTBE were compared to endogenous formate levels.

RESEARCH NEEDS

The HEI report makes a number of research recommendations for additional studies on the metabolism and disposition of MTBE and other oxygenates and notes that some work is already under way. As noted above, the committee concludes that additional research on the metabolism and disposition of MTBE would be very useful as a basis for extrapolating health-effects data from animals to humans (i.e., a physiologically based pharmacokinetic (PBPK) model). Research should also focus on determining a suitable biologic marker of exposure for use in any future epidemiological studies on the acute effects of MTBE-gasoline mixtures. It would be prudent to conduct deposition and metabolism studies on other oxygenates before they are introduced and extensively used.

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×

SHORT-TERM HEALTH EFFECTS

ANIMALS

DATA REVIEWED BY THE HEI AND OSTP REPORTS

The HEI report presents a thorough review of the animal studies that have been conducted on MTBE, ethanol, and other oxygenates. In animals, essentially all these compounds cause sedation and other reversible CNS effects, such as loss of motor coordination and decreases in motor activity. None of the compounds that have been studied appear to be irritants to the eye or upper respiratory tract or cause pulmonary irritation even at very high levels (i.e., 4,000-8,000 ppm for MTBE). Most ethers studied also appear to cause neurotoxic effects following exposures to high concentrations. For most effects, the no-observed-adverse-effects level (NOAEL) is at least 1,000 times higher than predicted human exposures.

One major difference between the HEI and OSTP reports is that the HEI report states that a NOAEL for motor activity was not achieved in inhalation studies in which rats were exposed to MTBE. The HEI report emphasizes the alteration in motor activity observed in rat inhalation studies was reversible and that no neuropathologic condition was observed. The CDC white paper discussing differences between the two reports states that OSTP examined the raw data from the study in question and concluded that the effect on motor activity at 800 ppm was not significant when examined with appropriate statistics which corrected for multiple comparisons. If this is the case, there would not appear to be a need for additional studies.

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×
COMMITTEE CRITIQUE

One area not addressed in either the HEI or the OSTP report is the question of TBF toxicity. TBF is one of the major photooxidation byproducts of MTBE. If TBF levels are increased in the ambient air due to MTBE use, the available literature on TBF toxicity needs to be reviewed in the report. Based on that review and the extent of the exposures predicted, additional studies to characterize the acute and chronic toxicity of TBF may need to be added.

Based on the available data, the committee is skeptical about the need for additional studies based solely on the motor-activity studies conducted in rats. The committee notes that even at 800 ppm the effect, if any, is at an exposure of 100-1,000 times greater than predicted human exposures. It is also a reversible effect characteristic of this class of compounds and there is no indication of neuropathologic condition or persistent neurotoxicity following exposure to MTBE or other ethers.

CONCLUSIONS

The HEI report represents a thorough review of the short-term animal studies that have been conducted on MTBE, ethanol, and other oxygenates. However, one area not addressed in either the HEI or the OSTP report is the question of TBF toxicity.

Based on the available data, the committee does not feel the effect of MTBE on motor activity reported in rat inhalation studies is of major concern, for the following reasons: (1) the effect occurs at 100-1,000 times predicted human exposures, (2) the effect is reversible, and (3) there is no indication of neuropathologic condition or persistent neurotoxicity following exposure to MTBE or other ethers, even after long-term exposure to high levels of MTBE.

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×
RESEARCH NEEDS

The HEI report notes the need for additional short-term animal studies on MTBE that determine blood levels in addition to evaluating CNS function. The committee agrees that such studies would be useful because measurements of blood levels of MTBE and its metabolites in animals, above and below the no-observed-effects levels for CNS effects, could be compared to blood levels expected in people (from PBPK modeling) following occupational or environmental exposures. In particular, adequate studies on other proposed oxygenates should be conducted before they are extensively introduced into the U.S. gasoline supply.

HUMAN

EPIDEMIOLOGIC STUDIES
ALASKA STUDIES

DATA REVIEWED IN THE HEI AND OSTP REPORTS. The HEI report and the OSTP report reviewed four studies: (1) the cross-sectional studies conducted in Fairbanks (Beller et al., 1992) and (2) Anchorage (Chandler and Middaugh, 1992); (3) the longitudinal study which was conducted in Fairbanks by the State of Alaska Department of Health and Social Services and CDC in the winter of 1992-1993 (CDC, 1993a; Moolenaar et al., 1994); and (4) a retrospective study that compares outpatient insurance claims made in Alaska during the winter months of 1992-1993 (i.e., months in which oxygenated fuels were in use) to claims made during the same months of previous winters (Gordian et al., 1995). The OSTP report reviews the same four studies as the HEI report.

COMMITTEE CRITIQUE. The OSTP report provides more detail

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×

than does the HEI report, but both accurately reflect findings of the Alaska studies. With respect to the longitudinal study referenced above, the State of Alaska Department of Health and Social Services established a case definition as an increase in headache or an increase in at least two other symptoms (including nausea or vomiting, burning sensation of the nose or mouth, cough, dizziness, spaciness or disorientation, or eye irritation). Taxi drivers met the case definition more often than did health-care workers or university students (Beller et al., 1992 and Chandler and Middaugh, 1992). As part of the same study, CDC interviewed and collected blood samples from motorists, gas-station attendants, and mechanics living in Fairbanks, Alaska. It reported a higher prevalence of symptoms among workers interviewed during the oxygenated-fuel season than workers interviewed after the season. In addition, workers with MTBE blood levels in the upper quartile were more likely to report symptoms attributed to MTBE exposure, although the increases were statistically unstable due to the small sample size (CDC, 1993a, Moolenar, 1994).

In summarizing the retrospective study of outpatient insurance claims, the OSTP report concludes that in both Anchorage and Fairbanks there was an increase in visits for headaches in the winter of 1992-1993, when compared with the winter of 1990-1991, but not in the winter of 1991-1992, when the authors reported an epidemic of viral illness. The HEI report does not comment on this finding at all but states that the study indicates that ''hospital admissions for respiratory ailments and asthma were stable over the 3-year period" (Gordian et al., 1995).

Neither the OSTP report nor the HEI report comments on the fact that given the uncertainties in exposure measurement in the cross-sectional studies, the majority of cases reported in both Fairbanks and Anchorage were in workers spending a longer amount of time in their automobiles. Likewise, in the longitudinal study conducted in Fairbanks, workers with higher MTBE exposures had an increase in symptom reporting. These results are internally

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×

consistent and suggest that workers occupationally exposed to MTBE are at greater risk for the development of acute health effects.

CONNECTICUT AND NEW YORK STUDIES

DATA REVIEWED IN THE HEI AND OSTP REPORTS. The HEI report reviews the results of a study conducted in Stamford, Connecticut, by White et al., 1995. The study was conducted during a time when the area was participating in the winter oxygenated-fuel program. A similar study of a comparison population was conducted in Albany, New York, an area where oxygenated fuel was not being used (CDC, 1993c). Although it is listed in the section entitled "Literature Cited," it is not clear if the HEI report also reviewed the CDC report on Stamford, Connecticut. The CDC report on Stamford, Connecticut, contains more information than does the paper published by White et al. in 1995.

The OSTP report reviews the White et al. (1995) paper on the Stamford, Connecticut, study, as well as the CDC report of that study. It also reviews the CDC report on the comparison population in Albany, New York.

In the CDC study conducted in Stamford, Connecticut, during the oxygenated-fuel season, the 11 people with the highest blood MTBE levels were more likely to report one or more key symptoms (including headache, irritated eyes, burning of the nose and throat, cough, dizziness, spaciness or disorientation, and nausea) than were persons with lower blood MTBE levels (p < 0.05) (CDC, 1993b, White et al., 1995). However, the overall prevalence of symptoms was similar in the population groups studied in Albany and Stamford. There was no difference in symptoms among those reporting use of premium fuels (with MTBE) to those using regular fuels (without MTBE) in Albany, New York (CDC, 1993c).

COMMITTEE CRITIQUE. Both the OSTP and HEI reports

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×

accurately represent the Stamford, Connecticut, and Albany, New York, studies. Following an evaluation of both studies, the HEI report concludes that "although some symptoms were more prevalent in Stamford than in Albany, the pattern of elevation was not consistent." Thus, it discounts a relationship between MTBE exposure and symptoms, although this is not explicitly stated. The OSTP report notes that "qualitatively, the prevalence of the most common symptoms, such as headache and cough, occurring over the last month was not appreciably higher among men who worked around cars and gasoline in Stamford than men with similar occupations in Albany, where exposure to MTBE was generally much lower." This, too, in effect concludes that there were few data to support a relationship between MTBE exposure and the development of symptoms. The committee concludes that confounding due to exposure to gasoline itself and possibly temperature must be considered; however, despite confounding factors and instability due to small sample sizes, it is noted further by the committee that workers with the highest blood levels of MTBE in Stamford were more likely to report symptoms attributable to MTBE. This is consistent with symptom reporting among the occupationally exposed workers in the Alaska studies.

NEW JERSEY STUDIES

DATA REVIEWED IN THE HEI AND OSTP REPORTS. The HEI report and the OSTP report review the New Jersey garage-worker study, which compared symptom reporting in state-employed garage workers during the winter oxygenated-fuel season in northern New Jersey and workers in southern New Jersey after the oxygenated-fuel season was over (Mohr et al., 1994). The HEI report also remarks on a paper by Fiedler et al. (1994) which compares symptom reporting, associated with driving and automobile

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×

refueling activities, in a small group of individuals diagnosed as having multiple chemical sensitivities and chronic fatigue syndrome and normal controls.

COMMITTEE CRITIQUE. Neither the HEI report nor the OSTP report notes that exposed workers who pumped gasoline more than 5 hours per day had an average increase in symptom score of 0.75 (from 2.26 preshift to 3.37 postshift). This is in contrast to an average improvement in symptom score of 0.45 (from 2.45 preshift to 2.00 postshift) at the end of the shift among low-exposed age-matched southern controls (total possible score, 28) (Mohr et al., 1994). Both reports note that this result was not statistically significant, but neither report comments on the consistency of this finding with results reported in occupationally exposed workers in Alaska and Stamford, Connecticut.

Neither the HEI nor the OSTP report comments on the abstract published by Mohr in which 107 older motorists (men 50-84 years of age) in New Jersey were surveyed for symptom reporting associated with length of time spent in their automobiles and gasoline refueling (Mohr et al., 1995). A few of the key symptoms were statistically significant associated with the number of hours spent in the automobile or the number of times per week that the automobile was refueled.

Fiedler et al. (1994) compared symptom reporting in individuals reported to be sensitive to very low levels of chemical exposures (multiple chemical sensitivities, MCS) to individuals with chronic fatigue syndrome (CFS) and normal controls. Based on the results from this study, HEI concludes that "further efforts to identify and characterize sensitive individuals are needed." The OSTP report states that groups studied thus far contained so few human subjects that comparisons are difficult to interpret. Neither the HEI report nor the OSTP report comment on the presentation made by Fiedler (1993) at the EPA Conference on MTBE and Other Oxygenates, although the HEI report lists this presentation in its

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×

"Literature Cited" section. In this study, a small group of individuals, self-reported to the New Jersey Department of Health as sensitive to fuel containing MTBE, reported more symptoms associated with driving and refueling than did either the MCS or CFS controls. These individuals did not meet the author's MCS diagnostic criteria. The committee notes that the presentation made by Fiedler (1993) is the only scientific study done to date which may indicate that there are individuals sensitive to MTBE, and this study is limited in that it looked at only 5 or 6 individuals. In addition, the committee is surprised that this study is ignored in both reports which indicate further study on "sensitive" individuals is warranted. Thus, the committee questions the scientific basis of the recommendation by HEI that "further efforts to identify and characterize sensitive individuals are needed." It is the consensus of the committee that both the OSTP and HEI reports are way too premature in suggesting that almost all future research should be directed towards identifying and characterizing sensitive individuals and that occupationally exposed workers for whom there is consistent evidence of an increase in symptoms should be studied in more detail.

WISCONSIN STUDIES

DATA REVIEWED IN THE HEI AND OSTP REPORTS. Both reports review a study in which the Wisconsin Department of Health and Social Services conducted a random-digit-dialing telephone survey of individuals regarding their concerns over the use of reformulated gasoline (Anderson et al., 1995a) and a followup study in which the same survey was administered to people who had already called Wisconsin government agencies with health concerns regarding reformulated gasoline (Anderson et al., 1995b).

COMMITTEE CRITIQUE. The HEI report concludes from the

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×

first phase of the Wisconsin study that the "differences [in symptom reporting] are likely to be attributable to different levels of awareness about exposure to MTBE." This statement suggests that the HEI report supports the idea that symptom reporting in Wisconsin was mostly related to media attention. This is not entirely in keeping with comparisons made between Chicago and parts of Wisconsin outside the Milwaukee area, in which HEI reported that respondents in Chicago still reported a higher prevalence of eye irritation, headache, and sinus problems while pumping gas. In contrast, the OSTP report states, "the symptom prevalence was not elevated in Chicago compared with such prevalence in areas of Wisconsin where reformulated gasoline was not used." The committee reviewed the report by Anderson et al. (1995a). There are some differences in the way the symptoms are reported by region in relation to exposure in Tables 9, 10, 11, and 12. There is evidence in Table 12 that there was higher symptom-reporting prevalence in Chicago compared to areas in Wisconsin outside the Milwaukee area, and the conclusion drawn by the OSTP report is misleading.

As stated above, the same telephone-survey questionnaire was then administered to 1,339 persons who had called various Wisconsin government agencies with health concerns regarding reformulated gasoline. In this study, these contacts were slightly older and more likely to commute more than 1 h per day in a car than other Milwaukee respondents from the first phase of the study (Anderson et al., 1995b). The HEI report concludes that in this portion of the Wisconsin study, "exposure to RFG … was not a predictor of symptoms." The OSTP report concludes that the "health contacts also were more likely to have seen various news stories about MTBE than other Milwaukee residents." Both studies, although emphasizing different aspects of the Wisconsin survey, accurately reflect the findings.

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×
OTHER STUDIES AND REPORTS REVIEWED IN THE HEI AND OSTP REPORTS

DATA REVIEWED IN THE HEI AND OSTP REPORTS. Other studies and reports reviewed by HEI include (1) the presentation by Livo which noted a decline in the total number of complaints received by the Colorado Department of Public Health and Environment over several years of winter oxygenated-fuel seasons (Livo, 1995); (2) a survey of physicians by the Missoula City-County Health Department in 1993 to determine whether illnesses had increased that winter (Missoula City-County Health Department, 1993); (3) a survey of workers in two oil refineries by Mehlman (1995); (4) a survey conducted by McCoy et al. (1995); and (5) a study surveying individuals from Anchorage, Alaska, for symptoms due to exposure to fuel oxygenated with ethanol (Egeland and Ingle, 1995).

Data reviewed by the OSTP report include (1) the presentation by Livo (1995); (2) a personal communication of health complaints due to MTBE from persons living in Colorado (Pat McCord, 1993), which was apparently not available to the HEI committee; (3) the report from the Missoula City-County Health Department (1993) and a personal communication from E. Leahy (1995) to obtain followup information from this community, which was apparently not available to the HEI committee; (4) a presentation by Raabe (1993) regarding complaints of workers from companies represented by the American Petroleum Institute; (5) a study by Medlin (1995) of workers represented by the Oil, Chemical and Atomic Workers Union; and (6) the study by Egeland and Ingle (1995). The OSTP report does not review the papers by Mehlman (1995) or McCoy et al. (1995).

COMMITTEE CRITIQUE. Although the CDC white paper states that both the HEI and OSTP reports reviewed the same studies, it

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×

is not entirely true. In addition, neither the HEI report nor the OSTP report draws major conclusions from the studies listed directly above in the section "Other Studies and Reports Reviewed in the HEI and OSTP Reports." The OSTP report draws on the differences between the Livo (1995) presentation and the personal communication from McCord (1993) to conclude that the "analyses of the number of complaints received by different health departments or trends in the number of complaints received over time are difficult to interpret." The HEI report quotes Livo (1995) in stating that overall there did not appear to be sufficient evidence to confirm a link between MTBE exposure and health complaints.

The HEI report concludes from the Missoula City-County Health Department (1993) study that "the information provided by the physicians did not indicate that an outbreak of illness occurred." The OSTP report draws on the personal communication from Leahy (1995) to conclude that during the following winter, ethanol rather than MTBE was being used and that "public concern over this issue essentially disappeared."

The HEI report acknowledges that Mehlman (1995) reports that some workers exposed to gasoline containing MTBE experienced some symptoms. The study by McCoy et al. (1995) demonstrated that distribution workers reported headache, dizziness, and nausea more often than service-station attendants, who in turn reported these symptoms more often than production workers. The HEI report notes that although the highest number of complaints was received in the winter during the oxygenated-fuel season, the actual manufacture and transport of MTBE had begun several months earlier. The OSTP report uses the presentation by Raabe (1993) to describe a part of the same study and to conclude that "the few complaints recorded each year suggest that this reporting system is not sensitive." The OSTP report concludes from the Medlin (1995) paper that oil, chemical, and atomic workers have reported many of the same symptoms that were reported by motorists in Alaska

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×

and other symptoms as well, including sinus problems, fatigue, and shortness of breath.

Both the HEI and OSTP reports failed to acknowledge that while largely anecdotal, these occupational studies are consistent with the studies of Alaska, Connecticut, and New Jersey, all of which reported that workers who are exposed to higher levels of MTBE may experience symptoms due to those exposures.

The OSTP report comments on the study by Egeland and Ingle (1995), which surveyed 100 adult residents in Anchorage, Alaska, for possible health problems due to the use of ethanol as an oxygenate. It concludes that the results of this study indicate a lower prevalence of symptoms than had been reported 2 years earlier, when MTBE was the oxygenate used in gasoline. The HEI report reviews this paper in its ethanol section and raises the concern that the questionnaire used focused on the same "key" symptoms first linked to MTBE exposure in Alaska for ethanol as well as MTBE exposure, although there was no clear-cut evidence that the symptoms associated with ethanol exposure would necessarily be the same as for MTBE. The HEI paper did note that a higher percentage of people noted an unusual odor while pumping ethanol-containing gasoline (vs. conventional gasoline) and more symptoms while driving than while refueling.

CONTROLLED-EXPOSURE STUDIES
EPA STUDY

DATA REVIEWED IN THE HEI AND OSTP REPORTS. Both reports review the paper by Prah et al. (1994).

COMMITTEE CRITIQUE. Prah et al. (1994) conducted a chamber study to determine if exposure to pure MTBE would elicit responses similar to those reported in Alaska following the addition

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×

of MTBE to winter fuels. Subjects were exposed to 1.4-ppm MTBE for 1 h. The only statistically significant response was that female participants rated the quality of clean air higher than air containing MTBE (Prah et al., 1994). Both reports conclude that the controlled-exposure studies failed to demonstrate either subjective symptoms or objective measures of eye or nose irritation and CNS dysfunction in healthy young adults exposed to MTBE vapor alone. The committee agrees with these conclusions, but emphasizes that this study does not replicate the setting of environmental and occupational exposures, which are chronic, frequently smaller, and to a mixture vs. a pure chemical. Thus, the relevance of these data to the interpretation of the acute health effects which have been reported in the field needs to be extended to include more environmentally relevant circumstances.

YALE STUDY

DATA REVIEWED IN THE HEI AND OSTP REPORTS. The HEI report reviews the paper by Cain et al. (1996). The OSTP report reviews a preprint copy of the same paper.

COMMITTEE CRITIQUE. To examine the effect of exposing humans to MTBE in combination with other volatile organic compounds (VOCs), Cain et al. (1996) performed a double-blind trial in which subjects were exposed sequentially to 1.7-ppm MTBE for 1 h on one day, uncontaminated air for 1 h 2 days later, and a 7.1-ppm mixture of VOCs used to simulate a gasoline mixture without benzene or MTBE for 1 h 2 days later. The subjects were able to accurately detect the odor of MTBE and the mixture of VOCs (Cain et al., 1996). The study also found that exposure to the mixture of VOCs led to an increase in polymorphonuclear neutrophilic cells. The HEI report concludes from this study that "a hydrocarbon mixture simulating gasoline did produce a minor

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×

inflammatory reaction in the upper airways as found on nasal lavage at a time delayed after the exposure. Thus, … one would expect vapor from gasoline containing MTBE to produce, at most, modest symptoms of irritation or inflammatory changes that do not differ substantially from those produced by gasoline vapor alone.'' The OSTP report notes that the finding of increased inflammatory cells in nasal lavage on the day following exposure was "consistent with previous work done at the EPA laboratories." The OSTP report cites work done by Koren et al. (1992) which was not reviewed by the HEI committee. The overall conclusions, however, were similar. The committee agrees with these conclusions but emphasizes that this study does not replicate the setting of environmental and occupational exposures, which are chronic, frequently smaller, and to a mixture versus a pure chemical. Thus, the relevance of these data to the interpretation of the acute health effects which have been reported in the field needs to be extended to include more environmentally relevant circumstances.

SWEDISH STUDIES

DATA REVIEWED IN THE HEI AND OSTP REPORTS. Both reports review two presentations made by the Swedish National Institute of Working Life (Nihlen et al., 1994; Johanson et al., 1995).

COMMITTEE CRITIQUE. Nihlen et al. (1994) and Johanson et al. (1995) performed controlled-exposure experiments on healthy volunteers at higher concentrations (5, 25 and 50 ppm) than either EPA (Prah et al., 1994) or the Yale study (Cain et al., 1996). The HEI report notes that for all three studies "the blood levels of MTBE measured at the end of the exposure were much higher than the upper-quartile levels measured in workers and commuters in Stamford." The OSTP report notes that in the Swedish experiments

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×

there was a "marginally significant increase in … nasal swelling which was not concentration related." The committee agrees with these conclusions but emphasizes that this study does not replicate the setting of environmental and occupational exposures, which are chronic, frequently smaller, and to a mixture versus a pure chemical. Thus, the relevance of these data to the interpretation of the acute health effects which have been reported in the field needs to be extended to include more environmentally relevant circumstances.

ACUTE HUMAN HEALTH EFFECTS
EPIDEMIOLOGIC STUDIES

HEI REPORT. The HEI report states "formal epidemiologic investigations designed to test specific hypotheses concerning MTBE added to gasoline and specific human health or human comfort endpoints have not been undertaken." The committee disagrees with this statement. Several community studies were conducted in response to the public concerns that followed the widespread introduction of oxygenated fuel during the winter of 1992-1993. At least two of the studies had an open meeting where academicians, public-health officials, and industry representatives were invited to participate and provide input. At these meetings the goals of the studies were clearly presented, the dependent and independent variables defined, and the instrument used for outcomes measures extensively tested (Mohr et al., 1994; Fiedler et al., 1994; White et al., 1995; CDC, 1993b).

With respect to the epidemiologic studies, the HEI report concludes "some of these studies, for example, those in Alaska, New Jersey, and Wisconsin, were performed in response to outbreaks of complaints concerning symptoms after MTBE in gasoline had been

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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introduced; in contrast, the studies in Connecticut and in New Jersey [sic] were carried out at times when outbreaks of complaints were not occurring." The committee notes that studies carried out in New Jersey were performed during the winter oxygenated-fuel season and during a period of time when increasing media attention was being placed on oxygenated fuels (Mohr et al., 1994; Fielder et al., 1994). One study not referenced by either the HEI report or the OSTP report (Mohr et al., 1995) was carried out before much press coverage of oxygenated fuels had occurred.

The HEI report also notes that the epidemiological studies were limited in assessing the exposures of participants. It suggests that the symptoms reported in these studies were "mild and of short duration; no evidence of associated clinical morbidity has appeared although such outcomes were not specifically addressed." The HEI report attempts to summarize certain aspects of the epidemiologic studies in Tables 15-19. In Table 16 and 17 for the New Jersey study they use 30 day ever vs. never analyses of symptom reporting as "prevalence." This highlights the difficulty in comparing results from one cross-sectional study to the next, when the time frame used to define the prevalence of symptoms varied from 1 day to 3 months across the studies. They also list 835% [sic] of garage workers in southern New Jersey as having experienced skin irritation; this was not addressed in the New Jersey study.

The HEI report states that "the [epidemiological] studies described here do not provide definitive evidence for an association between exposure to MTBE and symptoms" and they go on to suggest a well-designed prospective study. It also suggests that "although more research is needed, these studies provide an indication that some individuals exposed to emissions from automotive gasoline containing MTBE may experience acute symptoms such as headache or eye and nose irritation." This suggestion fails to recognize consistencies in the data from many of the occupational studies of exposed workers. As stated previously, these studies indicate

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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that workers exposed to greater concentrations of MTBE experience more symptoms. By failing to recognize the relationship between exposure and response and subsequently suggesting that "some individuals" may have problems (suggestive of a more sensitive subpopulation), they marginalize the problem. Even if a more sensitive subpopulation exists, the data presented indicate that more research is needed on exposed populations, rather than on sensitive subpopulations. The committee would like to point out that it is widely recognized among epidemiologists that most noninfectious diseases have multifactorial etiology. There are few if any deterministic relationships between risk factors and diseases, e.g., only 10% of heavy smokers get lung cancer in their lifetime (Rothman, 1986). However, it is generally regarded as an unproductive research goal to attempt through epidemiologic methods to identify those 10%; rather, epidemiology seeks to identify those factors that increase (or decrease) the population incidence or prevalence of disease.

OSTP REPORT. The OSTP report raises several concerns with respect to the epidemiological studies reviewed, including inadequate sample size, potential bias in the sample selection, inadequate or unreliable exposure information, and reliance on highly subjective measures of effect. With respect to the latter, the committee notes that acute-health-effects epidemiology must rely on these highly subjective measures of effect. Despite these issues, the OSTP report concludes that "taken together, these studies suggest that most people do not experience adverse health effects from MTBE in gasoline, but the studies cannot rule out the possibility that some people do experience more acute symptoms from exposure to oxygenated gasoline than to conventional gasoline." The report goes on to say "a causal association between acute health effects and exposure to MTBE or other oxygenates in gasoline in a relatively smaller proportion of persons has not been demonstrated but cannot be ruled out … [and] more definitive studies are needed."

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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Not unlike the HEI report, the OSTP report fails to recognize the consistency of the findings reported in the occupational studies of exposed workers. Despite their limitations, many of the studies and anecdotal reports suggest that workers exposed to higher levels of MTBE have an increased rate of symptom reporting. By suggesting that "a relatively smaller proportion of persons" may have problems with exposure, they ignore consistent findings in exposed workers and rule out the possibility that typical occupational exposures may pose a problem, whether or not a more sensitive general subpopulation does exist. However, the committee agrees with OSTP's discussion of the shortcomings of the available data: inadequate exposure assessment, insufficient sample size, potential for selection bias, and subjective outcome reporting.

CDC WHITE PAPER. The CDC white paper indicates that overall the statements made by the HEI and OSTP reports with regard to the epidemiological studies are consistent, even though the two reviews emphasized somewhat different aspects and limitations of the papers reviewed. No additional conclusions are put forth by the CDC white paper.

CONTROLLED-EXPOSURE STUDIES

HEI REPORT. The HEI report notes that while all three exposure studies failed to demonstrate subjective symptoms or objective measures of irritation or CNS dysfunction, these studies only exposed healthy young adults to MTBE alone for short periods and not as a component mixture of gasoline. In the executive summary, the Oxygenates Evaluation Committee identified a need for further human environmental-chamber studies to evaluate metabolism, symptoms, and neurotoxic effects in a more diverse population of individuals following exposure to MTBE and MTBE-gasoline mixtures.

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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OSTP REPORT. The OSTP report also states that controlled-exposure studies of healthy adults exposed to MTBE alone did not show an increase in symptoms or any notable adverse effects. The report also states that reported effects might be associated with other factors—such as low temperature, odor, or concurrent illness—that were not reproduced in the controlled-exposure studies. This report concludes that "these findings do not rule out the possibility that a subpopulation of people in the general population may be especially sensitive to MTBE alone or in gasoline." This report also recommends further studies among volunteers with self-described sensitivity to oxygenated fuels or combustive and evaporative emissions.

CDC WHITE PAPER. The CDC white paper reaches the conclusion that both reports "recommended that additional experimental studies of the mixture of MTBE and gasoline or similar hydrocarbon mixture be undertaken on potentially sensitive subjects."

CONCLUSIONS
  • The committee believes that while the epidemiologic data currently available do not establish a causal relationship between exposure to gasoline containing MTBE and the development of symptoms, the studies do indicate that some people have experienced acute symptoms associated with exposure to gasoline containing MTBE. Limitations of the studies make it difficult to rule out the possibility of an association between exposure to gasoline containing MTBE and acute symptoms, and the studies contain enough suggestion of a dose-response effect to motivate further investigation.

  • The health effects investigated thus far have all been acute symptoms. No data are yet available to link MTBE exposure to measurable adverse public-health effects, such as increased visits to

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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health-care providers or increased days of missed work or to the development of clinical acute or chronic disease.

  • The data indicate that there is enough consistency among various studies to suggest that the levels of exposure to gasoline containing MTBE in certain occupational settings are associated with increased rates of symptom reporting.

  • There are not sufficient data to indicate that the reported acute health effects are confined to a sensitive subpopulation. Therefore, it seems inadvisable to focus research on such subpopulations.

  • The committee believes that there should be coordination between clinical observations, epidemiology studies, and exposure-chamber experiments regarding acute human health effects and exposure to oxygenated fuels.

RESEARCH NEEDS
EPIDEMIOLOGY

One or more analytical epidemiologic studies examining the association between exposure to MTBE resulting from winter oxygenated-fuel programs and acute health effects should be conducted.

Such studies should have the following features:

  • Exposure to MTBE should be quantitatively assessed on an individual level through the determination of MTBE concentrations in blood and breathing zones (TBA concentrations can be considered in place of MTBE, if the validity of TBA as a surrogate for MTBE is established in a pilot study of sufficient sample size).

  • Symptom prevalence should be assessed through questionnaires. To the extent possible, the reliability and validity of these

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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questionnaires should be determined in a pilot study. Validity can be established, at least in part, through coordination with chamber studies (see recommendation below), where symptoms are provoked and objective measurements are taken simultaneously.

  • Outcomes which can be assessed through objective measures should be included whenever possible, e.g., the inclusion of CNS function measures using the protocol of Baker et al. (1985) to provide assessment of "key" neurological symptoms—such as dizziness, light-headedness and sleepiness, and ocular hyperemia-redness—and possibly immunological measurements from blood samples, because some data (Anderson, et al. 1995b) suggested a higher prevalence of MTBE-associated symptoms among those with physician-diagnosed allergies.

  • High-quality data on potential confounders should be collected at the level of the individual and should include sex, race, age, educational level, occupation, the Barsky (1990) Amplification Scale, current use of medications, features of any automobiles driven (including vehicle year and status of antipollutant technology), type of gasoline used, amount of time spent in automobiles and in traffic, weather conditions at the time of measurements (including temperature, humidity, and air pressure), and concurrent exposures in both the blood and breathing zone (including benzene, toluene, formaldehyde, acetaldehyde, carbon monoxide, and xylene).

  • Power and sample-size calculations should be done carefully to ensure sufficient statistical power to detect health effects corresponding to a 50% increase or more (i.e., relative risk of 1.5). These calculations should consider the high correlation of simultaneous exposure to numerous chemicals with possible health effects.

  • Cross-sectional designs as well as "longitudinal designs" (pre-shift vs. postshift or beginning of day vs. end of day) should be considered, or perhaps a hybrid of these. These designs are relatively quick and inexpensive to conduct. Optimally, a more expensive,

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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time-consuming design to consider is a longitudinal study in which a sample of individuals are enrolled 1-2 months prior to the commencement of the winter oxygenated-fuel program and monitored at regular intervals subsequent to the commencement of the program and until its termination in the spring. Symptom diaries can be kept between monitoring visits. This design would be able to provide information on the time course between exposures and possible outcomes, as well as the possible development of sensitivity and/or tolerance to exposures over time. Since individuals are used as their own controls, confounding by many individual factors is eliminated.

  • To improve cost effectiveness of any study (studies), sophisticated modern designs in which detailed confounder, exposure, and outcome data are obtained in a subsample should be considered (two-stage designs) (Cain and Breslow, 1988; Tosteson, TD and Ware, JH, 1990). Since standard statistical software is generally not applicable when these designs are used, the assistance of a statistician with experience in the design and analysis of such studies will be required.

  • To ensure generalizability, study participants should include adequate representation of both environmental and occupational exposure levels.

  • Efforts to maximize participation rates of sampled individuals should be considered and should not exclude financial honoraria for participation; in addition, partnership with the gasoline industry should be considered, to facilitate access to exposed individuals and workers at filling stations and garages.

CHAMBER STUDIES

The reports reviewed by the committee noted that the "stimulus" of the effect requires further study. This would include the effects

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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of any fuel oxygenate, such as MTBE, alone, the effects of an oxygenate in a background of gasoline vapors, and the effects of vapors from combustion of oxygenated fuel. In addition to the stimulus, the system or modality of an effect (e.g., irritation of the eyes and nausea), the appropriate response (e.g., rating of severity), and any predisposing factors (e.g., age) should be investigated.

STIMULUS. Within the context of chamber studies, the committee endorses the need a) to study MTBE or other oxygenates against backgrounds of gasoline or combustion products (at open-loop and closed-loop conditions of operation of an engine) as deemed ethical, b) to vary the temperature of exposures in chambers in order to simulate cold-weather vs. warm-weather conditions, and c) to repeat exposures over time in order to simulate real-world circumstances. A series of chamber studies could not only help in development of a structured protocol for evaluation of acute human health effects of MTBE, but also of other oxygenates and of VOCs in general. (Protocols developed to explore acute effects of oxygenates might prove to be useful to explore effects associated with sick building syndrome and multiple chemical sensitivity as well.)

If an oxygenate is in use in a geographic area, it should be possible to recruit people from that area and from suitable control areas to record their symptoms or observations as they occur in everyday life. (Involvement of designated clinicians to examine any symptomatic individuals in such a group could prove quite valuable in this context.) Data collection and analysis would need to be sensitive to the variables of concentration, time, other situational factors, and susceptibility of the host. Observations of this nature would not prove cause and effect so much as they would narrow the range of possibilities for more controlled study. For example, they would help to set up uniform reporting requirements and thereby reduce the likelihood that symptoms would go unreported. They would also reveal, via accompanying monitoring, how symptoms

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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may vary with time and level of exposure; i.e., symptoms might lag behind exposures by some period of time or occur more frequently when a person is fatigued or when a person's ventilation is above average, as during physical labor. Since exposures in chambers cannot reproduce every circumstance of life, these prior observations could help to focus chamber studies on the most relevant circumstances.

Studies in chambers can in principle simulate many field exposures. If, for example, one learned from field observations that brief, high exposures seemed to trigger symptoms that persist for a while whereas longer, low exposures did not, then this could productively direct research in chambers. Merely measuring every conceivably relevant symptom using arbitrarily decided durations or duty cycles will detract from productive hypothesis-testing. The design of chamber studies should be informed by epidemiological studies and any clinical observations mentioned above and in turn, the chamber studies should entail development of techniques that may prove useful in epidemiological studies and perhaps in clinical objective validation of symptoms.

MODALITY. Symptoms reported in the field often involve irritation of the eyes or nose. In laboratory experiments, irritation in the nose or eyes can be induced without any systemic exposure. For example, induction of local irritation in the nose can occur via voluntary velopharyngeal closure (i.e., closing off the nasal cavities from the pharyngeal area) and restriction of oral breathing. Stimulation of the eyes requires no inhalation. Measurements of thresholds for irritation in brief or longer-term exposures could reveal the distribution of sensitivity in normal individuals. Investigation of a sample of appropriate size and composition would in essence allow a definition of hypersensitivity.

At present, the most feasible assays for human sensory irritation are psychophysical. These should entail exposures for durations commensurate with the time constants of chemosensory functioning.

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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Because irritation may take minutes or even tens of minutes to develop, exposures should last a commensurate length of time.

From the standpoint of objectivity, psychophysical assays of irritation should entail blinded exposures, i.e., subjects should not be able to determine the presence or the level of a stimulus via smell. One possibility for ''blinding" involves "separation" of the eyes from the upper airways in such a way as to remove olfactory cues. Blinding during nasal stimulation poses a more difficult challenge. Odor masking offers some possibilities, but requires the introduction of another chemical. Another possibility for blinding would involve use of anosmic subjects. In such subjects, velopharyngeal closure would, as in normal individuals, avoid systemic exposure. Use of such subjects would need to include tests for their comparability with normal individuals. (In major cities, it is not difficult to recruit a dozen or more persons with verifiable anosmia.)

There has been little study of how the eyes respond to chemical exposure that do not result in frank inflammation. For example, it is unknown whether susceptibility to irritation varies systematically during the day or as a function of the performance of particular tasks. Because of the absence of this background information, putative correlates of irritation, such as tear-film breakup and evaluation of scoring of the conjunctiva, both of which have been used in chamber studies, remain poorly verified with respect to reactions caused by exogenous chemicals. The same holds true for objective indexes of nasal irritation. All the various potential objective correlates of what we can term surface symptoms require further validation, which can only be done if there is a deliberate attempt to precipitate reactions. Such efforts to correlate symptoms with objective indexes may help determine requisite statistical power for measuring what might be meaningful changes in symptoms or their correlates.

Aside from chemosensory measurements, which are necessary to

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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specify the level at which a chemical may become bothersome, other measurements should be made with some hope of understanding the modality through which they operate. Field data have provided only weak specification of the symptoms allegedly caused by MTBE. For even a chance of appropriate specification of symptoms, data need to be collected prospectively. The possibility that nonspecific symptoms attributed to exposure to MTBE may have resulted from other causes requires careful attention. Not only is it a waste of time and money to study effects that may not be real, but such studies lead to indeterminacy and continued unresolved concerns.

Without understanding of why and when symptoms occur, there can be no true honesty in dealing with complaints. The current level of understanding allows no probative answers; accordingly, decisions regarding exposures to oxygenates may devolve to nonscientific considerations.

RESPONSE. Following characterization of stimulus-driven symptoms and their correlates, attention can presumably focus on the most important symptom and its objective correlate. This symptom should be studied in hypothesis-driven experiments. If the symptom were headache, for example, research would need to (1) establish the minimal conditions of exposure for it to occur in the typical case and (2) examine its correlates, e.g., blood flow and accompanying blood levels of oxygenate and/or gasoline. It is important to emphasize that the key symptom should be studied in order to be understood, not merely cataloged. If a second symptom seems relevant from field data, it too should receive attention.

A surface potential from the respiratory mucosa (i.e., the negative mucosal potential), if proved comparable with human psychophysical results on irritation, could provide an objective index even for subjects whose sense of smell is allowed to operate normally during exposure.

Separation of the surface effects of MTBE, gasoline, or any candidate

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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oxygenate from systemic effects could in principle simplify the study of acute reactions. For example, a study involving measurements of surface effects in anosmic persons in the manner described above can also include determining inhaled concentrations of MTBE that would give measurable blood concentrations. If elevated blood levels are not associated with sensitivity to surface exposure, then surface effects and systemic effects could perhaps be studied independently. Such an outcome may ultimately help determine whether surface effects "drive" other symptoms; e.g., irritated eyes might drive feelings of fatigue or listlessness, which might lead to reports of "spaciness."

Along the lines of separating surface from systemic effects, alternative routes of administration of the chemical of interest might prove worthy of consideration. Ingestion or infusion might replace inhalation as a way to investigate systemic symptoms or signs of impairment in humans. These alternative routes may permit double blinding more readily, though this would need to be demonstrated. (In theory, exhaled oxygenates could thwart blinding.) The time-course of blood concentrations of the relevant agent introduced by an alternate route would need to mimic that obtained via inhalation. Insofar as the principal systemic effects were neuropsychological in nature, the use of a positive control of ethanol would seem merited.

PREDISPOSING FACTORS. Field experience indicates that not every person will experience symptoms of exposure to oxygenates under common environmental conditions of exposure. Predisposing factors, insofar as they are demographic pr medical characteristics — such as sex, allergies, and history of exposure — could be studied in hypothesis-testing.

With respect to the recommendation for "additional controlled exposures of people with self-described sensitivity to oxygenated fuels" (OSTP report, p. 59), some people may indeed have greater sensitivity than others to MTBE, but it seems premature to focus

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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research on such individuals without objective criteria to suggest the existence of such a group. Nevertheless, some pilot testing toward development of criteria would not seem out of place. Although the majority of people exposed to MTBE via oxygenated fuel may voice no complaints, this does not mean that they fail to experience many of the same reactions as those who do complain or would complain under the same circumstances of exposure. There is presumably too little known about the interaction of circumstances of exposure and susceptibility to make the case for the existence of a sensitive group, as opposed to particular circumstances that precipitate complaints. Conceivably, persons who complain have experienced special circumstances (e.g., fatigue at the point of exposure or airway disease). The tendency to attribute the exposures in a chamber to a hypothetically sensitive group could prove unproductive or possibly even counterproductive in an environment of limited resources. The reports acknowledge the severe limitations of previous chamber studies, which would seem to argue strongly for further studies of normal subjects under various conditions of exposure (e.g., longer durations, use of mixtures of MTBE and gasoline) and of subjects with objective indications of risk (e.g., asthma).

In summary, the chemosensory properties of potential oxygenates form important parameters for detection and possible annoyance effects and should be delineated expeditiously. Symptoms associated with real-world exposures to agents should be characterized from prospective field data in order to be used in more formal studies. Such studies should offer insight into how a symptom occurs and should entail focused hypothesis-testing. Re-creation of the symptom in a chamber should, if possible, be accompanied by an objective correlate to verify its presence and perhaps to add insight into its mechanism. Field data could offer insights into predisposing factors for symptoms, with followup in formal studies. This work will undoubtedly yield both methodological and

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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substantive insights as studies are done. The methods used in human chamber studies may seem as routine as that used in toxicological screening, but they are not. There is a great deal to be learned about how to study such problems as those posed by MTBE. Researchers in this area need to refine their techniques with actual experience. This does not argue for an open account, but argues for acknowledgment that as VOCs are considered as potential oxygenates, research on their potential acute effects should begin with greater knowledge of how to screen for such effects than is now available.

ODOR STUDIES. For some oxygenates, the olfactory threshold is already known; for others, the data should be gathered.

There may be merit in conducting further studies of odor detection of oxygenated vs. conventional gasoline. One question that often arises is whether persons become more sensitive over time to the presence of oxygenates. Within this context, it may be advantageous to determine if people become primed by the odor of oxygenates. Perceptual priming has been the subject of hundreds of studies of which only few focused on olfaction.

In light of the high suggestibility toward false alarms in olfaction, it would be of interest if subjects show more likelihood of perceiving oxygenate when it is not present.

Insofar as odor of oxygenates plays a role in exacerbation of asthma in asthmatic patients, nasal exposures to odor independently of systemic exposure may help to determine whether the exacerbation might be "caused" by the odor.

ECOLOGICAL STUDIES

Due to the difficulties (e.g., high cost, long followup time, and large required sample size) of designing an analytical epidemiologic study in which individual data are linked to cancer and other

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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chronic morbidity outcomes, attention must be turned to ecologic designs, despite their widely acknowledged deficiencies. Death-certificate data are collected by all states, making it possible to link exposures with cancer, cardiovascular, and respiratory mortality, by ICD code. In addition, nearly all states have cancer registries, making it possible to calculate cancer incidence rates. Geocoding by the unit of environmental sampling should be considered as a method for controlling for bias due to differences in the distribution of other determinants of the diseases under study. However, sufficient exposure data at the community level which could be linked to routine mortality and cancer incidence data are not presently available, so such studies are impossible today. Thus, the committee does not recommend that ecological studies be undertaken at the present time, but recommends that the most important pollutants be identified and environmental monitoring data, such as those discussed in chapters 2 and 3, begin to be collected, so such ecological studies can be conducted in the future, perhaps in 10 years or so. Measurement techniques should be developed for pollutants for which adequate techniques are not available.

REPRODUCTIVE AND DEVELOPMENTAL EFFECTS

DATA REVIEWED IN THE HEI AND OSTP REPORTS

The HEI report reviews the data available on the reproductive and developmental effects of MTBE and ethanol. A number of animal studies have been conducted on the potential reproductive and developmental effects of MTBE. Maternal toxicity and effects on reproductive indexes have been observed at exposure concentrations of 3,000-8,000 ppm. In offspring, developmental effects have also been observed at these concentrations. No maternal or developmental effects have been observed at lower concentrations (300-400

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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ppm). Actual human exposures are expected to be lower than these no-observed-effect levels by a factor of 1,000 or 10,000.

Ethanol is a known potent developmental toxicant in humans. However, it is not anticipated that exposures to ethanol from use of ethanol as an oxygenate will result in a substantial deviation in blood ethanol from endogenous levels.

The OSTP report reaches essentially the same conclusions with regard to the potential for reproductive and developmental effects in humans.

COMMITTEE SUMMARY

The committee agrees with both the HEI and OSTP reports that adverse reproductive and developmental effects are not expected to result from MTBE exposure at the levels at which most people would be exposed.

RESEARCH NEEDS

The HEI report does not give high priority to research on reproductive or developmental effects. The committee feels this is reasonable. However, appropriate studies should be conducted on other proposed oxygenates before they are extensively introduced in the U.S. gasoline supply.

LONG-TERM HEALTH EFFECTS

HUMAN

Both the HEI and OSTP reports failed to identify any human

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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studies on the potential long-term health effects of MTBE or other oxygenated fuels. Chronic health effects due to the ingestion of ethanol have been well studied and are not addressed in this review.

ANIMALS

DATA REVIEWED IN THE HEI AND OSTP REPORTS

As noted in the CDC white paper, while there are many similarities between the HEI and OSTP reports regarding the carcinogenicity of MTBE, there are also notable differences. The HEI report gives a more comprehensive review of the various animal studies than does the OSTP report. Neither the HEI nor the OSTP report evaluates the potential of other ether oxygenates, because no long-term carcinogenicity studies have been conducted.

COMMITTEE CRITIQUE

ORAL ADMINISTRATION IN RATS (BELPOGGI ET AL., 1995). The HEI and OSTP reports accurately describe the results of the study, but both fail to note the deficiencies in study design, conduct, and reporting. For example, decreases in survival of 15% (at 250 mg/kg) to more than 20% (at 1,000 mg/kg) in females were noted as early as 9-12 months. That there was no concurrent effect on bodyweight gain suggests that the deaths were directly attributable to the toxic effects of MTBE, and therefore that both exposure levels probably exceeded the definition of a maximum tolerated dose (MTD). Survival in males was also decreased but not until late in the study.

There is no information on the cause of death in the early-death

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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females which would help in the interpretation of the study. In addition, no rationale is given for the selection of dose levels or the highly unusual dosing regimen, i.e., dose on Monday and Tuesday, no exposure on Wednesday, then dose on Thursday and Friday.

As noted in both the HEI and OSTP reports, a dose-related increased incidence of lymphomas and leukemias (combined) was observed in female rats, but neither report mentioned or highlighted the fact that it was found only at doses which clearly decreased survival and that no such increase in tumors was observed in male rats where survival was not so impacted. Also, there was no description of the morphologic criteria for these two entities.

The other reported increase in tumor response related to MTBE exposure was interstitial-cell (Leydig's cell) tumors of the testes at 1,000 mg/kg, but not 250 mg/kg. Neither the HEI nor the OSTP report notes that the Belpoggi et al. (1995) study fails to give any description of the lesions in terms of size or the criteria used for their diagnosis, which is extremely important for these types of neoplasms, which have a morphologic continuum from hyperplasia to neoplasia. Also, unlike the lymphoma-leukemia situation, where possible "preneoplastic" lesions of the same cell type are described and tabulated, no such Leydig's cell proliferative lesions are mentioned. A concordant increase in hyperplastic lesions would add evidence to the observations. Neither report takes note of the fact that the high-dose male rats showed increased survival after 88 weeks (compared to the middle-dose and controls) and therefore were at greater risk for development of these late-appearing neoplasms (first tumor was found at 96 weeks). It is not clear if the statistical analysis adjusted for this.

Finally, because of the importance of this study for eventual use in risk assessment, the superficial reporting of the data, and the nature of the observed lesions, the committee feels strongly that an independent in-depth review of the data, especially the pathology (microscopic slides) of the critical lesions, is warranted (as was done

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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with the inhalation studies) before the data are used for risk assessment.

INHALATION EXPOSURE IN RATS. Both the HEI and OSTP reports state that the increased incidence of renal adenomas in male rats was related to MTBE exposure and speculate that it may be due to the metabolite TBA. Both reports discuss in some depth the possibility of 2u-globulin's being responsible for the kidney tumors but conclude that this is probably not the case. The committee, after hearing about and evaluating studies (Prescott-Mathews et al., 1996; Poet et al., 1996) conducted recently at the Chemical Industry Institute of Toxicology, feels that 2u-globulin may, in fact, be involved in the causation of these neoplasms. It appears that this research has fulfilled the EPA criteria of causation in this regard. In any event, both reports need to revisit this issue in light of these new findings.

INHALATION EXPOSURE IN MICE. Both the HEI and OSTP reports are in agreement with regard to the principal finding in this study, i.e. the induction of liver tumors. There was a mild but statistically significant increase in benign (only) tumors in females at the high dose (8,000 ppm), which was also statistically significant (compared to controls) when benign and malignant tumors were combined. In contrast, while there was an increase in carcinomas in male mice at 8,000 ppm (only), there was no statistically significant increase when they were combined with adenomas — the more appropriate method of analysis.

The question raised in both reports was whether the study was of sufficient length (18 months) to support conclusions concerning the carcinogenic potential. Both reports suggest that the study should have gone to 24 months, as is routine in the National Toxicology Program (NTP). However, the committee felt that both reports fail to note that CD-1 mice (used in the inhalation study) do not live as long (on average) as the standard NTP mouse (B6C3F1) and that therefore the CD-1 mouse study may not be adequate for

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×

risk-assessment purposes. Moreover, the quantitative potency estimate derived from this study included an upward adjustment of risk to account for the ''less than lifetime exposure."

The committee agreed with the discussion in the HEI report concerning the possible mechanisms for induction of the liver tumors and also agreed that nongenotoxic hormonally related mechanisms were the most plausible explanation. Thus, the committee feels that it is inappropriate to combine the male and female tumor responses for determining "maximum likelihood estimates" and "upper confidence limits," as was done in the OSTP report.

COMPARISON OF ANIMAL STUDIES. Neither the HEI nor the OSTP report discusses comprehensively the long-term animal studies in their totality, i.e., a weight-of-evidence approach. While the reports note that MTBE is a multispecies, multisite, and multisex animal carcinogen, they fail to take note of the inconsistencies in this regard as follows.

LYMPHOMAS AND LEUKEMIAS. There was a reported increase in these tumors in female SD rats exposed via gavage at 1,000 mg/kg but not at 250 mg/kg, nor in males at either dose. In contrast, neither sex of F344 showed this effect even at an air concentration at 8,000 ppm, which corresponds to a dose at least 4 times greater than the largest gavage dose, that was clearly toxic. This incongruity is especially noteworthy in light of the fact that this strain of rat (F344) is highly prone to the induction of leukemia, which is in fact an important cause of death in older F344 rats.

RENAL TUBULAR-CELL TUMORS. While the inhalation study in F344 rats showed an increase in these tumors in males (only) at 3,000 and 8,000 ppm, no such effect was found in the SD rat. One has to question why this is so in light of the fact that both strains of rats are susceptible to 2u-globulin nephropathy and resulting tumors. While the routes of exposure are different, this is a systemic effect which should be present with either exposure regimen.

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×

One possible explanation (which should be addressed in the OSTP report) is that the highest gavage dose is still approximately one-third less than the lowest inhalation dose. However, because of the bolus nature of the gavage dose, it would be expected that peak blood levels would actually be greater in the gavage exposure than in the lowest inhalation exposure, "3,000 ppm," in which these tumors were observed. However, the situation is complex because the metabolite of MTBE, TBA, may be responsible for the effects. In any case the OSTP report should discuss this issue in some depth in an attempt to explain this apparent discrepancy in results.

LEYDIG'S CELL TUMORS. Both the inhalation and gavage studies report an increase in Leydig's cell tumors of the testes, although the increase is not as impressive in the inhalation study, probably due to the high spontaneous rate in this strain (F344) of rat. However, this response is inconsistent with the TBA study conducted by the NTP in the F344 rat, where no such increase was observed. It is unclear why this should be the case in light of the proposed (HEI report) mechanism of tumor induction.

Such inconsistencies are rather unusual in rodent bioassays, especially when it is clear that the dose levels are at or above the MTD, as is the case in these studies. At a minimum, these inconsistencies need to be investigated in some depth before the animal data are used for risk assessment. To resolve this issue, the committee suggests that the Belpoggi et al. (1995) pathology slides be reviewed by a group of independent pathologists, as was done with the inhalation studies of MTBE and TBA, to verify the findings and resolve these inconsistencies.

GENOTOXICITY. The committee agrees with the HEI and OSTP reports, although it was noted that both are incomplete, i.e., each contains studies that are missing in the other report. The committee feels they should be reconciled. As noted in the HEI report, little information on the genotoxicity of the other oxygenates is available, other than ethanol.

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
×

MECHANISMS OF TOXICITY. The HEI report gives much more attention to the issue of possible mechanisms of carcinogenicity than the OSTP report. In fact, this is an important component of the report and should be considered before conducting any risk assessment.

CONCLUSIONS
  • Because of the inconsistencies and unsolved questions with regard to the animal-carcinogenesis studies, cancer-potency estimates of MTBE as proposed in the OSTP report should be considered carefully. The committee feels that the male rat kidney-tumor data probably should not be used for this purpose in light of the new information on its probable causation, i.e., 2u-globulin nephropathy, which is thought to be unique to the male rat and not relevant to humans.

  • The use of the lymphoma and leukemia data should also be questioned until a thorough review of this study, including an objective third-party review of the pathology, is accomplished.

  • The most reliable data available for risk-assessment purposes are on the induction of benign liver tumors in female mice exposed to 8,000 ppm MTBE via inhalation. Although it should be recognized that this amounts to extremely weak evidence of carcinogenicity, it cannot be discounted.

RESEARCH NEEDS

If other oxygenates become or are expected to be used in formulated gasoline to which large numbers of humans are exposed, indepth chronic-toxicity and carcinogenicity studies in animals should be conducted (before the introduction of other oxygenates).

Suggested Citation:"5 POTENTIAL HEALTH EFFECTS OF OXYGENATES." National Research Council. 1996. Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels. Washington, DC: The National Academies Press. doi: 10.17226/5321.
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This book reviews a draft report from the federal government that assesses the effects of oxygenated gasoline on public health, air quality, fuel economy, engine performance, and water quality. In addition to evaluating the scientific basis of the report, the book identifies research needed to better understand the impacts of oxygenated fuels. Methyl tertiary-butyl ether (MTBE), which is intended to reduce carbon monoxide pollution during winter, is the most commonly used additive in the federal oxygenated fuels program. MTBE has been implicated in complaints by the public of headaches, coughs, and nausea. Other questions have been raised about reduced fuel economy and engine performance and pollution of ground water due to the use of MTBE in gasoline. The book provides conclusions and recommendations about each major topic addressed in the government's report.

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