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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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.
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels Both the HEI report and the OSTP report relied upon published, peer-reviewed literature; unpublished reports from a number of sources, including industry, government agencies, and scientists; and personal communications.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.
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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.
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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.
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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.
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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.
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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.
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Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels 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).
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Representative terms from entire chapter: