Toxicological and Performance Aspects of Oxygenated Motor Vehicle Fuels (1996) / Chapter Skim
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5 POTENTIAL HEALTH EFFECTS OF OXYGENATES
5 POTENTIAL HEALTH EFFECTS OF OXYGENATES
Pages 75-116
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From page 75... ...
, the OSTP report; and a memorandum from the Centers for Disease Control and Prevention signed by Richard I Jackson and directed to the Interagency Oxygenated Fuels Assessment Steering Committee detect March 12, 1996, the CDC white paper, which compared and contrasted the other two reports.
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From page 76... ...
OWED ~ N TH E H E] AN D OSTP REPORTS The HET report reviews what is known about the metabolism, disposition, and toxicokinetics of MTBE and ethanol in both animals and humans.
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CONCLUSIONS The committee is in basic agreement with the review and evaluation of the data presented in the HE} and OSTP reports. No major
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From page 78... ...
. 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.
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From page 79... ...
One major difference between the HE] 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.
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However, one area not adclressed in either the HEl or the OSTP report is the question of TBF toxicity. Based on the available data, the committee does not fee} the effect of MTBE on motor activity reported in rat inhalation studies is of major concern, for the following reasons: (~)
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From page 81... ...
HUMAN EPIDEMIOLOGIC STUDIES ALASKA STUD/ES DATA REVIEWED IN THE HEI AND OSTP REPORTS The HE! report and the OSTP report reviewed four studies: (~)
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From page 82... ...
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.
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From page 84... ...
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.
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From page 85... ...
COMMITTEE CRITIQUE. Neither the HET 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)
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From page 86... ...
AN D 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)
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From page 87... ...
. 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.
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From page 88... ...
and OSTP reports reviewed the same studies, it
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From page 89... ...
In addition, neither the HE} report nor the OSTP report draws major conclusions from the studies listed directly above in the section "Other Studies and Reports Reviewed in the HE] and OSTP Reports." The OSTP report draws on the differences between the Livo (1995)
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From page 90... ...
and shortness of breath. ~Cat 1 ~ Both the HEl 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.
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From page 92... ...
. 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 ravage 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.
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From page 93... ...
. 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.
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From page 94... ...
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.
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From page 95... ...
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 .
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From page 96... ...
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.
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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.
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_ The committee believes that there should be coordination between clinical observations, epidemiology studies, and exposurechamber experiments regarding acute human health effects and exposure to oxygenated fuels.
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. · 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 I.5~.
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CHAMBER STUD/ES The reports reviewed by the committee noted that the "stimulus" of the effect requires further study. This would include the effects
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From page 101... ...
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.
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From page 102... ...
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.
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From page 103... ...
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.
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From page 104... ...
accompanying blood levels of oxygenate anci/or gasoline. It is important to emphasize that the key symptom shouic!
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From page 105... ...
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.
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From page 106... ...
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.
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From page 107... ...
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.
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From page 108... ...
Measurement techniques should be developed for pollutants for which adequate techniques are not available. REPRODUCTIVE AN D DEVELOPS ENTAL EFFECTS DATA REVI OWED IN THE H El AND OSTP REPORTS The HEl report reviews the data available on the reproductive and developmental effects of MTBE and ethanol.
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From page 109... ...
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. RES MARCH N BEDS The HE} report does not give high priority to research on reproductive or developmental effects.
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From page 110... ...
AN ~ MALS DATA R~V/EWED IN THE HEI AND OSTP REPORTS As noted in the CDC white paper, while there are many similarities between the HET and OSTP reports regarding the carcinogenicity of MTBE, there are also notable differences. The HEl report gives a more comprehensive review of the various animal studies than does the OSTP report.
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From page 111... ...
c, , . As noted in both the HEl and OSTP reports, a dose-related increased incidence of lymphomas and leukemias (combined)
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INHALATION EXPOSURE IN RATS. Both the HE} 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 clue to the metabolite TBA.
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From page 113... ...
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 mate and female tumor responses for determining "maximum likelihood estimates" and "upper confidence limits," as was done in the OSTP report.
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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.
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From page 115... ...
In fact, this is an important component of the report and should be consiclered 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.
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