Health Risk Issues for Methyl tert

Chapter 6

Health Risk Issues for Methyl tert-Butyl Ether

Downloaded by PENNSYLVANIA STATE UNIV on September 14, 2012 | http://pubs.acs.org Publication Date: November 6, 2001 | doi: 10.1021/bk-2002-0799.ch006

J. Michael Davis National Center for Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

A substantial database exists on the inhalation toxicity of MTBE, but exposure information and health effects data for non-inhalation routes of exposure are limited. In addition, several issues complicate the interpretation of the available data in assessing the health risks of MTBE. These issues are discussed in terms of non-cancer and cancer health risks. Some current and further activities in support of MTBE health risk assessment are described.

To assess the potentialrisksof methyl tertiary butyl ether (MTBE) quantita tively, information on the potential for population exposures as well as both qualitative and quantitative information on the health effects of MTBE is needed. Although the focus of MTBE health risk assessment efforts was initially on the effects of inhalation exposures, evidence of groundwater contamination by MTBE has also led to concerns about contamination of drinking water and the potential for human exposure and consequent health effects. In some respects, MTBE health effects have been well characterized, but in other respects significant uncertainties have contributed to the difficulty in resolving debates about the potential human health hazards and risks related to MTBE.

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U.S. government work. Published 2002 American Chemical Society

In Oxygenates in Gasoline; Diaz, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2001.

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Non-Cancer Health Risks Several inhalation studies on the toxic effects of MTBE were conducted under provisions of an enforceable consent agreement between EPA and oxygenate manufacturers in the late 1980s and early 1990s (7). These studies yielded a substantial amount of information that was evaluated by EPA in deriving an inhalation reference concentration (RfC) for MTBE. The RfC is defined as an estimate (with uncertainty spanning about an order of magnitude) of a continuous inhalation exposure level for the human population (including sensitive subpopulations) that is likely to be without appreciable risk of deleterious noncancer effects during a lifetime. Reference concentrations have generally been derivedfromhealth effects studies by (1) identifying a no-observed-adverse-effect level (NOAEL), lowest-observed-adverse-effect level (LOAEL), or an alternative benchmark value obtained through mathematical analysis ofthe data; (2) adjusting this concentration to reflect continuous human exposure; and (3) dividing the adjusted concentration by uncertainty factors (UFs) as appropriate for extrapola tions across species, to sensitive subpopulations, from subchronic to chronic exposures, or for other limitations in the available data. The original RfC for MTBE was initially based primarily on effects observed in rats exposed by inhalation for 13 weeks to concentrations of 2,880, 14,400, or 28,800 mg/m MTBE (2, subsequently published in 3). Various "moderately adverse" effects in different organ systems (brain, adrenal, female kidney, and liver), along with decreased body weight, were cited as the basis for an RfC of 0.5 mg/m MTBE (4). After the results of 2-year bioassays became available, EPA revised the RfC in 1993, based on findings of increased liver and kidney weights and increased severity of spontaneous renal lesions in female rats, as well as increased prostration in females and swollen periocular tissue in male and female rats (5, subsequently published in 6). The concentrations in the chronic study were nominally 1,440,10,800, and 28,800 mg/m MTBE. Although the NOAEL was lower in the chronic study (1,440 mg/m ) than in the subchronic study (2,880 mg/m ), the total UF used in deriving the revised RfC was 10-fold lower because no UF was needed for extrapolatingfromsubchronic to chronic exposure. Thus, after adjusting the NOAEL for continuous duration exposures and dividing by a total UF of 100, the RfC for MTBE is 3 mg/m (7). Although adequate exposure data on population exposures to MTBE were not available, the U.S. Environmental Protection Agency (8, 9) considered various "worst case" scenarios and estimated potential long-term average exposure levels to MTBE in relation to both winter oxyfuel (containing 15%-vol MTBE) and yearround reformulated gasoline (containing 11%-vol MTBE). These worst-case 3

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average exposures were less than 0.2 mg/m , or about an order of magnitude below the RfC of 3 mg/m . Thus, based on the available information, EPA (P) concluded that "long-term exposures to MTBE vapors are not expected to cause adverse noncancer health effects, but effects of...mixtures of gasoline and MTBE...are unknown." This conclusion was essentially affirmed by subsequent reviews and assessments by other organizations (10-13). When oxygenated gasoline was first introduced in late 1992, complaints of headache, nausea, eye and nose irritation, and other health symptoms were registered in Fairbanks, Alaska, and a few other locales. These health complaints were associated with acute exposures to MTBE-oxygenated fuel. Although several studies were initiated in response to these complaints, a basis for the acute symptoms attributed to MTBE has not been established. These studies included experimental investigations with laboratory animals (e.g., 14) as well as human volunteers (e.g., 75-77). In addition, epidemiological studies were conducted in communities where MTBE-oxygenated fuels were used (e.g., 18, 19). However, none of these studies investigated the reactions of self-reported sensitive (SRS) individuals under controlled conditions. The only experimental study of such individuals to date is that of Fiedler et al. (20). Twelve SRS subjects were compared to 19 control subjects under four exposure conditions: clean air, gasoline alone, gasoline with 11%-vol MTBE, and gasoline with 15%-vol MTBE. Compared to control subjects, the SRS subjects reported significantly more symptoms of all types (including some not previously associated with complaints about MTBE) under all conditions, including clean air. Apart from these subjective reports, the SRS and control subjects did not differ on objective measures (neurobehavioral or physiological responses) or in their ratings of the odors of the exposure conditions. The SRS subjects did, however, report significantly more symptoms (but no other objective response measure) when exposed to 15%-vol MTBE-gasoline than to clean air or, for that matter, 11%-vol MTBE-gasoline. Thus, the SRS subjects appear to have been more "sensitive" to (15%-vol) MTBE-gasoline, and this differential symptom response does not appear to have been mediated by an ability to discriminate the different exposure conditions by odor. On the other hand, the lack of difference in symptom reports between 11%-vol MTBE-gasoline and gasoline alone (or even clean air) suggests that an MTBE-oxygenated reformulated gasoline, which is the predominant use of MTBE in the United States, would probably not pose a problem for these SRS individuals, assuming their actual exposures are comparable to the test conditions.


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Cancer Risk The potential for MTBE to cause cancer also has been a matter of consider able discussion and debate. Three chronic studies have been conducted in laboratory rodents exposed to MTBE by either the inhalation route or oral route. Two inhalation studies (6) were conducted, one with rats and the other with mice


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exposed to 0, 1440, 10,800 and 28,800 mg/m MTBE 5 days per week for 24 months (rats) or 18 months (mice). The oral bioassay (21) was conducted with rats given MTBE in olive oil by gavage at doses of0,250, and 1000 mg/kg body weight once daily for 4 days per week for 24 months. Various types of tumors were observed in these studies: liver tumors in female mice exposed by inhalation, kidney tumors in male rats exposed by inhalation, testicular tumors in male rats exposed by either inhalation or ingestion, and lymphomas and leukemia in female rats exposed by ingestion. Each of these findings has had some degree of uncertainty surrounding it. The female mouse liver tumors have been viewed by some experts as an indirect consequence of a disinhibitoiy effect of MTBE, in which MTBE disrupts the normal suppressive effect of estrogen on liver tumor induction (22). This interpretation implies that MTBE is a tumor promoter rather than a tumor initiator and that tumor induction is likely to occur at some threshold level, which would have important implications for how the cancer risk is estimated quantitatively. Rather than assuming a linear concentration-response relationship that extrapo lates to zero, the potency estimate would be lower if effects were only observable at much higher concentrations. Although subsequent work (23, 24) has not fully supported the tumor-promoter hypothesis, neither has it ruled out a thresholdacting mechanism. In the matter of male rat kidney tumors, considerable research has gone into elucidating the mechanism underlying such tumors and understanding their implications for human cancer risk (25). A protein, alpha-2u-globulin (

Health Risk Issues for Methyl tert

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