August, 1995

Executive Summary

ORS has reviewed the most current data on the toxicology of methyl tertiary butyl ether (MTBE) and has concluded that a decrease by a factor of ten is appropriate and protective of public health for MTBE in drinking water. The factor of 10 results in an ORS guideline of 0.07 mg/l (70 ppb) compared to the previous guideline of 0.7 mg/l (700 ppb).

The reevaluation of the toxicology data was done by ORS because the results of several cancer bioassays recently became available (Burleigh-Flayer et al. 1992; Chun et al. 1992; Belpoggi et al. 1995). These data were also reviewed by the United States Environmental Protection Agency (USEPA 1995) the States of New Jersey (NJDEP 1994) and North Carolina (NCDEHNR 1994). The USEPA has tentatively classified MTBE as a Group C (possible human) carcinogen based on the results of the cancer bioassays mentioned above and ORS agrees with this classification.

Summary of the Toxicology Data

Non-cancer

The study by Robinson (1990) is the only available study of MTBE in drinking water and therefore it is the most appropriate to uses as a basis for the derivation of a drinking water guideline. In this study mice were exposed to MTBE in their drinking water for 90 days. The critical effect was increased relative kidney weights in female and male mice which occurred in a dose-dependent manner. A No Observed Adverse Effect Level (NOAEL) of 100 mg/kg/d was identified from the study and used as the basis for the calculation of a drinking water guideline. The following safety factors were used by both ORS and USEPA:

10 for subchronic to chronic extrapolation
10 for intraspecies extrapolation
10 for interspecies extrapolation
10 added for a group C carcinogen

Cancer

Reviews of three cancer bioassays done by USEPA, and the States of North Carolina and New Jersey were used by ORS as a basis for the cancer classification of MTBE as a group C carcinogen. Statistically significant increases in tumor incidence were observed in two inhalation studies: Burleigh-Flayer et al. 1992 noted increased adenomas in female mice and increased carcinomas in male mice; Chun et al. 1992 reported a significant increase in interstitial cell testicular tumors and kidney tumors in mid and high dose male rats. In an oral study, Belpoggi et al. 1995 reported an increase in Leydig cell and testicular tumors in male rats and statistically significant increases in lymphomas and leukemias in female rats.

Comparison of the ORS Guideline and the USEPA's Draft Lifetime Health Advisory

The USEPA has derived a draft lifetime health advisory range for MTBE in drinking water of 20-200 ug/l (USEPA 1993). The reason for the range is the current uncertainty regarding the cancer classification. If a final decision is made to classify MTBE as a group C carcinogen then the drinking water guideline would be 20 ug/l. If the classification is a group D, then the value would be 200 ug/l. The USEPA also added a modifying factor of 3 to the calculation to account for a lack of developmental, reproductive and teratogenic studies in drinking water. However, there have been several of these types of studies through the inhalation route (Biles et al. 1987; Conaway et al. 1965; Tyi 1984; Neeper-Bradley 1991). There is little indication' that MTBE is a developmental, reproductive or embryonic toxin. When ORS developed the guideline of 0.07 mg/l, it was felt that the existing reproductive, developmental and mutagenicity studies, even though they were administered via the inhalation route, we evidence enough not to warrant an additional uncertainty factor of 3. But there is a more compelling reason not to use an added modifying factor of 3.

The total uncertainty factor used by ORS, including the one for C carcinogens, is 10,000. An added a factor of 3 brings the total uncertainty factor to 30,000 which is not consistent with EPA's policy of applying uncertainty factors (Dourson, per. comm.) and which ORS believes in overly conservative. Therefore, ORS does not agree with applying the added uncertainty factor of 3 used by EPA.

Mathematical Derivation of the Guideline

100 mg/kg/d x 70 kg x (20%) = 0.07 mg/l =70ppb 2 I/d x 10,000

The uncertainty factor of 10,000 is based on:

UF:
10 = Extrapolation from a Subchronic to Chronic study
10 = Extrapolation from an Animal study to a Human study
10 = Protection of Sensitive humans
10 = Potential carcinogenicity

20% is for Relative Source Contribution

Conclusions 

1. The Robinson study is the only drinking water study available and therefore the most appropriate upon which to base a drinking water guideline.

2. An uncertainty factor of 10,000 is the highest that should be applied to the Robinson study.

3. A guideline of 0.07 mg/l (70 ppb) for MTBE in drinking water is protective of public health.

References

Belpoggi, P., M. Soffritti and C. Maltoni. 1995. Methyl-Tertiary-Butyl Ether (MTBE) - A Gasoline Additive - Causes Testicular and Lymphohematopoietic Cancers in Rats, Toxicol. Ind. Health.

Biles, R.W., R.E. Schroeder and C. E. Holdworth. 1987. Methyl Tertiary Butyl Ether Inhalation in Rats: A Single Generation Reproduction Study. Toxicol. Ind. Health. 3(4) : 519-538.

Burleigh-Flayer. H.D., J.S. Chun and W.J. Kintigh. 1992. Methyl tertiary butyl ether: Vapor oncogenicity study in Fisher 344 rats. Export, PA: Union Carbide, Bushy Run Research Center; BRRC Report 91N0013A.

Chun, J.S., H.D. Burleigh-Flayer and W.J. Kintigh. 1992. Methyl tertiary butyl ether: Vapor inhalation oncogenicity study in Fisher 344 rats. Export, PA: Union Carbide, Bushy Run Research Center; BRRC Report 91N0013B.

Conaway, C.C., R.E. Schroeder and N.K. Snyder. 1985. Teratology evaluation of methyl tertiary butyl ether in rats and mice. J. Tox. Env. Health. 16: 797-809.

Neeper-Bradley, T.L. 1991. Two generation reproductive study of inhaled methyl t-butyl ether in CD Sprague-Dawley rats. Bushy Run Research Center (unpublished report). Cited in USEPA 1992.

Tyi. R. 1989. Developmental toxicity study of inhaled methyl tertiary butyl ether in New Zealand White rabbits. Bushy Run Research Center. Report No. 51-628. May 12, 1989.

USEPA. 1993. Drinking Water Health Advisory. Methyl-t-Butyl Ether. Health and Ecological Criteria Division. Office of Science and Technology. Office of Water. Washington, D.C.