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Outline of Report

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Outline of Report

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  1. An Evaluation of the Scientific Peer-Reviewed Research and Literature on the Human Health Effects of MTBE, its Metabolites, Combustion Products and Substitute CompoundsJohn R. Froines, Ph.D. Principal InvestigatorMichael Collins, Ph.D. Elinor Fanning, Ph.D. Rob McConnell, M.D. Wendie Robbins, Ph.D. Ken Silver, M.S.Heather Kun Rajan Mutialu Russell Okoji, MSPH Robert Taber, M.D., MPH Naureen Tareen, MPH Catherine Zandonella

  2. Outline of Report MTBE • Taste and Odor • Toxicokinetics • Acute Effects and Asthma • Neurotoxicity • Developmental and Reproductive Toxicity • Genotoxicity • Carcinogenicity Substitutes • Ethanol • Acetaldehyde • PAN • Ethers ew fanning

  3. Taste and Odor of MTBE • Range of thresholds for taste: 2 ppb to 190 ppb • Range of thresholds for odor: 1.4 ppb to 680 ppb • Conclusion: Detection in the low ppb range by sensitive individuals will impact aesthetics of drinking water ew fanning

  4. Acute Effects of MTBE • Studies of workers and general population Headache, dizziness, nausea, respiratory irritation, have been observed. Study limitations and confounding make interpretation difficult. • Positive findings: • Results of one chamber study (out of four reviewed) found statistically significant increase in “heavy headedness” (Riihimaki et al, 1997) • One occupational study found that 20% of tanker drivers compared to 1% of milk drivers experienced acute effects (dizziness, dyspnea, nausea, salivation) (Hakkola et al, 1997) • Therapeutic use of MTBE associated with affects in some patients • Formaldehyde and TBA are irritants • Conclusion: Reports of acute effects cannot be dismissed ew fanning

  5. MTBE and Asthma • No epidemiological studies • Insurance claim study did not detect an increase in asthma reporting in first year of MTBE use • MTBE combustion produces formaldehyde and TBA, both of which have irritant effects. • Studies of FA and asthma yield mixed results • Conclusion: There is a need for epidemiological studies to assess what effect, if any, MTBE has on population asthma rates ew fanning

  6. Developmental Toxicity of MTBE • 4 studies (2 in mice, 1 in rat, 1 in rabbit) • Mice are most sensitive species • No significant effects in rat or rabbit studies • Skeletal defects and cleft palate, dose-related • Some defects occur below significant maternal toxicity • Conclusion: MTBE has limited potential to act as a developmental toxicant ew fanning

  7. Reproductive Toxicity of MTBE • 2 Studies (SD rats, inhalation) • Two generation • One generation, two matings • Findings: • Decreased pup weights at day 21 in both studies • Maternal toxicity • Conclusion: MTBE has low potential to act as a reproductive toxicant, except at maternally toxic doses ew fanning

  8. Metabolism of MTBE • After exposure to MTBE, humans and rodents excrete the following compounds to the urine: • Alpha-hydroxyisobutyric acid (HBA, major urinary metabolite) • 2-methyl-1,2-propanediol (MPD) • Glucuronide and sulfate conjugates of TBA • Pathways by which the major metabolites are formed are unknown, and therefore potentially toxic intermediates have not been identified • Toxicology of HBA and MPD, and potential intermediate forms is not known • Which metabolite or metabolites are involved in carcinogenicity of MTBE is not known ew fanning

  9. Genotoxicity of MTBE • Positive tests • Forward mutation in mouse lymphoma cells (2) • Comet assay in fresh lymphocytes (abstract only) • Negative tests: • Salmonella strains (3 reports) • Mouse micronucleus assay (3 reports, ) • Chromosomal aberrations (4 reports) • Recessive lethal in Drosophila (2 reports) • Hprt mutation in spleen lymphocytes • Conclusions: • MTBE displays little genotoxic activity in testing done to date • Tests for clastogenicity in target tissuesare needed ew fanning

  10. Carcinogenicity of MTBE • No human data available • Excess cancer found in 3 animal studies: Sprague Dawley rats (oral exposure) • females leukemia/lymphoma • males leydig cell adenoma Fischer rats (inhalation exposure) • females no significant increase • males renal tubular adenoma and carcinoma leydig cell adenoma CD-1 mice (inhalation exposure) • females hepatocellular adenoma • males hepatocellular carcinoma ew fanning

  11. Exposure: oral gavage 4d/wk, 104 wks References: Belpoggi et al., 1995; 1997; 1998 * statistically significant relative to controls, by either FET or Mantel-Cox test Oral Study in Sprague-Dawley Rats ew fanning

  12. Inhalation Study in Fischer Rats • Exposure 6hr/d, 5d/wk, 104 wk • High dose males terminated at 82 weeks • Mid-dose males terminated at 96 weeks • Bird et al, 1997 • Mortality corrected data from USEPA, 1995 *statistically significant by FET (P<0.05) ew fanning

  13. Inhalation Study in CD-1 Mice • Exposure 6hr/d, 5d/wk, 68 wk • Bird et al, 1997 *statistically significant by FET (P<0.05) ew fanning

  14. Conclusions on Carcinogenicity • MTBE is an animal carcinogen • Concordance of one tumor site (LCT in testes) • Supporting evidence: • TBA caused renal tubular tumors in rats • FA is an IARC 2A carcinogen • Mechanisms suggested to date are not adequately supported by available data • In the absence of data clearly showing otherwise, all four tumor endpoints must be considered potentially relevant to humans. ew fanning

  15. Other Reviews of MTBE carcinogenicity • Proposition 65 Carcinogen Identification Committee Apparent 3 to 3 tie (resulted in not listing) Discussion based on whether MTBE had been clearly shown to cause cancer • National Toxicology Program Report on Carcinogens Report on Carcinogens Voted 6 to 5 not to list • International Agency for Research on Cancer Classified in group 3, “not classifiable” (Inadequate evidence in humans; limited evidence in animals) ew fanning

  16. Other Reviews of MTBE carcinogenicity • National Science and Technology Council “Experimental studies indicate that MTBE is carcinogenic in rats and mice at multiple organ sites after inhalation or oral-gavage exposure. There is sufficient evidence to indicate that MTBE is an animal carcinogen and to regard MTBE as having a human cancer potential.” • Health Effects Institute (HEI) “Tumors have been observed at multiple sites in rats and mice after exposure to high levels of MTBE. The Oxygenates Evaluation Committee consider these findings to be cause for concern. The Committee noted that the mechanisms that caused these tumors and the likelihood that these or other tumors will occur in humans exposed at substantially lower levels are both unknown.” ew fanning

  17. Other Reviews of MTBE carcinogenicity • Office of Environmental Health Hazard Assessment “There is evidence for the carcinogenicity of MTBE at multiple sites in both sexes of the rat and mouse, MTBE is a multi-species, multi-strain, multi-sex, and multi-route carcinogen. Positive animal carcinogenicity data for HCHO and TBA, metabolites of MTBE, provide support for this conclusion.” ew fanning

  18. Ethanol • Acetaldehyde • IARC 2B, TAC, irritant, clastogen, anueploidogen • Peroxyacetylnitrate (PAN) • Respiratory and ocular irritation • Synergy with respiratory infection (mice) • Mutagenicity weak, but positive • Potential carcinogen • Conclusions • Oxygenation with EtOH should not be taken lightly • Critical Research Needs: • Carcinogenicity bioassay of PAN • Respiratory effects of acetaldehyde and PAN • Synergy in respiratory effects with other TACs ew fanning

  19. Conclusions (short list) • Given widespread exposure to MTBE, the data should be treated conservatively. • MTBE is an animal carcinogen and could potentially cause cancer in humans. • Further research is needed on tissue-specific metabolism and genotoxicity of MTBE. • Further research is needed on the respiratory effects, including asthma, of MTBE, combustion by-products, acetaldehyde and PAN. • While ethanol may be relatively safe, combustion by-products of ethanol have been associated with respiratory effects. PAN needs to be tested for carcinogenicity. ew fanning

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