IRIS Public Science Meeting (Oct 2016)

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Meeting Details
Meeting Materials

Meeting Details

Meeting Objective

At IRIS Public Science Meetings, the IRIS Program encourages the scientific community and the public to participate in discussions on IRIS draft assessment materials. The scientific information and perspectives from the meeting would be considered as this assessment progresses.

At this meeting, the IRIS Program invited a public discussion on the following draft assessment material(s):

Ethyl Tertiary Butyl Ether (ETBE): draft assessment for public comment.

Dates

The meeting was held on October 26, 2016.

Meeting Agenda

Final meeting agenda for the October 26, 2016 IRIS Public Science Meeting (2 pp, 298 K)

Meeting Materials

Ethyl Tertiary Butyl Ether (ETBE) Key Science Topics and Materials

Assessment Manager: Keith Salazar

IRIS Toxicological Review of Ethyl Tertiary Butyl Ether (Public Comment Draft) (155 pp, 3 MB)
Supplemental Information on the IRIS Toxicological Review of Ethyl Tertiary Butyl Ether (Public Comment Draft) (162 pp, 2 MB)
Draft peer review charge for reviewers (5 pp, 360 K)
Tables of evidence pertaining to kidney effects in animals exposed to ETBE (18 pp, 1 MB)
Primary literature search references sorted by author (ETBE) (dynamic literature link - generated by HERO)
Provide comments on these materials in the ETBE docket at EPA-HQ-ORD-2009-0229.
Federal Register Notice: Sep 1, 2016 announced the availability of the public comment draft for a 60-day public comment period.

NOTE:

In June 2016, EPA convened a public science meeting to discuss the public comment draft of tert-butanol during which time EPA received written and oral comments on the physiological-based pharmacokinetic (PBPK) model and the interpretation of renal effects pertinent to both the tert-butanol and ethyl tertiary butyl ether (ETBE) IRIS assessments. These comments are being reviewed by EPA and any necessary revisions will be incorporated into both assessments prior to external peer review.

Key Science Topics
1. Liver tumor modes of action Lifetime inhalation exposure to ETBE increased liver adenomas and carcinomas in male F344 rats. Data are available suggesting that ETBE may activate PPAR, PXR, and/or CAR pathways all of which increase cell proliferation, hypertrophy, and clonal expansion of preneoplastic foci in the liver. Determining the relative contribution of each pathway on tumor development is problematic. In addition, there is uncertainty on the relevance of PPAR-induced tumors to human risk assessment (Guyton et al., 2009; Corton et al., 2014). Acetaldehyde, a metabolite of ETBE, is considered by other agencies to be carcinogenic. Aldh2 deficiency enhanced ETBE-induced genotoxicity in hepatocytes and leukocytes from exposed mice; but while suggestive, the available data overall are inadequate to establish acetaldehyde-mediated mutagenicity as a MOA for ETBE-induced liver tumors. EPA found that the database was inadequate to draw any conclusions regarding a liver MOA. The public comment draft of the Toxicological Review for ethyl tertiary butyl ether presents a synthesis of the liver effects in Section 1.2.2 and further evaluation of carcinogenicity is provided in Section 1.3.2. The IRIS program is seeking discussion on PPAR, PXR, CAR, and acetaldehyde as possible modes of action for ETBE-induced liver tumors. *Related References:* Guyton, KZ; Chiu, WA; Bateson, TF; Jinot, J; Scott, CS; Brown, RC; Caldwell, JC. (2009). A reexamination of the PPAR-alpha activation mode of action as a basis for assessing human cancer risks of environmental contaminants [Review]. Environ Health Perspect 117: 1664-1672. http://dx.doi.org/10.1289/ehp.0900758 Corton, JC; Cunningham, ML; Hummer, BT; Lau, C; Meek, B; Peters, JM; Popp, JA; Rhomberg, L; Seed, J; Klaunig, JE. (2014). Mode of action framework analysis for receptor-mediated toxicity: The peroxisome proliferator-activated receptor alpha (PPARα) as a case study [Review]. Crit Rev Toxicol 44: 1-49. http://dx.doi.org/10.3109/10408444.2013.835784
2. The potential for increased susceptibility to toxic effects resulting from a decreased rate of acetaldehyde clearance in the liver Acetaldehyde, a metabolite of ETBE, is considered carcinogenic by other agencies. Acetaldehyde is metabolized by the enzyme ALDH2 and studies in Aldh2 knockout mice have demonstrated increased genotoxicity, centrilobular hypertrophy, and alterations to reproductive tissue compared with wild-type controls following ETBE exposure. Furthermore, one-half of East Asian populations possess a virtually inactive form of ALDH22 which is associated with slow metabolism of acetaldehyde and extended exposure to the compound. Analyses have shown that acetaldehyde produced as a result of ethanol metabolism contribute to human carcinogenesis in the upper aerodigestive tract and esophagus following ethanol exposure. Altogether, these data provide plausibility that reduced ALDH2 activity produces more severe health effects than in organisms with functional ALDH2. The public comment draft of the Toxicological Review for ethyl tertiary butyl ether presents a synthesis of the acetaldehyde-mediated liver effects and genotoxicity in Section 1.2.2 and a summary in Section 1.3.3. The IRIS program is seeking discussion on the increased susceptibility of cancer and noncancer effects due to reduced ALDH2 activity in humans and animal models.*
3. Use of 2-stage carcinogenicity bioassays Lifetime inhalation, but not oral, ETBE exposure has been associated with increased liver adenomas and carcinomas in male F344 rats. Toxicokinetic analysis comparing oral and inhalation exposures from these studies on the basis of metabolized dose of ETBE or tert-butanol (a metabolite of ETBE) indicated that these studies yielded comparable internal concentrations which suggests that the lack of carcinogenic effects via oral exposure is not likely due to a difference in administered dose. Notably, subchronic oral ETBE exposure increased 2-stage mutagen-initiated carcinogenesis in several tissues, including the liver. The 2-stage initiation-promotion bioassays were decisive in extending the weight of evidence descriptor to the oral route. The public comment draft of the Toxicological Review for ethyl tertiary butyl ether presents a summary of the carcinogenic evidence in the liver in Section 1.3.2. The IRIS program is seeking public discussion on the use of 2-stage bioassays for assessing carcinogenicity hazard.

Key Science Topics

1. Liver tumor modes of action

Lifetime inhalation exposure to ETBE increased liver adenomas and carcinomas in male F344 rats. Data are available suggesting that ETBE may activate PPAR, PXR, and/or CAR pathways all of which increase cell proliferation, hypertrophy, and clonal expansion of preneoplastic foci in the liver. Determining the relative contribution of each pathway on tumor development is problematic. In addition, there is uncertainty on the relevance of PPAR-induced tumors to human risk assessment (Guyton et al., 2009; Corton et al., 2014). Acetaldehyde, a metabolite of ETBE, is considered by other agencies to be carcinogenic. Aldh2 deficiency enhanced ETBE-induced genotoxicity in hepatocytes and leukocytes from exposed mice; but while suggestive, the available data overall are inadequate to establish acetaldehyde-mediated mutagenicity as a MOA for ETBE-induced liver tumors. EPA found that the database was inadequate to draw any conclusions regarding a liver MOA.

The public comment draft of the Toxicological Review for ethyl tertiary butyl ether presents a synthesis of the liver effects in Section 1.2.2 and further evaluation of carcinogenicity is provided in Section 1.3.2.

The IRIS program is seeking discussion on PPAR, PXR, CAR, and acetaldehyde as possible modes of action for ETBE-induced liver tumors.

Related References:

Guyton, KZ; Chiu, WA; Bateson, TF; Jinot, J; Scott, CS; Brown, RC; Caldwell, JC. (2009). A reexamination of the PPAR-alpha activation mode of action as a basis for assessing human cancer risks of environmental contaminants [Review]. Environ Health Perspect 117: 1664-1672. http://dx.doi.org/10.1289/ehp.0900758
Corton, JC; Cunningham, ML; Hummer, BT; Lau, C; Meek, B; Peters, JM; Popp, JA; Rhomberg, L; Seed, J; Klaunig, JE. (2014). Mode of action framework analysis for receptor-mediated toxicity: The peroxisome proliferator-activated receptor alpha (PPARα) as a case study [Review]. Crit Rev Toxicol 44: 1-49. http://dx.doi.org/10.3109/10408444.2013.835784

2. The potential for increased susceptibility to toxic effects resulting from a decreased rate of acetaldehyde clearance in the liver

Acetaldehyde, a metabolite of ETBE, is considered carcinogenic by other agencies. Acetaldehyde is metabolized by the enzyme ALDH2 and studies in Aldh2 knockout mice have demonstrated increased genotoxicity, centrilobular hypertrophy, and alterations to reproductive tissue compared with wild-type controls following ETBE exposure. Furthermore, one-half of East Asian populations possess a virtually inactive form of ALDH2*2 which is associated with slow metabolism of acetaldehyde and extended exposure to the compound. Analyses have shown that acetaldehyde produced as a result of ethanol metabolism contribute to human carcinogenesis in the upper aerodigestive tract and esophagus following ethanol exposure. Altogether, these data provide plausibility that reduced ALDH2 activity produces more severe health effects than in organisms with functional ALDH2.

The public comment draft of the Toxicological Review for ethyl tertiary butyl ether presents a synthesis of the acetaldehyde-mediated liver effects and genotoxicity in Section 1.2.2 and a summary in Section 1.3.3.

The IRIS program is seeking discussion on the increased susceptibility of cancer and noncancer effects due to reduced ALDH2 activity in humans and animal models.

3. Use of 2-stage carcinogenicity bioassays

Lifetime inhalation, but not oral, ETBE exposure has been associated with increased liver adenomas and carcinomas in male F344 rats. Toxicokinetic analysis comparing oral and inhalation exposures from these studies on the basis of metabolized dose of ETBE or tert-butanol (a metabolite of ETBE) indicated that these studies yielded comparable internal concentrations which suggests that the lack of carcinogenic effects via oral exposure is not likely due to a difference in administered dose. Notably, subchronic oral ETBE exposure increased 2-stage mutagen-initiated carcinogenesis in several tissues, including the liver. The 2-stage initiation-promotion bioassays were decisive in extending the weight of evidence descriptor to the oral route.

The public comment draft of the Toxicological Review for ethyl tertiary butyl ether presents a summary of the carcinogenic evidence in the liver in Section 1.3.2.

The IRIS program is seeking public discussion on the use of 2-stage bioassays for assessing carcinogenicity hazard.