The Health Effects Institute
"A Partnership of the U.S. Environmental Protection Agency and
Industry"
http://www.healtheffects.org/Pubs/st102.htm
STATEMENT
Synopsis of Research Report 102
Metabolism of Ether Oxygenates Added to Gasoline
Full report: 4.2 Mb http://www.healtheffects.org/Pubs/Oxygenates.pdf
This Statement, prepared by the Health Effects Institute, summarizes
three research projects funded by HEI from 1996 to 1999 and con-ducted
by Dr Jun-Yan Hong at University of Medicine and Dentistry of New
Jersey – Robert Wood Johnson Medical School, Dr Wolfgang Dekant at the
University of Würzburg, and Dr Janet Benson at the Lovelace
Respiratory Research Institute. The Research Report, Metabolism of
Ether Oxygenates Added to Gasoline, contains the three detailed
Investigators’ Reports, a Preface, and a Commentary on the studies
prepared by the Institute’s Health Review Committee. It can be
requested from HEI. OXYGENATES 102
INTRODUCTION
The Clean Air Act Amendments of 1990 required use of oxygenated fuels
in areas that exceeded the National Ambient Air Quality Standards for
carbon monoxide and in areas with very high ozone levels. Adding
oxygenates, such as MTBE (methyl tert-butyl ether), to gasoline
promotes more efficient combustion and reduces emission of carbon
monoxide, ozone-forming hydrocarbons, and some air toxics, by
increasing the oxygen content of the fuel. On the other hand, some
oxygenates may increase emission of toxic compounds such as
formaldehyde or acetaldehyde. Increased use of MTBE in fuel in the
early 1990s led to complaints of unpleasant odor, headaches, and
burning of eyes and throat. After reviewing the literature, HEI issued
a request for applications to fund research on the comparative
metabolism of ether oxygenates, such as MTBE, ETBE (ethyl tert-butyl
ether), and TAME (tert-amyl methyl ether). The three studies funded
are presented in this Research Report.
APPROACH
The studies reported here were initiated to increase our knowledge of
the metabolism of ether oxygenates in humans and other species. Dr
Jun-Yan Hong (the University of Medicine and Dentistry of New Jersey –
Robert Wood Johnson Medical School) used rat and human liver cells to
determine the relative contribution of different members of a family
of liver enzymes (cytochrome P450 [CYP] isozymes) to the metabolism of
MTBE, ETBE and TAME. Blood samples from human volunteers who reported
that they were sensitive to the health effects of MTBE were examined
by Hong and colleagues, in order to determine whether genetic variants
of CYP isozymes were present. Dr Wolfgang Dekant (University of
Würzburg) exposed rats and human volunteers by inhalation to two
concentrations of MTBE, ETBE or TAME in order to provide detailed data
for interspecies comparison. He also exposed human volunteers by
ingestion to MTBE or TAME to compare metabolic pathways after
inhalation and ingestion of these compounds. Dr Janet Benson (Lovelace
Respiratory Research Institute) exposed rats by inhalation to several
concentrations of MTBE alone or to MTBE in combination with gasoline
vapors in order to determine how the presence of gasoline affects the
uptake, kinetics, metabolism and excretion of MTBE.
RESULTS AND INTERPRETATION
These three studies have advanced our under-standing of the metabolism
of gasoline ethers after inhalation. The study by Dr Hong identified
one particular CYP isozyme, CYP2A6, as a major enzyme involved in
metabolism of MTBE, ETBE and TAME at the concentrations studied.
Although the relative importance of this isozyme over others (such as
CYP2E1, which was found to be important in previous studies) remains
undetermined, the results invite research into the involvement of
these and other isozymes in the health effects of ethers. Dr Hong also
found several genetic variants of CYP2A6 in some human volunteers who
reported sensitivity to MTBE. Further research should evaluate a
larger group of sensitive individuals to identify the prevalence of
such isozymes in the general population and to determine whether
expression of these isozymes may contribute to the reported
sensitivity.
The study by Dr Dekant provides a detailed characterization of
metabolites of MTBE, ETBE and TAME. The pathways for metabolism of
MTBE and ETBE were found to be similar, whereas the metabolism of TAME
followed a slightly different pathway with more steps involved and the
formation of more metabolites. For all three ethers the pathways of
metabolism in rats and humans were similar, and the blood levels were
not significantly different although the rate of metabolism was more
rapid in rats. The metabolic pathway after ingestion of MTBE and TAME
in humans was almost identical to the pathway after inhalation. No
first pass effect—in which the liver metabolizes a compound before it
enters into the general circulation—was observed after ingestion, and
rates of metabolism were similar for both exposure routes. These data
can be used, therefore, in extrapolating results across species and
routes of exposure for the human health risk assessment of ether
exposure by inhalation or ingestion.
The study by Dr Benson and coworkers has provided detailed data on the
metabolism and disposition of MTBE and its metabolites in rats after
inhalation of MTBE alone and of MTBE with gasoline vapors. The
investigators showed that MTBE was rapidly taken up into the blood and
distributed evenly over body compartments (such as liver, kidney, and
lungs). The uptake and metabolism were not linear between 4 and 400
ppm, suggesting that saturation may have occurred at the highest dose.
These results indicate that caution is needed in using linear
extrapolation of high doses to low doses for human health risk
assessment of MTBE exposure. Inhalation of MTBE in combination with
gasoline vapor (200 ppm) reduced the total amount of MTBE taken up
into the body and increased the amount of MTBE and metabolites exhaled
in breath, suggesting that the toxic effects of MTBE during refueling
may be lower compared to exposure to MTBE by itself.
In conclusion, the investigators successfully addressed the relative
importance of certain CYP isozymes, the metabolic pathways after ether
inhalation and ingestion, and the effects of coexposure to gasoline
vapors on ether metabolism; some results will require further research
to understand the range of their implications. Some avenues of needed
research include: investigating the prevalence of different CYP
isozymes in the general population, and determining whether the lack
of a specific enzyme correlates with increased susceptibility to the
health effects of oxygenates; further research into the toxicity of
ether metabolites; and further research into the effects of exposure
to mixtures (including gasoline vapors) on metabolism and the health
effects of exposure to individual compounds, such as oxygenates.
Metabolism of Ether Oxygenates Added to Gasoline
Table of Contents
STATEMENT
PREFACE
INVESTIGATORS’ REPORTS
Human Cytochrome P450 Isozymes in Metabolism and Health
Effects of Gasoline Ethers
Hong et al
Biotransformation of MTBE, ETBE, and TAME After Inhalation or
Ingestion in Rats and Humans
Dekant et al
MTBE Inhaled Alone and in Combination with Gasoline Vapor:
Uptake, Distribution, Metabolism, and Excretion in Rats
Benson et al
COMMENTARY
Technical Evaluation of Hong Report
Technical Evaluation of Dekant Report
Technical Evaluation of Benson Report
General Discussion
Health Effects of Ethers and Metabolites
Exposure Concentrations
MTBE Body Burden and Blood Levels
Elimination of MTBE
MTBE Metabolism and Biomarkers
Susceptible Populations
Recommendations
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Gary N. Greenberg, MD MPH Sysop / Moderator Occ-Env-Med-L MailList
gary.greenberg at duke.edu Duke Occupat, Environ, Int & Fam Medicine
OEM-L Maillist Website: http://occhealthnews.net
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