EPA/600/R-96/069
                                  May 1996
OXYFUELS INFORMATION NEEDS
         U.S. Environmental Protection Agency
           Research Triangle Park, NC 27711
                     and
               Washington, DC 20460

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                                    DISCLAIMER

     This document has been reviewed in accordance with U.S. Environmental Protection
Agency policy and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.

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                               ACKNOWLEDGMENTS

     This document was prepared by the National Center for Environmental Assessment
(NCEA)-RTP (MD-52) at Research Triangle Park, NC, with the collective guidance and
participation of the EPA Oxyfuels Workgroup and other contributors (listed below). The skillful
assistance of Douglas Fennell of NCEA, Susan McDonald of Information Organizers, and
Marianne Barrier, John Barton, Shelia Elliott, Sandy Eltz, Sheila Lassiter, and Carolyn Perry of
ManTech Environmental Technology, Inc., is gratefully acknowledged.
                                          m

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                   OXYFUELS WORKGROUP AND CONTRIBUTORS
Gerald Akland
National Exposure Research Laboratory
Office of Research and Development

Charles Auer1
Chemical Control Division
Office of Prevention, Pesticides, and Toxic
 Substances

Frank Black
National Exposure Research Laboratory
Office of Research and Development

James Caldwell
Office of Mobile Sources
Office of Air and Radiation

Ila Cote
National Health Effects and Environmental
 Research Laboratory
Office of Research and Development

J. Michael Davis1
National Center for Environmental
 Assessment-RTF
Office of Research and Development

Susmita Dubey
Air and Radiation Division
Office of General Counsel

Stanley Durkee
Office of Research and Science Integration
Office of Research and Development

Joe Elder
National Health Effects and Environmental
 Research Laboratory
Office of Research and Development
William Farland2
National Center for Environmental
 Assessment
Office of Research and Development

Charles Freed1
Office of Mobile Sources
Office of Air and Radiation

Lynn Goldman2
Office of Prevention, Pesticides, and Toxic
Substances

Lester Grant2
National Center for Environmental
 Assessment-RTF
Office of Research and Development

Judy Gray
Office of Mobile Sources
Office of Air and Radiation

Kent Helmer
Office of Mobile Sources
Office of Air and Radiation

Alan Huber
National Exposure Research Laboratory
Office of Research and Development

Margo Oge2
Office of Mobile Sources
Office of Air and Radiation

Courtney Riordan
National Center for Environmental
 Assessment
Office of Research and Development
                                          IV

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               OXYFUELS WORKGROUP AND CONTRIBUTORS (cont'd)

Charles Ris                                    Gary Timm
National Center for Environmental               Chemical Control Division
 Assessment                                  Office of Prevention, Pesticides, and Toxic
Office of Research and Development              Substances

Mary Smith3                                   Evelyn Washington
Office of Mobile Sources                       Office of Ground Water and Drinking Water
Office of Air and Radiation                      Office of Water
 'Oxyfuels Workgroup Co-chair
 2Ex-officio
 3Former Workgroup Co-chair; now with Office of Radiation and Indoor Air

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                OXYFUELS INFORMATION NEEDS

       The purpose of this document is to highlight the types of information needed to improve
scientific understanding of the environmental risks and benefits of oxygenated gasoline and
reformulated gasoline (collectively designated as "oxyfuels") in relation to conventional fuels.
The intention is that this broad description of needs will provide a foundation for further efforts to
establish priorities among different areas of work and to define specific studies in greater detail,
rather than attempting here to rank issues or needs in terms of their relative importance.
       This document is organized to provide first some background information on oxyfuels,
along with a general framework for comparative risk assessments of fuels. Next comes a very
brief summary of what has already been done in the way of scientific testing, research, and
assessments on oxyfuels and conventional fuels, and what work is currently underway or planned
to address such information needs. The final section of this document discusses further
information needs.
BACKGROUND
       Throughout much of the twentieth century, the general population has been routinely
exposed to conventional gasoline and its evaporative and combustion emissions.  The
environmental impacts of these emissions have been a principal focus of the Clean Air Act and
various efforts to improve air quality. The 1990 amendments to the Clean Air Act required two
separate programs to address air quality problems in areas that had failed to attain the national
ambient air quality standards (NAAQSs) for carbon monoxide and for ozone. Starting in
November 1992, oxygenated gasoline has been required during cold-weather months in several
CO-nonattainment areas. Reformulated gasoline has been required year-round in the worst
ozone-nonattainment areas since January  1995, with some additional areas voluntarily electing to
adopt the reformulated gasoline program.  Largely because of these programs, millions of people
in the United States are now exposed to oxyfuel emissions. Although exposure to conventional
gasoline has long been commonplace, the introduction of oxyfuels has raised new questions about
the benefits and risks of chemicals that are used on such a widespread scale.
       Oxygenated gasoline contains 2.7% oxygen (by weight), typically achieved by the addition
of 15% methyl tertiary butyl ether (MTBE) or 7.5% ethanol (by volume). Reformulated gasoline
(RFG)  has lower concentrations of certain volatile organic compounds in a formulation intended
to reduce ozone-forming hydrocarbons and air toxics (i.e., benzene, butadiene, formaldehyde,
acetaldehyde, POM) by 15 to 17% in Phase 1 and even further in Phase 2, which  begins January
2000. In addition, RFG has 2.0% oxygen (by weight), typically achieved by the addition of 11%
MTBE or 5% ethanol (by volume).  (MTBE has been used to enhance the octane rating of
conventional gasolines in the United States since the 1970s, with the MTBE concentration usually
between 2 and 9% by volume, but such fuels, to which MTBE is added for octane rather than
oxygenate purposes, are not encompassed by the present usage of the term oxyfuels, which can
also be defined as having >2.0% oxygen by weight.)
       Although other oxygenates, including (but not limited to) ethanol  and ethyl tertiary butyl
ether (ETBE), may be used in gasoline, MTBE is the most widely used oxygenate at present.
Very little or no information exists on the health effects of oxygenates other than MTBE and
ethanol (and that for ethanol pertains to ingestion, not inhalation). Therefore, much of the

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discussion here is dominated by the information that is available on MTBE. Notwithstanding this
focus on MTBE, a meaningful assessment of the environmental risks and benefits of oxyfuels
must be comparative; that is, it must consider any given oxyfuel in relation to the environmental
risks and benefits of conventional fuels. Simply stated, the question is whether public health and
the environment are or are not better off with the substitution of oxyfuels for conventional fuels.
       A general framework for the comparative assessment of the environmental (health and
ecosystem) risks and benefits of fuels may be found in Figure 1. The figure depicts the broad
areas of research needed to support comparative risk assessments of fuels and fuel additives:
emissions characterization, environmental fate, exposure, human health effects, ecosystem effects,
global climate change, and risk reduction. The figure also serves to illustrate the major
environmental pathways of impacts associated with motor fuel production, distribution,

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                    Emissions Characterization:
                Feedstocks, Fuel Production, Distribution, Use
                    Environmental Fate:
                        Air/Water Quality
                                                  Global Climate !
                                                       Effects     •
                         Exposures:
                          Human/Biota
         Health Effects
Ecosystem Effects
                        1	L
                   Scientific Assessment
                       Risk Reduction
Figure 1.    Areas of research needed for comparative risk assessments of fuels and fuel
           additives.
Source: U.S. Environmental Protection Agency (1992).

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storage, and use. As reflected in the figure, research in any one area is related to one or more
other areas of work. For example, health risk characterization requires not only information on
health effects but also on human exposures, which in turn requires air and soil/water quality data.
Each of the boxes in Figure 1 could be progressively expanded to indicate various subdisciplinary
areas of research and individual projects within those respective areas. For example, an
understanding of air quality impacts involves information on atmospheric emissions, transport,
and transformation, with each of these areas potentially encompassing several projects. Given this
general framework for comparing the relative benefits and risks of different fuels, this document
highlights certain priority areas of needed work specific to oxyfuels.
PAST WORK
       As suggested by Table 1, a great deal of work has been devoted to the environmental
effects of conventional (pre-1990) gasoline, including the characterization of mobile source
emissions, albeit more so for selected constituents of the combustion emissions of conventional
gasoline than for the whole combustion emissions or for evaporative emissions.  Similarly, the
health effects associated with conventional fuels have been extensively investigated and assessed
[e.g., see recent symposia papers in Environmental Health Perspectives Supplements, 101 (suppl.
6), 1993, and 102 (suppl. 4), 1994].  To a lesser extent, concentration data collected in
microenvironmental studies of conventional fuel emissions are available for estimating exposures.
However, with the exception of carbon monoxide, population exposures to mobile source
emissions have not been measured.  In this and other respects, Table 1  provides only a rough
indication of the information available under the various categories listed;  however, it provides no
guidance as to the extent or adequacy of the information.
       Despite the many studies related to conventional fuels, much remains to be learned.  For
example, in contrast to the extensive databases on the health effects of some of the constituents of
gasoline (e.g., benzene) and of wholly vaporized gasoline (which contains different proportions of
constituent compounds than the evaporative emissions one normally encounters) and combustion
emissions or by-products (e.g., carbon monoxide, nitrogen oxides, ozone),

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Table 1. Categories of Health Effects and Exposure Data Available for Motor Vehicle Fuel Additives and Fuel Products1

Neat Additive:
MTBE
vapor
liquid
EtOH
vapor
liquid
ETBE
vapor
liquid
TAME
vapor
liquid
TEA
vapor
liquid
TAEE, DIPE, etc.23
Fuel Product:
Pre-1990 gasoline:
vapor"
combust.
Post- 1990 gasoline:
evap.
combust.
Animal
Pharmaco-
kinetics


++
+

+
+++

0
0

0
0

0
0
0


++
++

0
0
Muta-
genicity


++
0

0
+++

++
+

+
+

0
+
0


++
+++

0
0
Sub-
chronic
Toxicity


++
+

+
+++

+
+

+
+

+
+
0


++
++

0
0
Chronic
Non-
cancer


++
+

0
+++

0
0

0
0

0
+
0


++
++

0
0
Reproduc-
tive
Toxicity


++
+

0
+++

0
0

0
0

0
0
0


+
+

0
0
Develop-
mental
Toxicity


++
+

0
+++

0
0

0
0

0
0
0


+
+

0
0
Neuro-
toxicity


++
+

+
+++

+
0

0
0

0
0
0


++
+

0
0
Onco-
genicity


++
+

0
+++

0
0

0
0

0
++
0


++
++

0
0
Human
Acute
Toxicity


++
+

+
+++

0
0

0
0

0
0
0


++
+++

0
0
Chronic
Non-
cancer


0
0

0
+++

0
0

0
0

0
0
0


++
++

0
0
Cancer


0
0

0
+++

0
0

0
0

0
0
0


++
++

0
0
Pharmaco-
kinetics


++
+

0
+++

0
0

0
0

0
0
0


+
+

0
0
Exposure
Emissions


+++
++

+++
+++

+
+

+
+

+
+
0


+++
+++

++
++
Transport
and
Fate


++
++

++
++

+
+

0
0

0
0
0


++
++

+
+
Moni-
toring


+
+

0
0

0
0

0
0

0
0
0


++
++

+
+

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Table 1 (cont'd). Categories of Health Effects and Exposure Data Available for Motor Vehicle Fuel Additives and Fuel Products1

Post- 1990
gasoline plus:
MTBE
evap.
combust.
EtOH5
ETBE5
TAME5
TEA5
TAEE, DIPE,
etc.3-5
Animal
Pharmaco-
kinetics


0
0
0
0
0
0
0
Muta-
genicity


0
0
0
0
0
0
0
Sub-
chronic
Toxicity


0
0
0
0
0
0
0
Chronic
Non-
cancer


0
0
0
0
0
0
0
Reproduc-
tive
Toxicity


0
0
0
0
0
0
0
Develop-
mental
Toxicity


0
0
0
0
0
0
0
Neuro-
toxicity


0
0
0
0
0
0
0
Onco-
genicity


0
0
0
0
0
0
0
Human
Acute
Toxicity


++
+
0
0
0
0
0
Chronic
Non-
cancer


0
0
0
0
0
0
0
Cancer


0
0
0
0
0
0
0
Pharmaco-
kinetics


0
0
0
0
0
0
0
Exposure
Emissions


++
++
++
++
0
0
0
Transport
and
Fate


+
+
+
0
0
0
0
Moni-
toring


+
+
+
0
+
0
0
'+++ = extensive data; ++ = moderate; + = some; 0 = none.
Includes both vapor and liquid.
'Several other fuels and fuel additives (e.g., various ethers and esters) could be added to this list of fuels and fuel additives; however, any attempt to list all such products would be almost certainly
incomplete, and at this time there is little distinction among them in terms of the information available or needed.
"Experimental animal studies have generally used wholly vaporized gasoline, whereas typical vapors to which humans are exposed are likely to have fewer of the heavy molecular weight VOCs
contained in liquid gasoline.
Includes both evaporative and combustion emissions.
N.B.: These characterizations of the data available for the specified endpoints are not intended to denote the quality or adequacy of the
database for risk assessment purposes. Moreover, the headings may be collapsed across quite disparate types or levels of information
(e.g., "Transport and Fate" and "Monitoring" do not differentiate between air, water,  and soil).

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information on the effects of gasoline evaporative and whole combustion emissions (with or
without atmospheric transformation) is limited. Moreover, most of the older data available on
unleaded gasolines are based on formulations that are not necessarily representative of current
(post-1990) formulations of gasolines.
       With respect to oxyfuel emissions characterization, the Auto/Oil Air Quality Improvement
Research Program (e.g., 1990, 1991a,b,c; Carter et al., 1991; Kiskis et al., 1989) has provided a
considerable body of data on emissions from various formulations of gasoline, including MTBE-
oxygenated gasoline. A limited amount of work on MTBE exposure levels in relation to oxyfuel
use has been conducted thus far (Clayton Environmental Consultants, 1993; Hartle, 1993;
Johnson,  1993; Lioy et al., 1994; Anderson et al., 1995). For example, using limited
measurement data (rounding up to the nearest half order of magnitude) along with data on typical
activity patterns, Huber (1993) estimated inhalation exposure levels for various scenarios such as
refueling, commuting, and private or public garages and dwellings.  Although the air
concentrations experienced during refueling (as high as 36 mg/m3 for a reasonable worst case)
were estimated to be highest of all the scenarios considered, the cumulative exposure levels
associated with refueling (94 mg/m3 x h) did not rank as high as some other scenarios because less
time is spent refueling than in other activities. Annual exposure estimates were 187 mg/m3 x h for
commuting (assuming 10 h/week commuting) and 75 to 150 mg/m3 x h for personal residence
with attached garage (assuming 98 h/week at home and different MTBE concentrations emitted
from a vehicle in the garage).  Assuming 20 h/week in outdoor activities and an ambient MTBE
concentration ranging from 0.036 to 0.36 mg/m3, cumulative annual exposure levels outdoors
might range from 37 to 370 mg/m3 x h. This example illustrates the importance of having
microenvironmental concentration data in developing exposure estimates for health study "range
finding" purposes.
       Adjusting the above estimates for the differing concentrations of MTBE in oxygenated
and reformulated gasolines for different periods of time during the year, EPA estimated high
(reasonable worst case) annual inhalation exposures to be on the order of 0.11 mg/m3 (U. S.
Environmental Protection Agency, 1994). More recent exposure estimates (Health Effects
Institute,  1996; Interagency Oxygenated Fuels Assessment Steering  Committee, 1996) are not
inconsistent with such an estimate. However, insufficient data exist to state definitively what a
"true upper bound" exposure may be or even what an "average" exposure may be for the general

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population. Also, these estimates do not address the possibility of exposure via other routes, e.g.,
through drinking water.
       Studies on MTBE health effects date back to the early 1980's, including some animal
toxicity studies (e.g., Greenough et al., 1980) and several reports of the clinical use of MTBE to
dissolve gallstones in human patients (e.g., Allen et al., 1985).  However, most of the information
on MTBE health effects has come from a program of testing conducted under a 1987 negotiated
enforceable consent agreement between EPA and the Oxygenated Fuels Association (OFA),
which provided several studies on the inhalation toxicity of MTBE in laboratory  animals (Table
1).  In one of these studies, rats were exposed to approximately 1,450, 10,900, or 28,700 mg/m3
(Chun et al., 1992). Based on findings of increased kidney and liver weights, increased severity of
spontaneous renal lesions, prostration, and swollen periocular tissue at 10,900 mg/m3, an
inhalation reference concentration (RfC) of 3 mg/m3 was  derived for MTBE (IRIS, 1993).  The
reference concentration 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.
       The database on MTBE toxicity also includes reproductive and developmental effects.
A two-generation rat study (Neeper-Bradley, 1991) showed reduced offspring growth at 10,900
mg/m3 but not at  1,450 mg/m3MTBE. Based on this finding, a conservative preliminary estimate
of a level at which no adverse developmental toxicity is likely to occur in humans (including
sensitive subpopulations) was judged to be 48 mg/m3 (U.S. Environmental Protection Agency,
1994).
       Two cancer studies of laboratory rodents exposed by inhalation to pure MTBE and eleven
mutagenesis studies were also conducted pursuant to the  1987 consent agreement.  Based on
these studies, EPA's Office of Research and Development (ORD) considered the weight of
evidence for MTBE carcinogenicity to fall in Group C (possible human carcinogen based on
limited evidence  from animal studies), but a more recent report of a study of cancer effects in rats
exposed to MTBE by gavage (Belpoggi et al., 1995) would tend to support a B2 classification
under the 1986 guidelines (Federal Register, 1986). However, no formal assessment of the
carcinogenicity of MTBE has been performed by EPA at this time. Further discussion of this

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issue may be found in the "Interagency Assessment of Potential Health Risks Associated with
Oxygenated Gasoline" (Interagency Oxygenated Fuels Assessment Steering Committee, 1996).
       Following the introduction of MTBE-oxygenated gasoline in Fairbanks and Anchorage,
Alaska in November 1992, numerous reports of acute health symptoms in connection with the
new fuel were registered by residents in those areas. In response to the concerns expressed by
officials of the State of Alaska, a research program involving government, industry, and academia
was initiated to investigate the acute human health effects of MTBE.  This effort included two
independently conducted inhalation chamber studies (Prah et al., 1994;  Cain et al., 1994) on a
total of 80 human volunteers who breathed neat MTBE concentrations  of 5 to 6 mg/m3 for 1 hour
at a time. Subjects were evaluated for both subjective (self-reported) symptoms and objective
(inflammation, neurobehavioral) effects. No effect of MTBE exposure  could be detected in either
study.  More recently,  a chamber study in Sweden (Johanson et al., 1995) using 2-hour exposures
to MTBE concentrations up to 180 mg/m3 also showed no effects in 10 subjects.
       Field studies of human populations were also conducted in various locations.  A study in
New Jersey (Mohr et al., 1994) evaluated 237 garage workers from two groups: (1) northern
New Jersey workers sampled during the wintertime oxyfuel program  and (2) southern New Jersey
workers sampled 10 weeks after the phase-out date for the program in that area. Essentially no
differences in symptom reports were found between the northern (high-exposure) and southern
(low-exposure) groups. (Subgroups of refuelers differed significantly in pre/postshift symptom
reports between north and south, but not significantly when matched  for age, gender, and
education.) Another study in the New Jersey area (Fiedler et al., 1994) investigated MTBE-
related symptom reports in 14 persons with known multiple chemical sensitivity (MCS), 5 persons
with chronic fatigue syndrome (CFS), and 6 normal controls. Both MCS and CFS subjects
reported more symptoms than controls, but the pattern of their reports "did not provide clear
evidence to support that an unusually high rate of symptoms or an increase of symptoms was
occurring uniquely where MTBE was most prevalent" (i.e., refueling  or driving an automobile).
       Another field study (White et al., 1993) attempted to compare the prevalence of symptom
reports in 221 Stamford, CT, residents (with oxyfuels) and 265 Albany, NY, residents (without
oxyfuels). The area without MTBE-oxyfuel had symptom prevalences  as high as those in the area
with MTBE-oxyfuel (possibly because of the prevalence of illnesses due to allergies and viruses at
the time of the study).  In Stamford, 8 workers with the highest blood MTBE levels were

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significantly more likely to report symptoms (although the relationship between symptom reports
and tertiary butyl alcohol [TEA], a major metabolite of MTBE and indicator of MTBE exposure,
was not significant). A field study in Fairbanks, AK (Moolenaar et al., 1994), found evidence of a
significant correlation between MTBE exposure and MTBE concentrations in the blood, but the
positive relationship between health symptom reports and blood MTBE levels was not statistically
significant.
       Experimental studies of odor thresholds in human subjects indicate that MTBE has very
low detection and recognition thresholds. Moreover, recent experimental work (Smith et al.,
1994) on odor thresholds indicates interactive effects of MTBE and different types of gasoline.
Alaskan gasoline with MTBE added was more readily detected than "lower 48" gasoline with
MTBE.
       In 1995, the State of Wisconsin conducted a random-digit-dial telephone survey of
residents of Milwaukee and two control areas in response to the concerns of Milwaukee citizens
regarding health effects of reformulated gasoline after the initiation of the RFG program in
January 1995.  In addition to  about 500 residents of Milwaukee who were interviewed by
telephone, approximately equal numbers of residents in Chicago and in non-RFG areas of
Wisconsin were surveyed.  Chicago was selected because essentially the same RFG fuels were
used there, but very few health complaints had been registered by Chicagoans. The results  of the
study indicated that symptom prevalence was significantly higher in Milwaukee than in either
Chicago or Wisconsin.  In Milwaukee, persons were more likely to report symptoms if they had
experienced a cold or flu, smoked cigarettes, or were aware that they had purchased RFG.  The
fact that symptom prevalence was essentially equivalent in Chicago and Wisconsin suggested "that
factors, other than RFG use, significantly contributed to the differences in symptom prevalence
between Milwaukee and the other two areas studied" (Anderson et al., 1995). However, because
of its unavoidable design limitations, the study could not "rule out subtle effects of RFG exposure,
or the possibility that a relatively small number of individuals may have a greater sensitivity to
RFG mixtures."
       In Milwaukee, MTBE was the oxygenate in 49% of the RFG samples, ethanol in 38%,
and ETBE in 14%. It was not possible to identify with any  confidence the specific type of these
three oxyfuels to which individual Milwaukee residents were exposed.  This raises the point that
the use of multiple oxygenates in an area greatly complicates exposure analysis. It also

                                           10

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underscores the point that information on exposure and health effects for oxygenates other than
MTBE is quite limited. However, a study in Alaska investigated personal exposures to gasoline
during refueling with either regular unleaded gasoline or gasoline oxygenated with 10% ethanol
(Backer et al., 1995). Blood samples provided before and after refueling, along with ambient air
and personal breathing zone (PBZ) samples, were analyzed for selected volatile organic
compounds (benzene, ethylbenzene, toluene, m-/p-xylene, and o-xylene). The presence or
absence of ethanol in the gasoline made no difference to the concentrations of VOCs in blood or
in PBZ air.
       Although a very large body of literature on the health effects of ingested ethanol is
available, virtually no work has been devoted to the effects of inhaled ethanol at environmentally
relevant concentrations.  Four-week inhalation toxicity studies of ETBE (Ryan et al., 1991; IIT
Research Institute, 1991; Wells, 1993) and tertiary amyl methyl ether (TAME) (White, 1993;)
have provided some evidence of hepatic, renal, and neurobehavioral toxicity, but these  studies in
themselves are not an adequate basis for inhalation health risk assessments of ETBE or TAME.
No inhalation toxicity information is available for tertiary amyl ethyl ether (TAEE) or diisopropyl
ether (DIPE).
       The above discussion applies to inhalation health risks. The effects of exposure via other
routes must also be considered. A recent report of a preliminary assessment by the U. S.
Geological Survey (Squillace et al., 1995) indicates that MTBE was detected in approximately
80% of monitoring wells sampled in the Denver area. The report raises questions about the
persistence of MTBE in groundwater and whether such apparently widespread contamination
could be attributable solely to point source releases (e.g., leaking underground storage tanks).
The potential for human exposure to MTBE in drinking water remains to be determined.
However, even if no human exposure occurs, excessive levels of oxygenates in groundwater could
possibly have adverse effects on ecosystems.
       As indicated in Table 1, information on the health effects of oral exposure to MTBE is
quite limited. To date, it has not been possible to establish an oral reference dose (RfD) for
MTBE, because of the inadequate database.  A study of carcinogenic effects in Sprague-Dawley
rats exposed to MTBE in olive oil by gavage for 2 years showed dose-related increases in
lymphomas and leukemias in females and in interstitial cell tumors of the testes in males (Belpoggi
et al., 1995). No results of chronic cancer bioassays for any of the other oxygenates have been

                                           11

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published to date, except for TEA, which is also a metabolite of both MTBE and ETBE. Cirvello
et al. (1995) administered TEA to rats and mice in their drinking water for two years and found
an increased incidence of rare kidney tumors in male rats and thyroid tumors in female mice. The
study did not determine whether alpha-2//-globulin was present in the male rat kidneys.
Genotoxicity and subchronic toxicity studies in rodents dosed orally with TAME showed no
evidence of mutagenicity or clastogenicity but did show dose-related increases in adrenal and
kidney weights (Daughtrey and Bird, 1995).
       In November 1993, ORD issued an "Assessment of the Potential Health Risks of Gasoline
Oxygenated with MTBE" (U.S. Environmental Protection Agency, 1993).  In assessing the
evidence on acute inhalation health effects available at that time, the ORD assessment concluded:
       "There is unlikely to be a substantial risk of acute health symptoms among healthy
       members of the public receiving 'typical' environmental exposures under temperate
       conditions.... This leaves the question open about more subtle health risks, especially
       among susceptible subpopulations."
Also, in an effort to respond to evident public concerns about the MTBE cancer issue as well as
acute inhalation health effects, ORD prepared "Health Risk Perspectives on Fuel Oxygenates"
(U.S. Environmental Protection Agency, 1994), concluding:
       "With the currently available information, there is no basis to expect that the use of
       MTBE-oxygenated gasoline or MTBE-reformulated gasoline will pose a greater public
       health risk than traditional gasoline.  [However], no conclusions are drawn about major
       fuel formulations using oxygenates other than MTBE because of the lack of health or
       exposure data on them."
The latter report also noted, "To improve understanding of the health trade-offs between different
types of fuels, more research and evaluation is needed," particularly if one wants "to quantitatively
estimate the relationship between use of these fuels and improvements in ozone and CO air
quality" (U.S. Environmental Protection Agency, 1994).
       More recently, a Federal Interagency Oxygenated Fuels Assessment Steering Committee,
under the coordination of the National Science and Technology Council and the Office of Science
and Technology Policy under the Executive Office of the President, concluded: "The available
scientific evidence regarding human exposure to oxygenated gasoline and acute health symptoms
was considered insufficient to develop estimates of exposure-related effects" (Interagency
Oxygenated Fuels Assessment Steering Committee, 1996). As for cancer, "it is not known
                                           12

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whether the cancer risk of oxygenated gasoline containing MTBE is significantly different from
the cancer risk of conventional gasoline," due in part to "a lack of health data on the
nonoxygenated gasoline vapors to which humans are actually exposed."  Moreover, "[t]he data
were generally inadequate to evaluate the health risks of oxygenates other than MTBE, a factor
which makes other oxygenates and gasoline mixtures to which they are added all the more
important to investigate further" (Interagency Oxygenated Fuels Assessment Steering Committee,
1996).
       Similar conclusions were reached by the Oxygenates Evaluation Committee convened by
the Health Effects Institute.  A special report of the Committee stated: "Adding oxygenates is
unlikely to substantially increase the health risks associated with fuel used in motor vehicles:
hence, the potential health risks of oxygenates are not sufficient to warrant an immediate
reduction in oxygenate use at this time.  However, a number of important questions need to be
answered if these substances are to continue in widespread use over the long term" (Health
Effects Institute, 1996).
       The above reports are currently under review by a panel of scientists organized by the
National Academy of Science of the National Research Council, with a report of the panel
expected in mid-1996. It is already quite evident, however, that a consistent theme in all of the
reports is the need for more information on the exposure and health aspects of conventional and
oxygenated fuels.
WORK CURRENTLY UNDERWAY OR PLANNED
       As listed in Table 2, several initiatives are currently planned or underway to obtain
information that may be of value to future health risk assessments of oxyfuels. It should be
understood that the checked categories of work may reflect quite different levels of effort and that
the presence of a check mark does not necessarily signify that the work to be conducted will
provide adequate information for the endpoint in question.
       Under a cooperative agreement between EPA and the State of Alaska, several projects are
being conducted to investigate emissions related to ethanol-oxygenated gasoline, including studies
of the evaporative and combustion emissions from Alaskan gasoline with and without 10%
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ethanol. A study of the odor thresholds for these fuels is also included in this effort, which is
expected to be largely completed by mid-1996.
       Plans exist to conduct experimental chamber studies of persons with self-reported
sensitivity to oxyfuels.  These studies would attempt to produce symptoms and signs of oxyfuel
exposure under controlled conditions and explore some of the variables contributing to any such
effects.  Various issues about the design of such a study were discussed at a workshop convened
by EPA on April 5, 1995, and a report summarizing those discussions and an outline of a study
protocol was prepared by Benignus (1995).  At this writing, EPA is attempting to recruit subjects
for the study. A similar study is  planned by the Environmental and Occupational Health Sciences
Institute (Lioy, personal communication).
       The feasibility of designing an epidemiological study on acute health effects of MTBE was
the subject of a workshop held by EPA on April 4, 1995.  A panel of outside experts was charged
with preparing a report for the Agency on issues to be considered in designing such an
epidemiological study.  That report (SRA Technologies, Inc., 1995) offered several
recommendations, in particular suggesting that "[a] broad cross-section of epidemiologists should
be provided an opportunity to develop study designs..., compete for funding, and investigate
specific hypotheses on exposed populations before and after the introduction or use of
MTBE/gasoline." However, the report cautioned that "[s]urveillance programs to monitor the
public health impact of changes in gasoline formulation should not be considered in the absence of
a clear and clinically-based case  definition," although if suitable biomarkers of
                                            14

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Insert Table 2 here.
Table 2 is available as a separate PDF file.
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Insert Table 2 cont'd here.
Table 2 is available as a separate PDF file.
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exposure can be identified, it may be useful to monitor such indicators. The report also suggested
that aldehydes associated with oxyfuel combustion or photo-oxidation could be contributing to
symptom reports and that this hypothesis needed further study.
       Some work is currently being done on a voluntary basis by industry. The OFA is
sponsoring work by the Chemical Industry Institute of Toxicology (CUT) on the
pharmacokinetics and cancer mechanisms of MTBE.  A physiologically based pharmacokinetic
(PBPK) model for MTBE and TEA has been developed in rats (Borghoff et al., 1996) to help
interpret results of animal studies and to serve as a basis for developing a human PBPK model.
The human PBPK model is then in turn to be used to integrate mechanistically the internal
(effective) dose for various MTBE exposures with potential responses to MTBE.  Mechanistic
studies are also being conducted at CUT to evaluate the relevance of male rat tumors to humans
(Prescott-Mathews et al., 1996; Poet et al., 1996) and to determine if MTBE acts to initiate or to
promote liver tumors in female mice (Moser et al., 1996). In addition, a molecular-dosimetry
study is to evaluate whether the formaldehyde formed from the metabolism of MTBE results in
the formation of DNA-protein cross-links in targeted tissues. Other tumor sites in rats and mice
exposed over a lifetime to MTBE or TEA are also to be investigated for their relevance to
humans.
       Testing of TAME is being done under the terms of an enforceable consent agreement
under the Toxic Substances Control Act (TSCA). A  consortium of companies has agreed to
conduct studies on pharmacokinetics, subchronic toxicity in two species, reproductive and
developmental toxicity, mutagenicitiy, and neurotoxicity (Federal Register, 1995).  ARCO
Chemical has also indicated a commitment to conduct more in-depth studies of ETBE, including
pharmacokinetics, a 90-day subchronic toxicity study in two species, cell proliferation studies, and
a neurotoxicity screening battery (functional observation battery, motor activity, and
neuropathology). The company also plans future studies of the developmental and reproductive
effects of ETBE.
       As provided for under Section 211 of the Clean Air Act, certain information on fuels and
fuel additives must be supplied to EPA under terms specified in the Fuel/Fuel Additive (F/FA) rule
(Code of Federal Regulations, 1994a; Federal Register, 1994). A consortium of oxygenate
manufacturers coordinated through the American Petroleum Institute (API) has
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formed to respond to testing requirementsl for baseline gasoline and for gasoline with MTBE,
ETBE, TAME, DIPE, ethanol (EtOH), and TEA). It remains to be seen whether sufficient
interest exists within the industry to test other oxygenates, such as TAEE. An important feature
of the F/FA rule is that it focuses on evaporative as well as combustion emissions from the fuels.
The information obtained through the F/FA rule is expected to provide a basis for directly
comparing effects of the baseline fuel emissions with oxygenated fuel emissions. The 90-day
subchronic inhalation toxicity study and additional carcinogenicity/mutagenicity,
reproductive/developmental, and neurotoxicity assays required under Tier 2 of the F/FA rule are
summarized in Table 3.
FURTHER INFORMATION NEEDS
       Past work on conventional gasoline and certain gasoline constituents points to various
types of effects that warrant particular attention in investigating the health effects of fuels, namely,
carcinogenic effects, lung, kidney and liver toxicity, neurotoxicity, and
reproductive/developmental toxicity. Despite a substantial database on such inhalation health
effects for MTBE as well as for conventional gasoline (see Table  1), a comparative assessment of
the two remains problematic for several reasons. Differences over time in fuel formulations and in
testing methods may make it difficult to compare older data on conventional gasoline with more
recent data on MTBE. In the case of MTBE-gasoline and conventional gasoline, even if the same
testing methods were used in both cases, a comparison would not be very meaningful, because the
most appropriate contrast would be between a baseline gasoline and gasoline with MTBE added,
not MTBE alone.
    The F/FA rule specifies a tiered approach to providing information to EPA. Tier 1 may take up to three years and
involves a literature search for specified health effects information, emissions speciation, and a qualitative exposure
assessment. If adequate information cannot be obtained from the existing health effects literature, Tier 2 requires 90-day
inhalation toxicity studies in rats exposed to evaporative as well as combustion mixtures of a base gasoline and the base
gasoline with the additive. An additional three years may be used to satisfy Tier 2 requirements. Based on a review of
information from Tiers 1 and 2, EPA may require additional testing under Tier 3.  In addition, the F/FA rule also allows
for Alternative Tier 2 testing, which can modify the standard Tier 2 testing requirements with substitute testing or
research studies.
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                  Table 3. Fuel/Fuel Additive (F/FA) Rule Standard Tier 2 Tests

 90-Day Subchronic Inhalation General Toxicity (Code of Federal Regulations, 1994b):  Screening info on target organ
 toxicities and on concentrations useful for running chronic studies.
          30 rodents per concentration per group (add specified numbers for different assessments combined with general
      toxicity); recovery group (N = 20) observed for reversible, persistent, or delayed effects
          Observation (including body weight)
          Clinical exams:  hematology (e.g. Hct, Hb, RBC, DLC); clinical biochemistry (e.g., electrolyte balance, liver and kidney
          funct, Ca-P-Cl-Na-K, glucose, BUN)
          Ophthalmological exam
          Urinalysis
          Gross pathology
          Histopathology  (especially respiratory tract)

 Fertility/Teratology (Code of Federal Regulations, 1994b):  Information on potential health hazards to fetus and on gonadal
 function, conception, and fertility.
          25 males, 40 females per group; mating after 9 weeks of exposure, then exposure of females continues through GD 15
          Limit test: if no effects at highest cone., then skip lower cones.
          Observation for < 13 weeks
          Vaginal cytology
          Mating and fertility
          Gross necropsy  (especially including reproductive organs)
          Fetal anomalies, resorptions
          Flistopathology  of reproductive organs

 In Vivo Micronucleus (Code of Federal Regulations, 1994b):  Detect damage to chromosomes or mitotic apparatus of cells
 (based on increase in frequency of micronucleated RBCs); provides information on potential carcinogenic and/or mutagenic
 effects.
          5 females and 5 males per group
          Positive control

 In Vivo Sister Chromatid Exchange (Code of Federal Regulations, 1994b): Detect enhancement of exchange of DNA between
 two sister chromatids of a duplicating chromosome (using peripheral blood lymphocytes grown to confluence in cell culture);
 provides information on potential mutagenic and/or carcinogenic effects.
          5 females and 5 males per group
          Positive control

 Neuropathology (Code of Federal Regulations,  1994b):  Provides data on morphologic changes in central and peripheral  nervous
 system.
          N = 10 per group; N = 20 for reversible, persistent, or delayed effects
          Positive control
          Limit test (highest concentration first; skip other if no response)
          Observations (including body weight, movement disorders, etc.)
          Brain size and weight; light (and possible EM) microscopy of sections
          Peripheral nerve teasing

 Glial Fibrillary Acidic Protein: An indicator of neurotoxicity associated with astrocytic hypertrophy  at site of damage.
          10 animals per group

 Salmonella Typhimurium Reverse Mutation (Code of Federal Regulations, 1994b):  Microbial assay that measures histadine
 (his) reversions (his to his+), which cause base changes or frameshift mutations in the genome; provides data on mutagenicity.
          Positive controls
          Data presented as number of revertant colonies per plate, per kilogram of fuel, and per kilometer for each replicate
	and dose.	

 Source:  Federal Register (1994).
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       Although a fundamental need is to determine what, if any, difference in exposures or
health effects is made by the addition of an oxygenate to a baseline fuel, other variables (e.g.,
differences in VOC proportions or in Reid vapor pressure) may also be changed in the actual fuels
in the current marketplace.  A thorough evaluation of the comparative risks and benefits of
oxyfuels would therefore need to consider not just the impacts of adding oxygenate to a baseline
fuel but the impacts of other changes in current fuels such as reformulated gasoline.  At a
minimum, the following description of needed information on oxyfuels assumes a baseline (1990)
gasoline as a fundamental frame of reference throughout.  Overarching all of these needs is the
question of what is the net benefit or risk to the environment and public health resulting from a
change from conventional gasoline to oxyfuels. Although the objectives of the oxygenated
gasoline and reformulated gasoline programs are quite explicit in seeking to reduce CO, ozone,
and air toxic pollutants, a thorough examination of the successes or failures of the oxyfuel
programs is needed to answer the question just posed.  To do so will require a quantitative and
rigorous evaluation of changes in emissions, air and water quality, exposures,  and health  and
ecosystem effects associated with a change from conventional gasoline to oxyfuels. Ultimately,
health and ecosystem effects would have to be assigned some monetary or societal value  as well.
Such a complete analysis is  clearly a very complex and difficult undertaking, but without this sort
of attempt to conduct a thorough consideration of the full impacts (positive and negative) related
to a change in fuel use, questions may continue to arise concerning the advisability of oxyfuel
programs.

Exposure Issues
       Exposure assessment is an essential element of a comparative assessment of conventional
and oxygenated fuels. As noted above, exposure assessment draws upon information on emissions
characterization as well as environmental fate in different media.
       Information on motor vehicle combustion and evaporative emissions exists for
conventional gasolines and for MTBE- and ethanol-oxygenated gasolines but not for all
conditions of potential importance (e.g., different meteorological, roadway, and other operating
conditions). The Auto/Oil program has not tested a wide variety of operating conditions, nor has
it evaluated vehicle emissions using the most recent (since January 1995) marketplace industry
average reformulated gasoline.  A more comprehensive characterization of vehicle emissions is
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needed for actual marketplace reformulated/oxygenated gasolines to understand fully the complex
emission mixtures potentially existing in important exposure microenvironments.
       Ambient monitoring is needed to ascertain which toxic and criteria air pollutants are
increased or decreased, and the extent of such changes, as a function of a change from
conventional gasolines to oxyfuels.  Empirical information of this type is essential to validating the
effectiveness of the oxyfuel programs.
       Very little is known about the atmospheric transport and transformation of the complex
mixtures associated with use of oxyfuels and their potential exposure significance.  For example,
tertiary butyl formate is a photochemical transformation product of MTBE, as is formaldehyde
(e.g., Tuazon et al., 1991).  The potential for increased human exposures to such irritant
substances as a result of oxyfuel use needs to be evaluated.  Ambient and microenvironmental air
monitoring needs to be conducted to determine the levels of these and other possibly significant
by-products  of oxyfuels. ARCO Chemical may attempt to conduct some work on TBF,  including
measurements of TBF in the atmosphere and comparative toxicity studies of its irritancy to the
respiratory system (Andrews, personal communication).
       Estimates of human exposure require concentration measurements at the points of human
contact with the pollutant.  Because humans typically spend more time indoors and in transit than
they do outside, ambient concentration levels may misrepresent levels of actual human exposure.
Thus, it becomes critically  important for health risk assessors to have concentration data in
locations where people spend large portions of their time and in locations where they might
receive a relatively high exposure.
       With some data indicating MTBE contamination of ground water, other pathways of
exposure in addition to direct inhalation from the atmosphere may be of importance.  It is first
necessary to determine the extent to which point sources (e.g., leaking underground storage
tanks) may be responsible for such contamination. If point sources are not found to account for
all of the observed contamination, atmospheric transport and fate processes would be a critical
focus for further investigation. At a minimum, such research would entail concurrent
measurements of MTBE in ambient air, precipitation, run off, surface, and ground water. The
U.S. Geological Survey has plans to conduct such a study (as part of a broader study of pesticides
and VOCs) at Glassboro, NJ, beginning in mid-1996, and may extend the work later to other
cities throughout the United States (Zogorski, personal communication).

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       Regardless of the source (i.e., whether from a point source or from atmospheric
deposition), if the oxyfuel is present in ground water, studies of the subsurface transport and
degradation of the fuel are needed to determine the environmental risks. Along with determining
what environmental transport and transformation processes may be involved, it is important to
investigate how biological processes may contribute to the net removal or accumulation of
oxygenated organic compounds in ground water.  Some efforts in this area have been or are now
underway in both the private and public sectors, including the American Petroleum Institute, the
U.S. Department of Energy, and the U.S. Geological Survey (Zogorski, personal
communication).  The impact on water quality and aquatic biota would also need to be assessed,
and the potential for human exposures through the ingestion of oxyfuel-contaminated drinking
water would need to be quantified.
       Quantitative exposure assessments of different oxyfuels in relation to conventional fuels
need to incorporate personal exposure scenarios involving various activities (e.g., refueling,
driving) and routes of exposure (inhalation, dermal, ingestion).  In past studies, limited
measurements and models have been useful to provide ranges of potential exposures in several
significant microenvironments. This limited scenario approach, while historically all that has been
provided, has a large degree of uncertainty, and does not provide an accurate estimate of
population exposures. To reduce these uncertainties, human exposure field studies and models
based on the resulting data would be needed.

Health Effects Issues
Methyl Tertiary Butyl Ether
Acute Effects
       Apart from the public attention that reports of symptom complaints have generated in
certain areas of the United States, the widespread exposures and remaining scientific uncertainties
associated with oxyfuels require that further consideration be given to potential acute inhalation
health effects related to these fuels.  At least three hypotheses warrant investigation and are
discussed in more detail below.  (1) Is it the mixture of MTBE and gasoline, rather than MTBE
itself, that is proximally or ultimately responsible for effects (where "the mixture" presumably may
include combustion as well  as evaporative emissions and may well vary from place to place and at
different times)? (2) Are some individuals especially sensitive to MTBE or one or more of the
                                           22

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chemicals in the MTBE-gasoline mixture (i.e., in evaporative and/or combustion emissions)?
(3) Does some unidentified factor (e.g., cold temperature) modulate the effect of MTBE or the
mixture? The question of nonbiological factors (e.g., economic concerns, social or psychological
factors) underlying or contributing to the symptom reports must also be recognized.

       Mixtures. All of the inhalation toxicity testing conducted with laboratory animals thus far
has dealt with the effects of neat, laboratory-grade MTBE, not a mixture of gasoline and MTBE
(much less an actual MTBE-oxyfuel that might contain various contaminants, including other
ethers or alcohols).  Similarly, the human clinical studies conducted at EPA (Prah et al., 1994),
Yale (Cain et al., 1994),  and the Swedish National Institute of Occupational Health (Johanson et
al., 1995) used pure MTBE vapors. Thus, the effects of MTBE-gasoline mixtures have not been
investigated under controlled inhalation conditions.  Apart from ethical and other questions about
the feasibility and practicality of inhalation chamber studies of humans or laboratory animals
exposed to MTBE-gasoline mixtures, there are questions about how best to investigate mixture
exposures that are more representative  of real world conditions (i.e., mixtures of combustion as
well as evaporative emissions). More emissions and human exposure data would help guide the
design of such inhalation experiments.

       Sensitive Individuals  The EPA (Prah et al., 1994) and Yale (Cain et al., 1994) clinical
studies of MTBE used healthy young adults with no evident medical problems. An epidemiologic
study (Fiedler et al., 1994) of persons with multiple chemical sensitivities (MCS) did not show a
significant relationship between MTBE exposure and symptom reports, but only 14 persons with
MCS were evaluated, and many individuals who describe themselves as sensitive to MTBE do not
claim a general  sensitivity to chemicals. Thus, the possibility that some portion of the general
population may be particularly susceptible to MTBE or one or more chemicals associated with
MTBE-gasoline is worthy of further investigation.  A basic question in this case is how best to
investigate this possibility (e.g., through a broad population study or by intensive evaluation of
self-described "sensitives"). If true sensitives represent less than 5 to 10% of the general
population, an epidemiologic study must be carefully designed with adequate power to detect
such a proportion. A laboratory study of self-described sensitive individuals who would volunteer
for exposure to MTBE-gasoline under  controlled conditions is needed to determine whether

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symptoms can be induced by such exposures. The anticipated chamber studies by EPA and
EOHSI would help address this need, but demonstration of a phenomenon is only the first step. If
symptoms can be induced until controlled conditions, further experimental investigation of the
possible chemical, physiological, or other factors contributing to the occurrence of different
symptoms would be warranted. For example, the possibility of metabolic polymorphisms that
could underlie individual differences in susceptibility to MTBE is a topic of particular interest.
The hypothetical possibility that some individuals might undergo sensitization through repeated
exposure to MTBE or a chemical related to MTBE-oxyfuel might also be considered.

       Interactive Factors.  Cold temperature has been considered a possible factor for
investigation in connection with the putative effects of MTBE since the first complaints arose in
Alaska, and reports from Montana and Wisconsin apparently have not diminished the plausibility
of very cold temperatures playing a role in symptoms that might be related to MTBE or MTBE-
oxyfuels.  The intentional correlation of the oxygenate program with cold weather and the
coincidental start of the RFG program during the winter make it difficult to rule out the possible
role of cold temperature as a  contributing factor to the higher prevalence of symptom complaints
in certain areas.  Moreover, clinical studies conducted at 75° F have not addressed this issue.
Other variables, such as odor or chemical differences in the fuels in different areas, might also be
considered for further investigation, as suggested by studies of Alaskan fuels (Smith et al., 1994).
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Cancer
       The currently available data from MTBE cancer bioassays leave some uncertainty about
the efficacy and potency of MTBE to induce cancer by inhalation at low concentrations.  One or
more replicative studies would help resolve uncertainties relating to early termination and high
mortality in the earlier inhalation bioassay results.  However, if mechanistic and pharmacokinetic
data prove to be adequate to demonstrate the irrelevancy of the rodent findings to human cancer
risk (e.g., due to the male rat-specific role of alpha-2//-globulin), the need for additional chronic
bioassay data might be obviated.  With respect to oral exposure and health risks associated with
MTBE in drinking water, a chronic bioassay using drinking water is needed to complement the
existing study (Belpoggi et al., 1995) that used olive oil as the vehicle for oral gavage
administration.
       The comparative carcinogenic potential of the combustion as well as evaporative
emissions of baseline gasoline relative to oxyfuels is an outstanding fundamental issue. Although
some studies have been conducted on the carcinogenicity of the combustion emissions of leaded
and unleaded gasoline (Brightwell et al., 1986, 1989; Stara et al., 1980; Heinrich et al., 1985), it
remains to be determined whether this evidence is adequate to conduct a quantitative cancer risk
assessment of baseline gasoline in comparison to oxyfuels.

Reproductive/Developmental Effects
       Although evidence of impaired growth in offspring of laboratory animals exposed to
MTBE qualifies the chemical as a developmental toxicant, the effective duration and timing of
MTBE exposure during gestation and/or postnatal development for the induction of such effects
are not known. More precise data on the developmental window of toxicity would be needed to
characterize better the developmental risk of MTBE in relation to potential human exposures.
Pharmacokinetic and mechanistic studies would enhance this endeavor. Moreover, given the
indication of neurotoxicity in adult rodents exposed to MTBE (including suggestions of decreased
brain weight and/or length), a more intensive evaluation of developmental neurotoxicity may be
warranted. The same needs pertain to baseline gasoline and MTBE-gasoline mixtures.
       In  addition, the reproductive effects of baseline gasoline and MTBE-gasoline mixtures
need to be investigated, especially with respect to apparent differences between rats and mice in
past work on gasoline. With respect to the effects of conventional gasoline, a particular need

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exists for a multi-generation reproductive study of inhaled benzene, including endpoints for estrus
cyclicity, oocyte toxicity, and sperm morphology and function. Indications of neuroendocrine
effects (e.g., increased corticosterone levels) in MTBE-exposed animal studies lend further
support to the need for closer examination of possible effects on reproductive function.

Chronic Noncancer Effects
       Given the rather extensive database on chronic noncancer effects of neat MTBE, the
primary need is evaluation of the effects of chronic inhalation exposure to MTBE-gasoline
evaporative and combustion mixtures.  Although standard Tier 2 testing, as prescribed under the
F/FA rule, addresses the mixtures aspect of this need, it is not clear that the standard Tier 2 tests
themselves will provide the type of information that is most critically needed to meet the objective
of quantitative, comparative assessments. As the F/FA rule notes, the 90-day subchronic study is
"...not capable of determining effects which have a long latency period...," and the tests
themselves afford only a broad screening level evaluation (e.g., the neurotoxicity tests "... are not
intended to provide a detailed evaluation of neurotoxicity [and] ... should be complemented by ...
e.g., behavioral and neurophysiological studies..."). At this writing,  alternatives to the standard
Tier 2 testing requirements are being considered by EPA.
       With respect to oral exposures, currently available data suggest that MTBE tends to lead
the plume in oxyfuel releases to soil and groundwater, and thus an obvious need is to evaluate the
effects of neat MTBE by ingestion.  The substantial database on the  effects of inhalation exposure
to neat MTBE might suffice for this purpose if adequate pharmacokinetics data support such
extrapolation. However, to the extent that MTBE may be present in a mixture with other
compounds, the effects of such mixtures may have to be evaluated in their own right.

Pharmacokinetics
       As suggested above, pharmacokinetics information could assist efforts to investigate
various types of health effects and exposure by different routes. The role  of metabolites of
MTBE, such  as formaldehyde and TEA, needs to be better understood. Pharmacokinetics data
might also provide a basis for better predicting and assessing the effects of different ethers (see
below). It may also be worthwhile to investigate the possibility of synergistic, competing, or
antagonistic processes in the metabolism of MTBE.

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Other Oxygenates
       By comparison to MTBE, much greater data gaps exist for the other oxygenates that are
currently in use or under development. This statement might not apply to ethanol (EtOH) if
pharmacokinetics work were to establish a basis for quantitatively relating EtOH inhalation
exposure to a large body of existing research on EtOH exposure and health effects by ingestion.
At present, it is not evident that any organization is planning to conduct such work. However,
even the massive database  on pure EtOH does not address the evaporative and combustion
mixtures issues, as there may be differences in exposure or health effects that would not be
predicted by the effects of EtOH itself.
       The limited data on ETBE and TAME toxicity are inadequate to support quantitative risk
assessments of the individual chemicals, much less a comparative  assessment.  Thus, ETBE,
TAME, TAEE, and DIPE remain to be fully tested and evaluated  for cancer and chronic
noncancer health effects, both in pure form and as evaporative and combustion mixtures. The
same is true for TEA except that a cancer bioassay study of ingested TEA in two rodent species
has been completed.  Other oral-route cancer  studies are apparently underway on MTBE-
gasoline, EtOH and EtOH-gasoline, ETBE and ETBE-gasoline, TAME, DIPE, and gasoline alone
(Belpoggi et al., 1995), but these studies may  not provide a sufficient basis for assessing cancer
risks for inhalation exposures. As noted above, standard Tier 2 testing under the F/FA rule will
provide only basic toxicity  screening data, which are not expected to provide an adequate basis
for quantitative, comparative risk assessments of the oxyfuels versus a baseline gasoline.
SUMMARY
       The available information on conventional gasolines and neat oxygenates (viz., MTBE) is
not sufficient to support quantitative, comparative assessments of the health and environmental
benefits and risks of oxyfuels in relation to conventional fuels. Such assessments must address the
differences between conventional fuels and oxyfuels in their public health and environmental
impacts.  A complete assessment requires information on emissions, air and water quality impacts,
population exposures, and effects on health and ecosystems. Within these broad areas, certain
needs are particularly evident, including exposure evaluations and studies of chronic as well as
acute health effects of evaporative and combustion emissions of base gasoline with and without
                                           27

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oxygenate added. Ultimately, the basic objective is to determine the net benefit or risk of oxyfuels
compared to conventional gasoline.
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Anderson, H. A.; Hanrahan, L.; Goldring, J.; Delaney, B. (1995) An investigation of health concerns attributed to
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Belpoggi, F.; Soffritti, M.; Maltoni, C. (1995) Methyl-tertiary-butyl ether (MTBE)—a gasoline additive—causes
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