EPA/600/R-05/094
February 2003
Human Exposure to Methyl tert-Butyl Ether
(MTBE) While Bathing with Contaminated
Water
by
Sydney M. Gordon
Atmospheric Science and Applied Technology
Battelle Memorial Institute
Columbus, Ohio 43201
Task Order No. 0006 (ORD-99-105)
EPA Contract 68-D-99-011
EPA Project Officer
Ellen W. Streib
National Exposure Research Laboratory (MD-56)
Research Triangle Park, North Carolina 27711
Task Order Project Officer
Lance A. Wallace
National Exposure Research Laboratory
Reston, Virginia 20192
National Exposure Research Laboratory
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina 27711
-------
EPA Disclaimer
The information in this document has been funded wholly or in part by the United States
Environmental Protection Agency under Contract 68-D-99-011 to Battelle Memorial Institute. It
has been subjected to the Agency's peer and administrative review and has been approved for
publication as an EPA document. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
-------
Foreword
The mission of the National Exposure Research Laboratory (NERL) is to provide
scientific understanding, information, and assessment tools that will quantify and reduce the
uncertainty in EPA's exposure and risk assessments for environmental stressors. These stressors
include chemicals, biologicals, radiation, and changes in climate, land use, and water use. The
Laboratory's primary function is to measure, characterize, and predict human and ecological
exposure to pollutants. Exposure assessments are integral elements in the risk assessment
process used to identify populations and ecological resources at risk. The EPA relies
increasingly on the results of quantitative risk assessments to support regulations, particularly of
chemicals in the environment. In addition, decisions on research priorities are influenced
increasingly by comparative risk assessment analysis. The utility of the risk-based approach,
however, depends on accurate exposure information. Thus, the mission of NERL is to enhance
the Agency's capability for evaluating exposure of both humans and ecosystems from a holistic
perspective.
The National Exposure Research Laboratory focuses on four major research areas:
predictive exposure modeling, exposure assessment, monitoring methods, and environmental
characterization. Underlying the entire research and technical support program of the NERL is
its continuing development of state-of-the-art modeling, monitoring, and quality assurance
methods to assure the conduct of defensible exposure assessments with known certainty. The
research program supports its traditional clients - Regional Offices, Regulatory Program Offices,
ORD Offices, and Research Committees - and ORD's Core Research Program in the areas of
health risk assessment, ecological risk assessment, and risk reduction.
Monitoring techniques for volatile organic compounds (VOCs) in air or exhaled breath
are constantly evolving as the needs of the exposure assessment and health effects communities
change. The continuous real-time breath analyzer provides a unique means of collecting
abundant data with which to track the uptake, distribution in the body, and decay of numerous
compounds of interest to NERL. The purpose of the present study was to better understand the
uptake and disposition of methyl r-butyl ether (MTBE) and dibromochloromethane (DBCM)
within the human body during bathing or showering following realistic dermal exposures
through the use of contaminated tap water.
Gary J. Foley
Director
National Exposure Research Laboratory
in
-------
Abstract
The oxygenate methyl tert-butyl ether (MTBE) has been added to gasoline to meet
national ambient air quality standards in those parts of the U.S. that are non-compliant for carbon
monoxide. Although MTBE has provided important health benefits in terms of reduced
hazardous air pollutants, the increasing occurrence and detection of MTBE in drinking water
sources in California, New Jersey, and elsewhere has raised concerns about potential exposures
from water usage and resulting health effects. In addition to MTBE, disinfection byproducts can
be present in the water people use for showering, bathing, or drinking, as a result of the reaction
of disinfection agents with organic material already present in water. Chlorine, a widely used
disinfection agent, reacts with humic acids to form the trihalomethanes, which are the most
common and abundant byproducts in chlorinated water. Besides chloroform, which has been
extensively studied, the byproduct dibromochloromethane (DBCM) occurs as a result of the
chlorination process in those areas that naturally have bromide in their ground water.
Because the breath analyzer showed almost no discernible change in MTBE and DBCM
breath concentrations in the shower experiments that were conducted, we abandoned all further
shower exposure efforts in favor of the bath water experiments.
Three male and two female volunteers participated in the bath water study, in which each
was exposed to 40 |ig/L of DBCM and 150 |ig/L of MTBE-di2 in water for 30 minutes. We
were unable to derive meaningful results from the real-time breath analyzer data generated for
DBCM, largely because of what appeared to be an interfering contaminant with mass spectral
fragment ions that occurred at the same mass as the mass used to monitor for DBCM.
All of the breath concentration/time profiles obtained for the five participants, as a result
of dermal exposure to MTBE-di2 and MTBE in water, showed similar small increases in breath
concentrations, from pre-exposure levels of 2 - 9 |ig/m3 to peak levels of 7 - 15 |ig/m3. After
exposure ended, breath levels slowly decreased and tended toward the pre-exposure levels during
the 30-minute elimination monitoring period. In all cases, except for one subject, the measured
levels throughout the monitoring periods were above the limits of detection obtained with the
real-time breath analyzer. The pre-exposure levels were roughly equal to the detection limits for
MTBE-di2, which ranged from 2.3 to 10.6 |ig/m3. This concentration range is similar to that
reported for background levels of MTBE in previous studies that relied on batch collection and
gas chromatographic/mass spectrometric (GC/MS) analysis for breath sample measurement.
Uptake and elimination residence times were estimated using a one-compartment linear
model. The mean residence times for the decay phase were roughly twice as long as the mean
IV
-------
residence times for the uptake phase, viz., Tuptake = 21.2 ± 13.1 min and Tdecay = 41.5 ± 26.3 min
[mean ± standard deviation]. The reasonably good agreement obtained for the residence times
among the five participants suggests that our estimates of the model parameters may be fairly
robust. These estimated values are much greater than the residence times obtained in our earlier
study of the dermal absorption of chloroform from bath water, for which the mean uptake residence
time was 8.2 ± 3.1 min and the mean decay residence time was 7.7 ±1.0 min. This may be due to
the greater solubility of MTBE in water, which is reflected by their respective Henry's Law
coefficients, namely, 1.6 mole/atm for MTBE vs. 0.26 mole/atm for chloroform. These residence
times also are significantly larger than the uptake and decay residence times for MTBE determined
in our companion inhalation study.
The total amount of MTBE-di2 exhaled during the exposure and post-exposure periods
was estimated by integrating the area under the breath uptake and elimination curve. The mean
amount of MTBE-di2 exhaled at an average temperature of 39.5°C was 3.0 ± 1.1 (SD) jig (range:
1.7- 4.6 jig). The mean exhaled amount obtained in our earlier bath water study of chloroform
absorption at roughly the same temperature was 7.0 ± 2.0 jig. This indicates that the dermal
uptake of MTBE from bath water is significantly smaller than that of chloroform under similar
exposure conditions.
It is interesting to note that, although dermal absorption of MTBE from water has been
measured directly in the blood of human subjects in at least one earlier study, our measurements
appear to be the first of the dermal uptake of MTBE using continuous breath analysis. Finally,
the model parameters determined in this study may be useful to risk assessors in EPA State and
Regional offices for estimating dermal exposure to this contaminant while bathing.
The work reported herein was performed by Battelle Memorial Institute under U.S.
Environmental Protection Agency Contract 68-D-99-011, and covers the period from December
1999 to January 2002. Work was completed as of January 31, 2002.
-------
Contents
Foreword iii
Abstract iv
Figures vii
Tables x
Acknowledgments xi
Chapter 1 Introduction 1
Chapter 2 Conclusions 3
Chapters Recommendations 5
Chapter 4 Experimental Procedures 6
Experimental Procedures 6
Data Analysis 15
Quality Control 19
Chapters Results 23
Experiments atEOHSI 23
Experiments atBattelle 26
Total Exhaled Dose 27
Empirical Modeling of Uptake and Decay
Breath Concentrations 27
Quality Control Data 40
Chapter 6 Discussion 42
Breath Concentration/Time Profiles 42
Breath Residence Times 43
Steady-State Ratio/' of Exhaled Breath to Water Concentration 43
Total Exhaled Dose of MTBE 43
References 45
VI
-------
Figures
4-1 System for sampling exhaled breath samples in real time from subject
exposed by dermal absorption to MTBE and DBCM in shower water.
(Schematic shows only one shower unit for clarity.) 9
4-2 System for sampling exhaled breath samples in real time from subject
exposed by dermal absorption to MTBE and DBCM in bathtub water 10
4-3 Continuous real-time breath analyzer (RTBA), consisting of breath inlet
(breath holding volume) attached to direct breath sampling interface
(glow discharge ionization source) and ion trap mass spectrometer
(GD/ITMS) 11
4-4 Plot showing rapid increase in alveolar breath concentration Caiv as a
result of step function exposure to a constant water concentration Cwater,
followed by a rapid decrease in breath concentration as a result of
exposure to clean air. Tis the lag time, i.e., the time to the first
measurable increase in the breath concentration; Texpo is the time at
the end of exposure 16
5-1 Exhaled breath concentrations of MTBE-di2 and DBCM as a function
of time for Subject TF06 during and following dermal exposure while
bathing. Upper plot: MTBE-di2 data from canister and Tenax sorbent
samples collected from real-time breath analyzer system; lower plot:
DBCM data from canister and Tenax sorbent samples collected from
real-time breath analyzer system. All samples analyzed by GC/MS.
Nominal water concentration was 150 |ig/L for MTBE-di2 and 40 |ig/L
for DBCM; water temperature was 40°C 24
5-2 Exhaled breath concentrations of MTBE-di2 and DBCM as a function
of time for Subject TM07 during and following dermal exposure while
bathing. Data obtained from canister samples collected from real-time
breath analyzer system. All samples analyzed by GC/MS. Nominal
water concentration was 150 |ig/L for MTBE-di2 and 40 |ig/L for
DBCM; water temperature was 40°C 25
5-3 Mean perfusion of surface of first two fingers on hands of two male subjects
as a function of temperature 26
vn
-------
Figures (continued)
5-4 Continuous exhaled breath concentrations for MTBE-di2 (upper plot) and
DBCM (lower plot) as a function of time for Subject BCOM1T during
and following dermal exposure while bathing. Exposure duration was
34.1 min; post-exposure monitoring continued for another 31.0 min.
Water temperature was 39.7°C. Nominal concentrations were 150 |ig/L
for MTBE-di2 and 40 |ig/L for DBCM. RTBA LOD designates detection
limit with real-time breath analyzer 28
5-5 Continuous exhaled breath concentrations for MTBE-di2 (upper plot) and
DBCM (lower plot) as a function of time for Subject BCOF1T during
and following dermal exposure while bathing. Exposure duration was
33.0 min; post-exposure monitoring continued for another 33.1 min.
Water temperature was 39.0°C. Nominal concentrations were 150 |ig/L
for MTBE-di2 and 40 |ig/L for DBCM. RTBA LOD designates detection
limit with real-time breath analyzer 29
5-6 Continuous exhaled breath concentrations for MTBE-di2 (upper plot) and
DBCM (lower plot) as a function of time for Subject BCOM2T during
and following dermal exposure while bathing. Exposure duration was
33.1 min; post-exposure monitoring continued for another 31.0 min.
Water temperature was 38.8°C. Nominal concentrations were 150 |ig/L
for MTBE-di2 and 40 |ig/L for DBCM. RTBA LOD designates detection
limit with real-time breath analyzer 30
5-7 Continuous exhaled breath concentrations for MTBE-di2 (upper plot) and
DBCM (lower plot) as a function of time for Subject BCOF2T during
and following dermal exposure while bathing. Exposure duration was
33.0 min; post-exposure monitoring continued for another 29.5 min.
Water temperature was 39.8°C. Nominal concentrations were 150 |ig/L
for MTBE-di2 and 40 |ig/L for DBCM. RTBA LOD designates detection
limit with real-time breath analyzer 31
5-8 Continuous exhaled breath concentrations for MTBE (upper plot) and
DBCM (lower plot) as a function of time for Subject BCOM3T during
and following dermal exposure while bathing. Exposure duration was
29.5 min; post-exposure monitoring continued for another 30.4 min.
Water temperature was 40.4°C. Nominal concentrations were 150 |ig/L
for MTBE and 40 |ig/L for DBCM. RTBA LOD designates detection
limit with real-time breath analyzer 32
Vlll
-------
Figures (continued)
5-9 Measured MTBE-di2 exhaled air exposure uptake plot for Subject BCOM1T
compared with modeled curve. Bath exposure details as described in
Figure 5-4. Data smoothed using 155-s block averaging time 34
5-10 Measured MTBE-di2 exhaled air exposure decay plot for Subject BCOM1T
compared with modeled curve. Bath exposure details as described in
Figure 5-4. Data smoothed using 155-s block averaging time 34
5-11 Measured MTBE-di2 exhaled air exposure decay plot for Subject BCOF1T
compared with modeled curve. Bath exposure details as described in
Figure 5-5. Data smoothed using 5-point moving average 35
5-12 Measured MTBE-di2 exhaled air exposure uptake plot for Subject BCOF1T
compared with modeled curve. Bath exposure details as described in
Figure 5-5. Data smoothed using 5-point moving average 35
5-13 Measured MTBE-di2 exhaled air exposure uptake plot for Subject BCOM2T
compared with modeled curve. Bath exposure details as described in
Figure 5-6. Data smoothed using 5-point moving average 36
5-14 Measured MTBE-di2 exhaled air exposure decay plot for Subject BCOM2T
compared with modeled curve. Bath exposure details as described in
Figure 5-6. Data smoothed using 5-point moving average 36
5-15 Measured MTBE-di2 exhaled air exposure uptake plot for Subject BCOF2T
compared with modeled curve. Bath exposure details as described in
Figure 5-7. Data smoothed using 5-point moving average 37
5-16 Measured MTBE-di2 exhaled air exposure decay plot for Subject BCOF2T
compared with modeled curve. Bath exposure details as described in
Figure 5-7. Data smoothed using 5-point moving average 37
5-17 Measured MTBE exhaled air exposure uptake plot for Subject BCOM3T
compared with modeled curve. Bath exposure details as described in
Figure 5-8. Data smoothed using 5-point moving average 38
5-18 Measured MTBE exhaled air exposure decay plot for Subject BCOM3T
compared with modeled curve. Bath exposure details as described in
Figure 5-8. Data smoothed using 5-point moving average 38
5-19 Plot of average ion signal (and standard deviation) at m/z 55 as a function
of time, obtained from constant source of 2-butanone in glass chamber
at a concentration of 866 |lg/m3 in zero-grade air 40
IX
-------
Tables
4-1 Characteristics of Subj ects who Participated in Dermal Exposure Study at
EOHSI and Battelle, and Associated Exposure Conditions 7
4-2 Mass spectral parent and product ions used to monitor MTBE, MTBE-di2,
DBCM, and TEA with the real-time breath analyzer 12
4-3 Battelle standard containing the target compounds, trichloromethane and
benzene, in nitrogen 20
4-4 Comparison of measured and certified concentrations of MTBE in certified
reference standard, and chloroform and benzene in NIST SRM 1804a 21
5-1 Total exhaled dose of MTBE-di2 or MTBE as a result of dermal absorption
in bath water 33
5-2 Theoretical calculations of MTBE model parameters 39
5-3 Limits of detection (LOD) for MTBE-di2 and DBCM in exhaled breath
measured with the real-time breath analyzer (RTBA) 41
-------
Acknowledgments
Funding support for this project was provided by U.S. EPA Region 9 under the Regional
Applied Research Effort (RARE) program. We thank Dr. Lance A. Wallace of EPA for his
expert advice and suggestions throughout this investigation. Major contributions to the research
effort were made by Battelle personnel Marielle C. Brinkman and Jan Satola. We also wish to
thank Dr. Andrew Lindstrom of U.S. Environmental Protection Agency for the loan of several
stainless steel canisters, and Mr. Kevin Barrett of Lisca, Inc. (Mahwah, NJ) for the loan of the
Laser Doppler Perfusion Imager.
XI
-------
Chapter 1
Introduction
Methyl fert-butyl ether (MTBE) was first introduced in the U.S. as a synthetic gasoline
additive in the 1970s. The federal Clean Air Act requirements for oxygenates in wintertime
gasoline made MTBE, which has oxygen-containing properties, a popular choice of refineries
manufacturing reformulated gasoline. Added to gasoline at levels of up to 15% by volume,
MTBE reduces automotive emissions of carbon monoxide.
A survey of ground water throughout the United States by the US Geological Survey has
indicated that MTBE is one of the most frequently detected compounds in ground water.1
MTBE is highly water-soluble and appears to be resistant to chemical and microbial degradation
in water.2 When MTBE, which has a very unpleasant taste and odor,3 began appearing in
groundwater and some public drinking water systems throughout the U.S., environmental
agencies, state governments, regulatory groups, and researchers became concerned.2'3'4'5'6'7
Issues of toxicology and exposure during automobile refueling also pointed to the need for
information on the exposure levels and distribution of MTBE in the human body.
Besides MTBE, the trihalomethanes (chloroform, bromodichloromethane, dibromochloro-
methane, bromoform) can be present in the water people use for showering, bathing, or drinking,
if the water supply was disinfected with chlorine and contaminated with MTBE. The most
common method of disinfecting water in the U.S. is by adding chlorine directly to the water.
Disinfection byproducts (DBFs) result from the reaction of disinfection agents with organic
material already present in water. Chlorine reacts with humic acids to form the trihalomethanes,
the haloacetic acids, and many other halogenated compounds. Of the many classes of
disinfection byproducts that occur, trihalomethanes are the most common and abundant in
chlorinated water. The DBF, dibromochloromethane (DBCM) occurs in the chlorination process
in those areas that naturally have bromide in their ground water. Dibromochloromethane has
been reported to occur at about 40 ug/L at the 90l percentile in Los Angeles, CA8.
Exposure to MTBE can occur by inhalation, dermal contact, or ingestion.4'5'6'7'9 Vehicle
refueling activities lead to the highest potential exposures by inhalation, with breathing zone
levels ranging from 0.1 to 4 ppm for 1 - 2 min durations and peaks occasionally exceeding 10
ppm.10'11'1 The health effects of exposures to gasoline or water containing MTBE are not well-
established,13 although acute effects such as headaches, nausea or vomiting, nasal and ocular
irritation, and sensations of disorientation, have been associated with exposure to gasoline
containing MTBE.14'15 In those areas of the U.S. that use MTBE as a gasoline oxygenate, doses
from non-occupational exposure are between 0.4 and 6 |ig/kg-day, and roughly 1.4 |ig/kg-day as
a result of exposure via contaminated water.16
-------
Several studies, including some based on the analysis of exhaled breath, have
demonstrated significant dermal absorption of chloroform and trichloroethylene while showering
17 1& 109091999^ ^A
or bathing, and the dose is roughly comparable to that resulting from inhalation. >>>>'>>
The uptake of MTBE by inhalation has been measured in exhaled breath under controlled
conditions using integrated sampling techniques,11'25'26'27'28'29 but reports on the measurement of
the potential uptake of MTBE through the skin are sparse.9
We recently developed and applied real-time breath analysis technology to measure
dermal absorption of chloroform while bathing.21 Subjects bathed in contaminated water while
breathing pure air through a full face mask; the chloroform in their exhaled breath was analyzed
continuously in real time. Not only were we able to measure chloroform in the breath at levels
up to about 12 ppb, but we also found that water temperature has a powerful effect on dermal
absorption. An increase from 30°C to 40°C in bath water temperature produced about a 30-fold
increase in absorbed chloroform. The real-time breath measurement method21'30 provides
T 1 T'}
abundant data compared to previous discrete time-integrated breath sampling methods. ' It
measures inhalation exposure directly, allowing us to trace the uptake, distribution in the body,
and decay of various compounds of interest. Because the face mask eliminates exposure to
contaminated air, it is particularly well suited to measuring dermal exposure only.
The purpose of the present study was to use the real-time breath measurement technology
to determine potentially significant human exposure to MTBE and DBCM by the dermal route.
A major objective was to measure directly the uptake of MTBE by dermal absorption while
showering or bathing with contaminated water and the presence of tertiary-butyl alcohol (TEA)
in the exhaled breath. TEA is a metabolite of MTBE, so its occurrence in the breath would
provide a measure of metabolic activity. A second objective was to estimate the relative
contributions of dermal and inhalation exposure to MTBE while bathing and to incorporate the
breath measurements into an existing multicompartment chamber model to assess the relative
significance of MTBE exposure while bathing with contaminated water.
-------
Chapter 2
Conclusions
The real-time breath analyzer was used in an effort to better understand the uptake,
distribution, and elimination of dermally absorbed MTBE and DBCM within the human body
during bathing and showering as a result of realistic dermal exposures.
Two male subjects volunteered to participate in the shower experiments, which were
conducted in a bathroom at the Environmental and Occupational Health Sciences Institute
(EOHSI), Rutgers University, in Piscataway, NJ. However, the breath analyzer, which was used
in these experiments to measure the uptake of MTBE-di2 (water concentration 150 |ig/L) and
DBCM (water concentration 40 |ig/L), showed almost no discernible change in breath
concentration from pre-exposure levels throughout each 30-minute exposure period, even at the
highest temperature used, i.e., 40°C. Because these experiments exhibited no measurable effects,
we abandoned all further shower exposure runs in favor of the bath water experiments.
Although some bath water experiments were run at EOHSI, the temperature fluctuations
and other problems encountered in the bathroom where the experiments were conducted
prevented us from obtaining reliable data. As a result, we report here only on the 5 data sets that
were subsequently generated from the volunteers (3 males, 2 females) who participated in the
study in our laboratory at Battelle in Columbus, OH. Even so, the detection limits of the real-
time breath analyzer for exposure to 40 |ig/L of DBCM in water for 30 minutes were much
higher than for MTBE-di2 and we observed relatively high initial exhaled breath levels for
DBCM. This, together with the lack of agreement that was observed between the breath
analyzer and canister-gas chromatography/mass spectrometry (GC/MS) data provided a strong
indication that the measured breath analyzer signal was probably due to an unknown
contaminant with mass spectral fragment ions at the same mass. As a result, no meaningful
results were derived from the data obtained for DBCM.
For all five participants, the breath concentration/time profiles obtained for MTBE-di2
and MTBE for dermal exposure to a nominal concentration of 150 |ig/L for 30 minutes showed
similar relatively slow and small increases in breath concentrations, from pre-exposure levels of
2-9 |ig/m3 to peak levels of 7 - 15 |ig/m3. After exposure ended, breath levels slowly
decreased and tended toward the pre-exposure levels during the 30-minute elimination
monitoring period. In all cases, except for one subject, the measured levels throughout the
monitoring periods were above the limits of detection obtained with the real-time breath
analyzer. The pre-exposure levels were roughly equal to the detection limits for MTBE-di2,
which ranged from 2.3 to 10.6 |ig/m3. This concentration range is similar to that reported for
-------
background levels of MTBE in previous studies that relied on batch collection and GC/MS
analysis for breath sample measurement.
Uptake and elimination residence times were estimated using a one-compartment linear
model. The mean residence times for the decay phase were roughly twice as long as the mean
residence times for the uptake phase, viz., Tuptake = 21.2 ± 13.1 min and Tdecay = 41.5 ± 26.3 min
[mean ± standard deviation]. The reasonably good agreement obtained for the residence times
among the five participants suggests that our estimates of the model parameters may be fairly
robust. These values are much greater than the residence times obtained in our earlier study of the
dermal absorption of chloroform from bath water, for which the mean uptake residence time was
8.2 ± 3.1 min and the mean decay residence time was 7.7 ± 1.0 min. This may be due to the greater
solubility of MTBE in water, which is reflected by their respective Henry's Law coefficients,
namely, 1.6 mole/atm for MTBE vs. 0.26 mole/atm for chloroform. These values also are
significantly larger than the uptake and decay residence times for MTBE determined in our
companion inhalation study.
The total amount of MTBE-di2 exhaled during the exposure and post-exposure periods
was estimated by integrating the area under the breath uptake and elimination curve. The mean
amount of MTBE-di2 exhaled at an average temperature of 39.5°C was 3.0 ± 1.1 (SD) jig (range:
1.7- 4.6 jig). The mean exhaled amount obtained in our earlier bath water study of chloroform
absorption at roughly the same temperature was 7.0 ± 2.0 jig. This indicates that the dermal
uptake of MTBE from bath water is significantly smaller than that of chloroform under similar
exposure conditions.
It is worth noting that, although dermal absorption of MTBE from water has been
measured directly in the blood of human subjects in at least one earlier study, our measurements
appear to be the first of the dermal uptake of MTBE using continuous breath analysis.
Furthermore, the model parameters determined in this study may be useful to risk assessors in
EPA State and Regional offices for estimating dermal exposure to this contaminant while
bathing.
-------
Chapter 3
Recommendations
The real-time breath analyzer is a promising technique for the continuous monitoring of
trace-level VOCs in breath. It was used along with a specially designed face mask to isolate and
examine dermal exposure to MTBE and DBCM, resulting from bathing in contaminated tap
water.
Sensitivity limitations with the real-time breath analyzer prevented us from obtaining
usable exhaled breath data for either MTBE or DBCM from subjects while showering, or for
DBCM from subjects while bathing. Also, analysis problems experienced in the laboratory at
EOHSI and a subsequent lack of funds prevented us from measuring the actual water
concentrations of the target compounds. Because these data are important in developing a more
complete picture of the uptake and disposition of these chemicals in the human body as a result
of dermal exposures, we recommend that careful attention be paid in future studies to first
maximizing the sensitivity of the breath analyzer and to ensuring that the analytical techniques
for the characterization of target analytes in water are reliable and can be applied without
difficulty before embarking on similar studies.
-------
Chapter 4
Experimental Procedures
In this exposure scenario, subjects showered or bathed in water contaminated with MTBE
and DBCM while wearing a full face mask connected to a supply of pure air to eliminate
inhalation exposure. Exhaled breath was monitored continuously using the real-time breath
analyzer. Shower and bathtub experiments were conducted in a bathroom at the Environmental
and Occupational Health Sciences Institute (EOHSI), Rutgers University, in Piscataway, NJ;
additional bathtub experiments were carried out in our laboratories at Battelle, in Columbus, OH.
Experimental Procedures
Subject Selection and Recruitment
Volunteers for the first part of this study were sought from amongst the student
population at Rutgers University, in Piscataway, NJ by means of notices placed in buildings
around the University campus and local newspaper advertisements. For the additional
experiments conducted at Battelle, volunteers were recruited by word-of-mouth from amongst a
group of temporary technicians who were available on site at the time. Respondents with any of
the following medical conditions were excluded: neurologic disease or brain injury, significant
exposure to other neurotoxicants, chronic fatigue syndrome or multiple chemical sensitivity,
stroke or cardiovascular disease, serious pulmonary disease, liver or kidney disease, serious
gastrointestinal disorders (e.g. colitis), claustrophobia, and major psychiatric conditions
including psychoses, manic depression, alcoholism, or drug abuse. No pregnant or lactating
women were included.
The subjects were healthy, young nonsmoker adults of average weight and height.
Information on the subjects is provided in Table 4-1 along with a summary of the exposure
conditions. Information was collected from each subject on his/her age, height, weight,
respiration rate (using a dry gas meter), and percent body fat (from body circumferences and
height). The study protocol was reviewed and approved by both the Battelle Human Subjects
Committee and the EOHSI Institutional Review Board (IRB) before it was submitted to and
approved by the EPA Human Subjects Committee. Informed written consent was obtained from
each subject before participation. Each subject received financial compensation on completion
of the exposure experiments.
-------
Table 4-1. Characteristics of Subjects who Participated in Dermal Exposure Study at EOHSI and Battelle,
and Associated Exposure Conditions.
Subject
SM01
SM03
TM05
TF02
TM04
TF06
TM07
BCOM1T
BCOF1T
BCOM2T
BCOF2T
BCOM3T
Sexa
M
M
M
F
M
F
M
M
F
M
F
M
Height
(cm)
170
185
175
162
173
163
?
170
163
185
157
166
Weight
(kg)
77.1
90.7
83.9
58.1
61.2
54.4
?
60.8
57.2
90.7
61.2
65.8
Age
(yr)
20
36
54
21
21
19
?
21
25
23
29
21
Shower (S)
or Tub (T)
Exposure15
S (RTBA)
S (RTBA)
T (RTBA)
T (RTBA)
T (RTBA)
T(C)
T(C)
T (RTBA/C)
T (RTBA/C)
T (RTBA/C)
T (RTBA/C)
T (RTBA/C)
EOHSI
or
BCOa
EOHSI
EOHSI
EOHSI
EOHSI
EOHSI
EOHSI
EOHSI
BCO
BCO
BCO
BCO
BCO
Expt.
Date
02/12/01
02/13/01
02/14/01
02/14/01
02/14/01
02/15/01
02/16/01
06/21/01
06/22/01
06/22/01
06/29/01
06/29/01
MTBE-d12/DBCM
Concn. in Water
(ug/L)
150/40
150/40
150/40
150/40
150/40
150/40
150/40
150/40
150/40
150/40
150/40
150/40
Water
Temp
(°C)
41.0
40.5
39.7
40.0
38.5
40.0
40.2
39.7
39.0
38.8
39.8
40.4
Shower
Flow Rate
(L/min)
10.2
?
—
—
—
—
—
—
—
RTBA Sample/
Calibration
File ID
SM01a/Cal0212
SM03/cal0213
TM05/cal0214a
— /ca!0214b
— /ca!0214c
TF02/cal0214a
— /ca!0214b
— /ca!0214c
TM04/cal0214a
TM04a/cal0214b
— /ca!0214c
C
C
BCOMlT/cal0621a
BCOFlT/cal0622a
BCOM2T/cal0622b
BCOF2T/cal0629a
BCOM3T/cal0629b
a Abbreviations: M, male; F, female; EOHSI = Environmental and Occupational Health Sciences Institute (EOHSI), Piscataway, NJ; BCO = Battelle Columbus
Operations, Columbus, OH.
b Breath Measurements Made: RTBA = continuous real-time breath analyzer; C = discrete evacuated stainless steel canister samples.
0 No breath analyzer or calibration file generated since only discrete canister samples were collected.
-------
Exposure Conditions
Shower Facility
Shower experiments were conducted in a bathroom at EOHSI that contained a separate
shower stall. The real-time breath analyzer and associated equipment were set up in the
bathroom, next to the shower stall. Water for the shower was purified by flowing it through a
charcoal filter to remove disinfection by-products as well as any MTBE that may have been
present. A syringe-drive unit was connected by means of a T-piece to the inlet piping, just
before it entered the shower head, and was used to inject the MTBE-di2 (>99.8 atom %D; Lot
No. F65P1; C/D/N/ Isotopes; CAS No. 29366-08-3) and DBCM mix into the shower stream to
obtain the desired concentrations. Initial plans called for experiments at three concentrations of
MTBE (50, 100, and 150 ug/L) and a single concentration of DBCM (40 ug/L). These
concentrations have been found in tap or ground water in various areas of the United States. The
water temperatures of interest were 35°C and 40°C, to examine the effect of temperature on
dermal absorption.
The shower facility was modified by using two standard shower heads mounted opposite
each other, to allow the subject, wearing a face mask with supply tubes attached, to stand facing
in one direction. Thus, the subject did not have to turn around every few minutes in order to
ensure uniform exposure front and back. The two showers used were commercially-available
portable outdoor shower units. Each unit, which was adjustable up to a height of 1.87 m (73 ^
in), included a shower-head mounted on a plastic rod in a metal tripod, an adjustable on/off
valve, and a length of garden hose.
At the start of an experiment, the subject was fitted with a full face mask, which was
attached to a pure air supply to ensure that the only route of exposure to MTBE and DBCM was by
dermal absorption. The fit of the mask was checked for leak tightness before the experiment by
exposing the subject to isoamyl acetate ("banana oil") or acetic acid vapors and determining
whether the odor was detectable by the subject.
After putting on the face mask and immediately before entering the shower stall, the
outlet tube from the face mask was attached to the real-time breath analyzer and the subject
provided a pre-exposure breath sample (3-4 min duration). The subject then stepped into the
shower stall and positioned him/herself in the water spray. Exposure continued for 30 minutes,
during which time breath measurements were taken continuously to map the uptake curves for
MTBE-di2 and DBCM. At the end of the exposure period, the subject exited the shower stall and
quickly toweled him/herself down while continuing to breathe purified air and provide exhaled
breath samples. Figure 4-1 is a schematic of a subject in the test shower facility, showing the
subject wearing the face mask, attached to the pure air supply, and exhaling into the breath
analyzer. Post-exposure breath measurements were taken continuously for a further 30 min.
The subjects were requested to drink only bottled water from the evening before the
experiment, refrain from drinking any carbonated beverages, avoid bathing or showering the
morning of the experiment, and refrain from the use of perfumes or toiletries.
-------
H C
Water Supply
Figure 4-1. System for sampling exhaled breath samples in real time from subject exposed by
dermal absorption to MTBE and DBCM in shower water. (Schematic shows only
one shower unit for clarity.)
Bathtub Facility
The bathing experiments were carried out in a 380 L stainless steel hydrotherapy tub (109
cm long x 53 cm wide x 71 cm high). The tub was connected to the building hot and cold water
supply and, immediately before the start of an experiment, the water inflow was adjusted to give the
desired temperature, as indicated by an analog thermometer. After putting on the face mask, the
subject provided a pre-exposure breath sample. Then, the subject stepped into the tub and
immersed him/herself in the water up to neck height. MTBE-di2, DBCM, and TEA breath
measurements were made every 12s with the real-time breath analyzer while the subject
continued to breathe purified air, and readings of the water temperature were taken manually at
regular intervals throughout the exposure period. Figure 4-2 is a schematic of a subject in the
filled hydrotherapy tub, wearing the face mask while attached to the pure air supply and exhaling
into the breath analyzer.
The subject remained in the tub for 30 min, then stepped out of the tub and quickly dried
him/herself while continuing to breathe purified air and exhale into the analyzer. Post-exposure
breath measurements were taken for up to 30 min before the subject was allowed to remove the
face mask. This post-exposure period was sufficient to allow the breath levels of the target
compounds to approach the original pre-exposure levels. Water samples were collected
immediately before the subject entered the tub, midway through the exposure period, and
immediately before he/she stepped out of the tub.
To confirm the results obtained with the real-time breath analyzer, we collected
simultaneous whole-breath samples from the outlet of the breath analyzer system using
-------
HydrotherapyTub
Pure Air
3DQ Ion Trap
Mass Spectrometer
Figure 4-2. System for sampling exhaled breath samples in real time from subject exposed by
dermal absorption to MTBE and DBCM in bathtub water.
evacuated stainless steel (Summa) canisters, which were analyzed independently by gas
chromatography/mass spectrometry (GC/MS) for MTBE-di2, DBCM, and TBA-dio using a
procedure based on a standard method (EPA Method TO-15). These co-collected samples were
taken during the final two bathtub runs completed at EOHSI and in all of the additional tub
experiments that were subsequently conducted at Battelle. In one of these two experiments at
EOHSI, breath samples were also collected using actively-pumped Tenax sorbent tubes, and
these samples were subsequently analyzed at EOHSI by thermal desorption GC/MS.
Sampling and Measurement Procedures
Breath Samples
Real-Time Breath Analyzer
Exhaled breath was monitored for MTBE-di2, DBCM, and TEA using the real-time
breath analyzer and, in several cases, evacuated stainless steel canisters along with GC/MS.
The real-time breath analyzer, shown schematically in Figure 4-3, consists of a specially-
designed breath inlet unit, a direct breath sampling interface, and an ion trap mass spectrometer
(ITMS).21'30'33'34 For the breath measurements, a face mask (Model 8932, Hans Rudolph, Inc.,
Kansas City, MO) equipped with a two-way non-rebreathing valve set was attached to the breath
10
-------
Glow
Discharge
Source
Teflon Tubing
Quartz Fiber Filter
\
One-Way
Valve
\ \
JT
Ion Trap
Analyzer
Figure 4-3. Continuous real-time breath analyzer (RTBA), consisting of
breath inlet (breath holding volume) attached to direct breath
sampling interface (glow discharge ionization source) and ion
trap mass spectrometer (GD/ITMS).
inlet to isolate the subject from any MTBE or DBCM in the bathroom air. The inlet valve of the
face mask was connected to a cylinder containing hospital-grade breathing air. The exhaust
valve of the face mask was connected to the breath inlet. The breath sample is vacuum-extracted
at a constant rate from the breath interface volume by the vacuum in the direct breath sampling
interface and flows into the ion trap without any attention from the subject.
The volume of the breath inlet (Figure 4-3) is normally less than 100 mL, or roughly one-
fifth the mean value of the adult tidal volume. Thus, each breath exhalation effectively displaces
the previous breath sample while a steady gas flow is maintained into the analyzer. This ensures
that unit resolution is achieved between individual breath exhalations while at the same time
producing a constant and undiluted sample for analysis. A dry gas meter (Model DTM-115,
American Meter Co.), attached to the vent of the breath inlet system via wide-bore flexible
tubing, was used to record the respiration rate and total exhaled volume from each subject.
The direct breath sampling interface is a glow discharge ionization source, which is
attached to the ITMS. The operation of this system has been described in detail elsewhere.35'36'37
For the work described here, we used a Teledyne Electronic Technologies (Mountain View, CA)
TO
3DQ™ Discovery ion trap MS as the analyzer. The 3DQ is a compact, field-deployable
instrument with high sensitivity and specificity. The breath analyzer was set up to measure the
MTBE-di2, DBCM, and TBA-dio target analytes in both the single MS as well as the MS/MS
modes. The ions selected for this purpose are listed in Table 4-2. Calibration measurements
conducted in our laboratory showed that MTBE can be determined in humidified air with high
sensitivity and specificity. Although the measurement of the MTBE metabolite tertiary butyl
alcohol (TEA) requires the selection of the same parent ion as for MTBE, it dissociates to form
two different daughter ions, thus allowing us to distinguish between the two compounds.
However, tests have indicated that the sensitivity of the measurement is not as high as for
MTBE. Dibromochloromethane was monitored in the single MS mode since its dissociation
efficiency in the ITMS was found to be very small.
11
-------
Table 4-2. Mass spectral parent and product ions used to monitor MTBE,
MTBE-dn, DBCM, and TEA with the real-time breath analyzer.
Compound
MTBE
MTBE-d12
DBCM
TBA-d10
MW
88
100
208
84
Parent Ion
73
82
129
82
Product Ion
43,55
46,50
—
62
To calibrate the real-time breath analyzer in the laboratory, gas standards containing
MTBE-di2 and DBCM were prepared in high-pressure aluminum gas cylinders. To confirm the
concentrations of the standards, samples were taken from the cylinders in evacuated 6-L stainless
steel canisters, which were analyzed by a modified U.S. EPA Method TO-15.39 The gas
chromatograph/flame ionization detector/quadrupole mass spectrometer (GC/FID/MS) system, in
turn, was calibrated by analyzing aliquots taken from a gravimetrically-prepared standard.
Calibration of the breath analyzer itself was accomplished by connecting a gas cylinder
containing the standards to the glow discharge source inlet and measuring the resultant ion
signals of the target ions at the known concentrations. The instrument was calibrated each day
before experiments began.
During the exposure experiment, the carbon dioxide levels in the exhaled breath of each
subject were monitored using an Ohmeda 5200 CC>2 monitor (Datex-Ohmeda, Tewksbury, MA).
This unit provides continuous breath-by-breath measurements of CCh production. It is equipped
with an RS-232 communications interface, which provides a convenient means of assembling
and reducing the CCh data alongside that for breath MTBE-di2, DBCM, and TBA-dio in a
spreadsheet. The breath samples were introduced to the CC>2 monitor via a tube connected to the
vent port of the breath inlet device.
Breath Canister Samples
During several of the exposure experiments, breath samples were collected along with the
breath analyzer measurements using evacuated SilcoSteel® passivated 1-L stainless steel
canisters. Each sample was collected first in a 20-L Teflon bag that was attached to the outlet of
the dry gas meter. Once filled, the bag was removed from the system, attached via a short length
of Teflon tubing to an evacuated canister, and the sample was vacuum-extracted into the canister.
A label was attached to each canister recording subject identification, site location, date, start and
stop times, and miscellaneous information.
A Fisons MD 800 GC, equipped with a flame ionization detector (FID) and mass
spectrometer (MS) in parallel, was used for the analysis of the target compounds present in the
canister samples. The GC is connected to a Nutech 3500 pre-concentrator that contains a
cryogenic pre-concentration trap. The trap is a 0.32 cm by 20 cm coiled stainless steel tube
packed with 60/80 mesh glass beads. The trap is cooled to -185°C for sample collection and
12
-------
heated to 120°C during sample desorption. A six-port valve is used to control sample collection
and injection. The Nutech 3500 is also equipped with an autosampler so that up to 16 canister
samples can be analyzed in an automated fashion. Analytes are chromatographically resolved on
a Restek RTX-1, 60 m by 0.5 mm i.d. fused silica capillary column (1 |im film thickness).
Optimal analytical results are achieved by temperature programming the GC oven from -50°C to
220°C at 8°/min. The column exit flow is split to direct one-third of the flow to the MS and the
remaining flow passes through the FID. The mass spectrometer is operated in the full scan mode
so that all masses are scanned between 30 and 300 amu at a rate of 1 scan per 0.4 seconds.
Identification of VOCs is performed by matching the mass spectra acquired from the
sample to the mass spectral library from the National Institute of Standards and Technology
(NIST). The sample volume is 90 mL. With this sample volume, the MS detection limit is 0.05
ppb (full scan mode). Quantification of all identified peaks is based upon instrument response to
known concentrations from a dilute calibration gas containing the target compounds (traceable to
NIST calibration cylinders whenever possible).
Instrument calibrations were checked by first dynamically diluting a standard 6-
component cylinder (LL17298), which contains the target chemicals MTBE, MTBE-di2, and
DBCM, as well as chloroform, benzene, and 2-methyl-2-propanol. From the known
concentrations of these compounds in the cylinder (8-13 ppbv), we were able to generate average
response factors. The cylinders that were taken to the field for the exposure study were similarly
diluted, and the concentrations determined by GC/MS, based on the measured concentrations of
the components in standard cylinder LL 17298. These values were checked, in turn, by applying
the generated response factor for MTBE to the measurement of the concentration of MTBE in a
Scott Specialty Gas MTBE Certified Standard. Our measured values of 54.25 ppbv and 52.67
ppbv divided by the dilution factor of 0.0495 gave an estimated cylinder concentration of 1,080
ppbv versus a certified value of 1,030 ppbv. This agreement is regarded as satisfactory and
allowed us to use the generated response factors to determine concentrations of the target
compounds in the exposure experiments.
Water Samples
During each dermal exposure experiment, three samples each of the shower or bathtub
water were collected, using glass vials sealed with aluminum caps and fitted with Teflon-faced
septa. The samples were taken at the start of the sequence, midway through the exposure period,
and at the end of the exposure period. Twenty mL of the water sample were transferred to a 40
mL gas bubbling vessel using a disposable 20 mL pipette. The water sample was purged with
helium gas at 150 mL/min for 10 minutes at room temperature. One drop of antifoaming
solution (Dow Corning Antifoama 1510-US, Midland, MI) was added to the 200 mL urine
sample to prevent foaming during purging. The samples were analyzed by GC/MS.40
GC/MS Analysis
Target compounds were analyzed and quantified using a gas chromatograph (Hewlett
Packard 5890) coupled to a quadrupole mass spectrometer (Hewlett Packard 5971A Mass
13
-------
Selective Detector). Analytes were stripped from the Tenax trap and transferred to the GC/MS
system by thermal desorption (Perkin-Elmer, Inc, Model ATD-400). A 60 m, 5% diphenyl-95%
dimethyl polysiloxane capillary column (DB-5, 0.25 mm ID, 1 jim film thickness; J & W
Scientific, Folsom, CA) was used.
The GC temperature conditions were: injector 250° C; oven held at 35°C for 8 min, then
ramped at 10°/min to 170°C, ramped at 50°/minto 220°C, and held for 5 min. The target ions
for deuterated MTBE and TEA were m/e = 82 and 68, respectively, and their retention times
were 9.5 and 7.9 minutes, respectively. Ion intensity-area data were used to determine relative
response factors (RRF) for the compounds on each day the instrument was operated. This was
accomplished by injecting bromofluorobenzene (BFB) and 13C-benzene, using amounts similar
to those obtained from the purged samples.
The detection limit (DL) for each compound in the blood and urine samples was
determined by estimating the standard deviation of the blank (OB) and the level of the analytical
noise (VB). The standard error of the regression line was used as an estimated standard deviation
of the blank, and the intercept of the regression line was used as an estimate of the analytical
noise. The method detection limit (MDL) were calculated from
where OB = standard error of the regression line; ye = intercept of the regression line; andyDL =
signal level. When^ =yoi, DL has the value of x.
Skin Blood Flow Measurements
Our earlier work on the dermal absorption of chloroform suggested that water
temperature had a powerful effect on dermal absorption, with about a 30-fold increase in
absorbed chloroform resulting from a 10°C increase in bathwater temperature.21 This finding
was attributed to increased blood flow to the skin at the higher temperatures.
To further examine this effect, we used a Lisca PEVIII Laser Doppler Perfusion Imager to
make blood flow measurements and determine the relative change in skin perfusion near the skin
surface as a function of bathwater temperature. In this device, a low power solid state laser beam
successively scans the tissue of interest, recording several thousand measurement points. In the
tissue, the laser beam is scattered by reflective components within the tissue. A portion of the
light is reflected back onto a photodetector inside the device. Generally, this received light will
have been reflected many times by stationary structures within the tissue as well as by moving
particles (mainly red blood cells) within the tissue. This is the moving Doppler effect. The
received signal spectrum is processed in the monitor using algorithms applicable to this type of
reflective environment to calculate volume flow of tissue (in mL/min/gm tissue sampled).
To maximize the potential change with temperature, Lisca recommended that
measurements be confined to areas of the body with many blood vessels near the surface of the
skin, such as the upper shoulder area or the upper portions of the index and middle fingers on the
14
-------
hand. Because of the crowded conditions in which the tub experiments were conducted at
EOHSI, we chose the finger option. In setting up the data collection with the Laser Doppler
Imager, we found that the technique displays a great deal of inherent variability, even at the same
temperature. Consequently, in an effort to obtain reasonably reproducible baseline data,
measurements were limited to only one hand of a single subject.
Measurements were made using a regular bucket filled with water. The sensor (laser)
head was kept at a uniform distance from the fingers (15 cm) for each run. The entire hand was
submerged the same distance beneath the surface of the water (~2 cm), with the hand resting on
top of a submerged bottle near the top of the bucket, thus allowing the bulk of the water in the
bucket to act as a temperature reservoir. A dark cloth was placed beneath the hand to prevent
laser light reflections back into the detector, which would have given false high perfusion
readings. It was found that, to obtain the most reliable perfusion measurements, it was necessary
to allow a warming or cooling period for the hand, which typically took several minutes.
Multiple measurements were made over the range from 0°C to about 50°C.
Questionnaire
A brief questionnaire (shown in Appendix A) was administered to each participant to
assess the participant's potential exposure to MTBE and DBCM during the previous 24 hours.
Data Analysis
The shapes of the uptake and decay curves for MTBE-di2 and DBCM from dermal
absorption while bathing are similar to those observed in our earlier work on the dermal
absorption of chloroform while bathing.21 We, therefore, carried out the same analysis on the
data from this study as we did previously on the chloroform data.
Briefly, to estimate the total exhaled dose and obtain kinetics information, we used the
linear compartment model, developed by Wallace et al.,41 with an extension to the case of dermal
exposure.2 The one-compartment model treats the body as a single compartment, which is exposed
to a constant concentration of the contaminant in water. A very simple way to view the stratum
corneum is to regard it as a membrane of infinitesimal thickness, whose only function is to impede
the entry of the contaminant into the blood for a certain lag time T.
Total Exhaled Dose
The total exhaled dose is obtained by multiplying the sum of the areas under the exhaled
breath uptake and decay curves by the alveolar ventilation rate.
For the situation in which an exposure occurs to a constant concentration of the
contaminant in water, Cwater, as depicted in Figure 4-4, the uptake in the case of a single
compartment is given by21
15
-------
o
c"
o
ro
o
c
o
O
ro
0)
m
Elimination
T
T.
expo
Time, t
Figure 4-4. Plot showing rapid increase in alveolar breath concentration
Caiv as a result of step function exposure to a constant water
concentration Cwater, followed by a rapid decrease in breath
concentration as a result of exposure to clean air. T is the lag
time, i.e., the time to the first measurable increase in the
breath concentration; T^o is the time at the end of exposure.
(0T\
V ^ J /
(4-2)
where Caiv = exhaled alveolar breath concentration of the component; Cwater is the contaminant
concentration in the water; /' is a constant relating the final equilibrium concentration in the breath
to the concentration in the water; Uptake is the effective (uptake) residence time of the chemical in
the body; T is the lag time; and t is the time from the start of the exposure. The residence time
tuptake is expected to be affected somewhat by the fact that, in reality, the blood is not experiencing a
constant exposure but rather a rapidly increasing exposure for a short period immediately after the
first measurable increase. Thus, Uptake will probably be somewhat larger than the true residence
time r. The uptake model has three parameters to be determined from the data: /', T, and Tuptake-
During the decay phase, the breath concentration declines exponentially:
^alv J '^ water ~"~ ^Q
'decay
(4-3)
16
-------
where t is the time measured from when exposure ends; A is the breath concentration when
exposure ends; and Tdecay is the effective residence time in the body during decay. Tdecay is again
expected to be affected somewhat (i.e., increased over the true residence time T) by the fact that the
exposure experienced by the blood does not drop immediately to zero but falls off at a certain rate
determined by the characteristics of the stratum corneum. If exposure has lasted long enough to
reach equilibrium, then the value of^4 should be given by/' • Cwc
water-
The two-compartment model assumes a single metabolizing compartment and a second
compartment, generally considered to be the organs or blood vessel-rich tissues.41 Again, the
solution to continued exposure at a constant concentration is given by an initial period of zero breath
concentration followed by a period of increasing concentration toward an asymptote:
Calv = 0 (0 < t < T) (4-4)
Calv = f-Cmter + A^^"** + A2e-(t-T)/T^ (t > T) (4-5)
where Aj, A2 are lumped combinations of physiological parameters associated with the first and
second body compartments; and Tiuptake, ^uptake are the effective (uptake) residence times of the
chemical in the first and second body compartments. This model has six parameters:/', T, A], A2,
The decay phase for the two-compartment model is given by:
Calv =Ale~t/Tl^+A2e~t/T2d^ (4-6)
Again, if near-equilibrium has been reached, then^j + ^2 =/' • Cwater-
For the one-compartment case, the area under the uptake curve, AUCuptake, is given by:
AUCuptake=\Calvdt
0
^ exp o ,
= 4 ](i-e-(t-T]lT^dt
[/ \ ~l
_|T _r |/r
T7 _i_ —. ^, \Jexpo J II ^uptake. T"7 _
Jexpo ^ Luptake^ L Luptake \
A [y yj .4^ (1 p~Vex.yo~T I l?uptake J
1 \ exp o / 1 uptake \ /
If, now, we set T= 0, it follows that
17
-------
AUCuptake =4-4v-e~exVafe (4-8)
In practice, AUCuptake is estimated by integrating under the exponentially increasing curve used to
model the dati
Chicago, IL).
model the data, i.e.,^ = a(\ - e" x\ using the trapezoidal rule in SigmaPlot (Version 8.0, SPSS,
For the post-exposure decay period, the fraction/' • Cwater of the inhaled air concentration
of the chemical that is exhaled, is zero during elimination. If we assume that time t = 0 refers to
the start of the post-exposure phase and the upper time limit t = °°, it follows then from Equation
(4-3) that the area under the decay curve is given by:42
AUCdecay=\Calvdt
decay
Thus, AUC'decay may be estimated in practice from the best-fit parameters obtained from the
exponentially decreasing multi-compartment curve used to model the decay data, i.e., y = Ea;e" x.
For the one-compartment case, the total area under the uptake and decay curves, AUCtotai,
is given by:
AUCtotal = AUCuptake + AUCdeccy (4-10)
and the total exhaled dose, or "unmetabolized mass",42'43'44 (i.e., total amount (jig) exhaled
during uptake and decay) is given by:
Total Exhaled Dose (" Unmetabolized Mass") = A UCtotal .A VR (4-11)
where AVR = alveolar ventilation concentration (L/min).
Empirical Modeling of Uptake and Decay Breath Concentrations
The linear multicompartment model has the following solution for the uptake phase:41
C = f'-C y« (l-e tlTi"!"ak\ (4-12")
^alv J "- water Z-l >\ I ^ '
18
-------
where: Caiv = exhaled breath concentration of the component; at = capacity of the f
compartment at equilibrium (Ea; = 1); t = time from the onset of exposure; and 7J uptake = uptake
residence time of the chemical in the ith compartment.
The fraction/' of the compound exhaled unchanged at equilibrium, i.e., when t = °o3
follows from Equation (4-12) as:
— (4-13)
' water / j
During the post-exposure decay phase, the concentration declines exponentially:
^r|*- (4-14)
where, now, t is measured from the time exposure ends. In the experiment conducted here, the
water concentration Cwater was zero at the end of the exposure period, i.e.,/' • Cwater = 0. In
Equation (4-14), the first exponential term (compartment) is generally associated with blood, the
second with "highly perfused tissues," the third with "moderately perfused tissues," and the
fourth with "poorly perfused tissues." For a broad range of VOCs, it has been found that the
residence times for these compartments are roughly similar, namely, 3-1 1 min for the first
compartment, 0.4-1 .6 h for the second, 3-8 h for the third, and several days for the fourth
compartment.45 For the exposure times used in the present study, we apply a two-compartment
decay model to evaluate the contributions to the breath levels during the decay period.
The residence time is defined as the time it takes for the compound to decay to lie of its
initial concentration in the compartment, assuming all other compartments are at zero
concentration. The biological half-life ty2 of the compound in the body is related to the residence
time rthrough the relation:
T=tyj\n2 (4-15)
All of the parameters in Equations (4-12) and (4-14) are determined empirically by fitting
the background-corrected breath data using a nonlinear regression technique (SigmaPlot Version
8.0, SPSS Inc., Chicago, IL).
Quality Control
Two types of samples were collected in this study: exhaled breath (continuous real-time
and discrete) and water. Continuous breath samples were collected and analyzed simultaneously
using the real-time breath analyzer; discrete whole-breath samples were collected in stainless
steel canisters and analyzed by cryogenic preconcentration followed by GC/MS, using a
modified U.S. EPA Method TO-14.39 For these analyses, calibration curves were first prepared
from at least four standards. The curves are checked on a daily basis, using a standard prepared
19
-------
separately from the calibration standard. The tune settings on the analytical mass spectrometer
were verified daily. Holding times for the air samples were less than one week. Laboratory
blanks were analyzed on a regular basis. Reproducibility was estimated from duplicate analyses.
The instrument minimum detection limits were determined from multipoint calibrations.
Exhaled Breath
The 3DQ ion trap mass calibration was established and checked each day, using routine
operating procedures and internal 3DQ software designed for that purpose. Specific 3DQ
operating parameters and diagnostic checks were also evaluated daily.
Calibration of response of the real-time breath analyzer to the target breath components
was performed, as described earlier (cf Chapter 4, Breath Measurements), using gas standards
prepared in cylinders. Samples of the cylinder contents were collected in canisters and analyzed
using GC/MS. The concentrations of the MTBE, MTBE-di2, DBCM, tert-butyl alcohol (TEA),
and benzene in the canister samples were determined using a dynamic dilution of a
gravimetrically-prepared in-house standard (Battelle standard LL-17298). This calibration
mixture contains MTBE, MTBE-di2, DBCM, trichloromethane, TEA, and benzene prepared at
ppbv levels in nitrogen. Table 4-3 lists the target compounds and their concentrations in the
standard. These concentrations were derived from a knowledge of the original amount injected
and the pressure of the cylinder. The MTBE concentration was validated by analyzing a certified
reference gas (Scott Specialty Gas), which was also dynamically diluted under the same
conditions as the calibration standards.
Table 4-3. Battelle standard containing the target
compounds, trichloromethane, and benzene in nitrogen.
„ , Concentration
Compound , , ,
(ppbv)
MTBE 9.31
MTBE-d12 8.17
DBCM 12.9
Trichloromethane, CHC13 14.0
TEA 11.6
Benzene, C6H6 12.5
The accuracy of the Battelle standard LL-17298 was assessed, in turn, by analyzing
standard LL-17305 and the MTBE certified reference gas. Using the automated GC/MS system
described earlier, the resulting peak areas were used to quantify the target compounds in the
MTBE reference gas and Battelle standard. Then, the concentrations of MTBE, trichloro-
methane, and benzene in the standards were calculated from the peak areas using the average
20
-------
Table 4-4. Comparison of measured and certified concentrations of MTBE in
certified reference standard, and chloroform and benzene in NIST SRM 1804a.
Compound
MTBE
Chloroform
Benzene
Certified
Concentration
(ppbv)
51.0a
16.9b
14.8b
Measured
Concentration*
(ppbv)
53.5±1.1
16.6 ±0.6
15.6±0.8
% Difference
4.9
1.8
5.4
a Certified reference gas (Scott Specialty Gas).
b With respect to Battelle LL-17298 standard.
response factor (concentration/average peak area) obtained from Battelle standard LL-17298.
Table 4-4 compares the certified and measured concentrations for the Battelle in-house and
certified standards. These results indicate that the values obtained for the concentrations of
MTBE, chloroform, and benzene in Battelle standard LI-17298 are reliable.
The calibration standard for the real-time breath analyzer was prepared in-house by static
dilution in a 15.7 L cylinder. To prepare the standard, an intermediate standard consisting of 360
|lL of pure DBCM (Aldrich, 98% purity) was diluted to a final 2.0 mL volume with methanol.
To prepare the 3DQ calibration standard, 1.2 |iL of the intermediate standard and 0.6 |iL of pure
MTBE-di2 (C/D/N Isotopes, >99.8% atom % D) were injected into a 15.7 L cylinder through a
heated syringe injection port attached to the cylinder. The cylinder then was pressurized to 1,000
psig using medical grade breathing air (Praxair). A canister sample was collected and analyzed
in duplicate using the modified EPA TO-14 method and the automated GC/MSD/FID system
described earlier. The measured FID peak areas were used to quantify the MTBE-di2 and
DBCM in the sample. Then, as before, the concentrations of MTBE-di2 and DBCM in the
canister were calculated from the FID peak area using the average response factor
(concentration/average peak area) obtained from Battelle standard LL-17298. The concentration
of MTBE-di2 estimated in this way was 119.7 ppbv compared with the concentration injected,
viz., 100.0 ppbv, which represents a 19.7 percent difference. The concentration of DBCM
estimated in this way was 53.9 ppbv compared with the concentration injected, viz., 57.3 ppbv,
which represents a 5.9 percent difference. The good agreement obtained between the measured
and injected concentrations validates the accuracy of the spiking method, which has been used
extensively in our laboratory.34 The concentrations of MTBE-di2 and DBCM injected into the
cylinder (100.0 and 57.3 ppbv, respectively) and the average MTBE-di2 and DBCM peak areas
obtained for the canister sample were used to quantify the concentrations of MTBE-di2 and
DBCM in the breath sample data acquired continuously with the real-time breath analyzer. We
were unable to calibrate the breath analyzer for the target compound TEA because of its apparent
adsorption onto the inner surfaces of the ion trap. Consequently, the cylinders were only used to
calibrate the instrument for MTBE-di2 and DBCM.
21
-------
Water
Quality control measures undertaken for the collection and analysis of the water samples
included the following:
• All glassware used was first cleaned with 10% HC1 and rinsed with de-ionized water,
then baked at 300°C for 12 h before use.
• Soon after collection, all water samples were stored in a cold room at 4°C until analysis.
• Before purging a sample, helium gas was sparged through the entire system for 5 minutes
to remove any MTBE contamination. In addition, to avoid DBCM contamination, the
Tygon tubing connecting the purge vessel to the trap was replaced between samples.
• The operation and performance status of the GC/MS system was checked daily by
analyzing 50 ng of BFB (bromofluorobenzene) and 31.6 ng of 13C-benzene standards.
• Blank traps were checked for contamination by GC/MS before use in the purge-and-trap
analysis. These blank traps were analyzed with each set of samples to ensure that neither
the traps nor the analytical system were contaminated.
• External QC standards were prepared on Tenax traps by directly injecting the BFB/-
benzene standard into a flash evaporator and flushing the vapors onto the trap with zero-
grade nitrogen. The QC standards were analyzed after every sixth sample to verify the
stability of the GC/MS response.
22
-------
Chapter 5
Results
Experiments at EOHSI
Shower Exposures
A number of unforeseen problems were encountered while attempting to conduct the
shower experiments at EOHSI. Initially, difficulties were experienced with the temperature of
the hot water flow into the shower unit; the highest water temperature attainable was ~36°C,
about 4°C less than desired. After this problem was resolved and we were able to maintain a
water temperature of 40°C, the syringe-drive unit used to inject the MTBE-di2 and DBCM
mixture into the shower stream malfunctioned. This unit was replaced with a second syringe-
drive unit, which also proved to be unsatisfactory. The problems were compounded by the fact
that the bathroom in which the experiments were conducted was unventilated and had no
temperature control. Heat emitted by the real-time breath analyzer and associated equipment
during the day, along with the natural heat from the operators and subjects in the room, caused
the mass scale of the ITMS to drift in an unpredictable fashion, necessitating frequent
recalibrations.
The shower experiments that were conducted (see Table 4-1) with the breath analyzer to
measure uptake of MTBE-di2 and DBCM showed almost no change in breath concentration from
pre-exposure levels throughout the 30-minute exposure period, even at the highest temperature
used, i.e., 40°C. Because these experiments showed no measurable effects, we decided to curtail
further shower exposure runs and concentrate instead on the bathtub exposures.
Bathtub Exposures at EOHSI
To confirm that this minimal amount of dermal absorption observed in the shower
experiments was real, we switched activities from the shower facility to the bathtub unit. This
was based on the results of our earlier shower and bathtub experiments conducted with
9 1 Af\
chloroform, ' which indicated that exposure to compounds in tub water at 40°C would be more
likely to register measurable changes in breath concentration than in shower water. To avoid the
earlier problems experienced with the syringe-drive units, the MTBE-di2/DBCM mixture was
spiked directly into the water in the tub and mixed gently by hand. In all, five experiments were
run at 40°C with nominal concentrations of 150 |ig/L MTBE-di2 and 40 |ig/L DBCM in the tub
water. Of these, three (Subjects TF02, TM04, and TM05) were run using only the breath
analyzer to monitor exhaled breath levels and two (Subjects TF06 and TF07) were run using the
breath analyzer along with evacuated canisters to collect whole-breath samples from the outlet to
23
-------
the dry gas meter, as described above. The canister samples were returned to Battelle for
analysis. In one of these cases (TF06), actively-pumped Tenax sorbent tube samples were also
collected for comparison with the results from the canister samples. The Tenax samples were
subsequently analyzed at EOHSI.
Figure 5-1 compares the exhaled breath concentrations for MTBE-di2 and DBCM for
Subject TF06, obtained using evacuated canisters and Tenax sorbent tubes for sample collection,
^—^
"E
B>
o
15
01
o
o
O
t-
m
CM
•°
HI
00
H
rT~
E
zL
C
O
15
01
o
o
O
:
0 10 20 30 40
Time (min)
20
18
16
14
12
10
8
6
4
2
DBCM: Subject TF06
•
er Samples
Samples
-
_
-
_
•
-
i
50 6
:
__ Exposure ^ __ Post-Exposure _j
.
• ^ Canis
• Tena>
"
B ^ B
_
+
_
^^
- ^r
0, )....•
oy
0 10 20 30 40
Time (min)
-
-
:er Samples J
Samples -
"
•
;
J
\
m ':
-_
:
•
"
-
50 6
Figure 5-1. Exhaled breath concentrations of MTBE-di2 and DBCM as a function of time for
Subject TF06 during and following dermal exposure while bathing. Upper plot:
MTBE-dn data from canister and Tenax sorbent samples collected from real-time
breath analyzer system; lower plot: DBCM data from canister and Tenax sorbent
samples collected from real-time breath analyzer system. All samples analyzed by
GC/MS. Nominal water concentration was 150 ug/L for MTBE-di2 and 40 ug/L for
DBCM; water temperature was 40°C.
24
-------
«
E
"S
•M»
C
O
2
4-1
C
0
o
O
.E
4-1
ro
m
^t
22
20
IB
16
14
12
10
8
6
4
4
2
n
: Canister Samples: Subject TM07 :
I_ Exposure Post-Exposure ,J
| \
: ^ M
: • D
- •
1- • -
•
'- +
^ *
L 4 *
- ^
: B
TBE-d., :
12 _
BCM :
-
-
-
-
i
-_
"-i
•I
*^
-
10 20 30 40
Time (min)
50
60
Figure 5-2. Exhaled breath concentrations of MTBE-di2 and DBCM as a function of time for
Subject TM07 during and following dermal exposure while bathing. Data obtained
from canister samples collected from real-time breath analyzer system. All samples
analyzed by GC/MS. Nominal water concentration was 150 jig/L for MTBE-di2 and
40 jig/L for DBCM; water temperature was 40°C.
followed by GC/MS analysis. Overall, the agreement between the data obtained with the
canisters and the Tenax sorbent tubes is good, considering the very low concentrations involved
in the measurements. The data indicate that the breath MTBE-di2 and DBCM concentrations
increase with exposure duration, reaching maximum levels of 11 — 12 |ig/m3 in the case of
MTBE-di2, and 16 — 17 |ig/m3 in the case of DBCM, after -30 minutes exposure by dermal
absorption. Under the conditions which prevailed in the room in which the experiments were
conducted, these low levels were below the limit of detection of the real-time breath analyzer,
viz., -19 |ig/m3 for MTBE, -21 |ig/m3 for MTBE-di2, and -82 |ig/m3 for DBCM. These levels
are also much lower than the 55 — 70 ug/m3 maximum values that we observed for dermal
9 1
uptake of chloroform in our earlier bathtub study. Although the samples were examined for the
tertiary butyl alcohol (TBA-dio) metabolite of MTBE-di2, it was not observed in any of these
samples.
Figure 5-2 presents the breath concentrations for MTBE-di2 and DBCM for Subject
TM07 obtained using evacuated canisters. Here again, we see that the breath MTBE-di2 levels
increase with exposure, reaching a maximum of about 7 |ig/m3 before decreasing once the
subject stepped out of the bathtub and exposure ended. The data for DBCM do not show the
same trend, largely because of the high levels measured at the beginning of the exposure
sequence, at t = 0 min and after 10 min exposure. These high values may be due to the presence
of a contaminant with the same positive ion mass as that used to monitor DBCM, or it may be
25
-------
the result of inadvertent exposure to DBCM from a drinking water source prior to arriving at the
laboratory.
Skin Blood Flow Measurements at EOHSI
A large number of skin blood flow measurements were made at EOHSI with the Lisca
PEVIII Laser Doppler Perfusion Imager, using the upper portions of the first two fingers on the
hand of a subject. This is an area of the body known to have a large number of blood vessels
near the surface of the skin. About 70 measurements were taken from the one hand of the
subject over a temperature range from 0°C to about 47°C. For comparison, several
measurements were made on the first two fingers on the hand of a second subject. Both sets of
results are presented in Figure 5-3.
2.00
o
c
o
'in
•g
o
0.
c
CC
0)
0.00
10
20
30
40
50
Water Temperature (°C)
Figure 5-3. Mean perfusion of surface of first two fingers on hands of two male
subjects as a function of temperature.
The plots in Figure 5-3 suggest that perfusion, under these experimental conditions, is a
relatively simple exponential function of temperature and increases by about a factor of 7 as the
temperature increases from 0°C to ~47°C.
Experiments at Battelle
Because of the difficulties experienced in conducting the dermal exposure measurements
at EOHSI, arrangements were made to carry out a few more experiments in our laboratory at
Battelle. These experiments were limited to measurements in real time of exhaled breath levels
26
-------
of MTBE-di2 and DBCM along with the simultaneous collection in each case, except one, of a
total of six whole-breath canister samples for independent analysis by GC/MS.
The breath concentration/time profiles obtained in this way for the BCO subjects (at
Battelle) listed in Table 4-1 are presented in Figures 5-4 through 5-7 for MTBE-di2 and DBCM,
and in Figure 5-8 for MTBE and DBCM. Under the controlled conditions that prevailed in the
laboratory while these experiments were being conducted, the detection limits with the real-time
breath analyzer were ~4 |ig/m3 for MTBE-di2 and -13 |ig/m3 for DBCM; with the canisters, the
detection limits were -0.4 |ig/m3 for MTBE-di2 and -2 |ig/m3 for DBCM.
Total Exhaled Dose
The total exhaled dose of MTBE-di2 (or MTBE) to each subject was estimated, as
indicated earlier, by multiplying the sum of the areas under the exhaled breath uptake and decay
curves by the alveolar ventilation rate. Results are summarized for the five subjects in Table 5-1.
The total amount of MTBE exhaled varied from 1.94 to 5.16 jig, averaging 3.22 ± 1.23
jig at 39.5 ± 0.6°C [mean ± standard deviation (SD)]. This mean value is approximately half of
the total exhaled dose we obtained in our earlier study of dermal exposure to chloroform,21
despite the fact that the current investigation was conducted at a higher concentration (150 |ig/L
MTBE nominal vs. 85.8 |ig/L chloroform measured) and exposure occurred for a longer period
(32.5 min MTBE vs. 27.4 min chloroform). Furthermore, the average maximum observed breath
concentration in the chloroform study21 was significantly higher than the corresponding MTBE
concentration in the present study (44.9 ±15.3 |ig/m3 chloroform vs. 13 ± 4 |ig/m3 MTBE). The
results suggest that the uptake of MTBE by dermal absorption from bath water is much lower
than that of chloroform, under similar conditions.
Because of the lack of agreement observed in Figure 5-4 through 5-8 between the canister
and breath analyzer data for DBCM, together with the large scatter in the data for DBCM, no
attempt was made to determine the total exhaled dose for this chemical from these results.
Empirical Modeling of Uptake and Decay Breath Concentrations
The linear compartment model developed by Wallace et al.41 was used to model the
MTBE uptake and decay concentrations in the breath of the participants. The one-compartment
model, from Equations 4-12 and 4-14, for the uptake and decay phases, respectively, was fitted
to the observed uptake and decay data for all five subjects. Curve fitting to estimate the
coefficients in the equations was accomplished using SigmaPlot. The resulting curves for
MTBE-di2 and MTBE are shown in Figures 5-9 to 5-16, and 5-17 to 5-18, respectively. Values
obtained for/', ^uptake, and Tdecay are presented in Table 5-2. Application of a two-compartment
model to the decay data resulted in all cases in parameters strongly dependent on one another,
27
-------
-- 30
MTBE-d12: Subject BCOM1T
Canister - GC/MS
Real-Time Breath Analyzer (RTBA)
RTBA
LOD
10
20
30 40
Time (min)
50
60
160 :
DBCM: Subject BCOM1T
Canister - GC/MS
Real-Time Breath Analyzer (RTBA)
RTBA
LOD
10
20
30 40
Time (min)
50
60
Figure 5-4. Continuous exhaled breath concentrations for MTBE-di2 (upper plot) and DBCM
(lower plot) as a function of time for Subject BCOM1T during and following dermal
exposure while bathing. Exposure duration was 34.1 min; post-exposure monitoring
continued for another 31.0 min. Water temperature was 39.7°C. Nominal concentra-
tions were 150 jig/L for MTBE-d12 and 40 ug/L for DBCM. RTBA LOD designates
detection limit with real-time breath analyzer.
28
-------
O)
o
'^
re
o>
o
o
O
re
2
m
HI
m
MTBE-d,,: Subject BCOF1T
Canister - GC/MS
Real-Time Breath Analyzer (RTBA)
60
o>
o
+«i
re
o>
o
c
o
O
re
o>
CO
O
m
Q
RTBA
LOD
10
20 30 40
Time (min)
50
60
DBCM: Subject BCOF1T
Canister - GC/MS
Real-Time Breath Analyzer (RTBA)
RTBA
LOD
10
20
30 40
Time (min)
50
60
Figure 5-5. Continuous exhaled breath concentrations for MTBE-di2 (upper plot) and DBCM
(lower plot) as a function of time for Subject BCOF1T during and following dermal
exposure while bathing. Exposure duration was 33.0 min; post-exposure monitoring
continued for another 33.1 min. Water temperature was 39.0°C. Nominal concentra-
tions were 150 ug/L for MTBE-d12 and 40 jig/L for DBCM. RTBA LOD designates
detection limit with real-time breath analyzer.
29
-------
Canister - GC/MS
Real-Time Breath Analyzer (RTBA)
RTBA
LOD
10
20
30 40
Time (min)
50
60
100
90
DBCM: Subject BCOM2T
O
00
20
10
Canister -GC/MS
Real-Time Breath Analyzer (RTBA)
RTBA
LOD
10 20 30 40
Time (min)
50
60
Figure 5-6. Continuous exhaled breath concentrations for MTBE-di2 (upper plot) and DBCM
(lower plot) as a function of time for Subject BCOM2T during and following dermal
exposure while bathing. Exposure duration was 33.1 min; post-exposure monitoring
continued for another 31.0 min. Water temperature was 38.8°C. Nominal concentra-
tions were 150 ug/L for MTBE-d12 and 40 jig/L for DBCM. RTBA LOD designates
detection limit with real-time breath analyzer.
30
-------
O)
o
'•^
re
o>
o
c
o
O
re
2
m
24
22
20
18
16
14
12
10
UJ
co
o>
c
o
+«i
re
o>
o
c
o
O
re
o>
m
o
m
a
?! 6
MTBE-d12: Subject BCOF2T
90
80
70
60
Exposure
Post-Exposure
Canister -GC/MS
Real-Time Breath Analyzer (RTBA)
RTBA
LOD
10 20 30 40
Time (min)
50
60
DBCM: Subject BCOF2T
Exposure
Post-Exposure
Canister -GC/MS
Real-Time Breath Analyzer (RTBA)
RTBA
LOD
10
20
30 40
Time (min)
50
60
Figure 5-7. Continuous exhaled breath concentrations for MTBE-di2 (upper plot) and DBCM
(lower plot) as a function of time for Subject BCOF2T during and following dermal
exposure while bathing. Exposure duration was 33.0 min; post-exposure monitoring
continued for another 29.5 min. Water temperature was 39.8°C. Nominal concentra-
tions were 150 ug/L for MTBE-d12 and 40 jig/L for DBCM. RTBA LOD designates
detection limit with real-time breath analyzer.
-------
O)
20
18
16
14
re
I 12
o>
o
c
o
O
10
8
re
£ 6
m
m .
m 4
i-
S 2
re
o>
m
O
m
a
MTBE: Subject BCOM3T
Exposure
Post-Exposure
Canister - GC/MS
Real-Time Breath Analyzer (RTBA)
RTBA
LOD
10 20 30 40
Time (min)
50
60
50
45
40
35
o>
c
o
'^
re
*; so
o>
o
c
o
O
25
20
AT
15
10
5
DBCM: Subject BCOM3T
Exposure
Post-Exposure
Canister - GC/MS
Real-Time Breath Analyzer (RTBA)
RTBA
LOD
10 20 30 40
Time (min)
50
60
Figure 5-8. Continuous exhaled breath concentrations for MTBE (upper plot) and DBCM (lower
plot) as a function of time for Subject BCOM3T during and following dermal exposure
while bathing. Exposure duration was 29.5 min; post-exposure monitoring continued
for another 30.4 min. Water temperature was 40.4°C. Nominal concentrations were
150 ug/L for MTBE and 40 jig/L for DBCM. RTBA LOD designates detection limit
with real-time breath analyzer.
32
-------
Table 5-1. Total exhaled dose of MTBE-dn or MTBE as a result of dermal absorption in bath water.
Parameter
Target Analyte
Nominal Water Concentration, Cwater (jig/L)
Water Temperature (°C)
Total Exposure Time (Uptake Period), Tuptake (min)
Total Elimination Time Monitored, Tdecay (min)
Total (Uptake + Decay) Exhaled Air Volume (m3)
Overall Ventilation Rate (L/min)
Alveolar Ventilation Rate, ,4 FT? (L/min)a
Subj.
BCOM1T
MTBE-d12
150
39.7
34.1
31.0
0.593
9.11
6.10
Total Amount
Area Under Uptake Curve (|ig.min/m3)b 358
Total Amount Exhaled During Uptake (ug)
Area Under Decay Curve Over Monitored Period
((ig.min/m3)0
Normalized Area Under Decay Curve (|ig.min/m3)d
Total Amount Exhaled During Decay (jig)
2.18
Total Amount
404
391
2.38
Subj. Subj.
BCOF1T BCOM2T
MTBE-d12 MTBE-d12
150 150
39.0 38.8
33.0 33.1
33.1 31.0
0.531 0.648
8.03 10.11
5.38 6.77
Exhaled During Uptake
163 332
0.88 2.25
Exhaled During Decay
159 183
144 177
0.77 1.20
Subj.
BCOF2T
MTBE-d12
150
39.8
33.0
29.5
0.537
8.59
5.76
Period
210
1.21
Period
215
218
1.26
Subj.
BCOM3T
MTBE
150
40.4
29.5
30.4
0.590
9.85
6.60
194
1.28
205
202
1.33
Mean
—
150
39.5
32.5
31.0
0.580
9.14
6.12
251
1.56
233
226
1.39
Std Dev
—
0
0.6
1.8
1.3
0.048
0.86
0.58
88
0.62
98
96
0.60
Total Exhaled Dose
Total Amount Exhaled During Uptake + Decay (ug)
4.6
1.7 3.5
2.5
2.6
3.0
1.1
Alveolar ventilation rate assumed to be 67% of ventilation rate.
Determined from fitted uptake curve using trapezoidal macro in SigmaPlot 8.0 over total monitored exposure time.
Determined from fitted decay curve using trapezoidal macro in SigmaPlot 8.0 over total monitored decay time.
Area under decay curve normalized to 30.0 min.
33
-------
O)
o
s
•*•!
c
0)
o
c
o
o
30
25
20
15
re
S! 10
00 I
CM
•9"
MTBE-d12: Subject BCOM1T
Measured Breath Uptake
Modeled 1-Compartment Breath Uptake
10 20
Exposure Time (min)
30
Figure 5-9. Measured MTBE-di2 exhaled air exposure uptake plot for Subject BCOM1T
compared with modeled curve. Bath exposure details as described in Figure
5-4. Data smoothed using 155-s block averaging time.
O)
35
30
.2 25
n
o
o
c
o
O
n
o
m
CM
LJ
CO
20
15
10
MTBE-d12: Subject BCOM1T
Measured Breath Decay
Modeled 1-Compartment Breath Decay
10 20
Elimination Time (min)
30
Figure 5-10. Measured MTBE-di2 exhaled air exposure decay plot for Subject BCOM1T
compared with modeled curve. Bath exposure details as described in
Figure 5-4. Data smoothed using 155-s block averaging time.
34
-------
«"* 12
O)
c
O
'^
re
•4-i
0)
O
c
O
O
re
£
00
LLI
m
10
MTBE-d12: Subject BCOF1T
Measured Breath Uptake
Modeled 1-Compartment Breath Uptake
10 20
Exposure Time (min)
30
Figure 5-11. Measured MTBE-di2 exhaled air exposure decay plot for Subject BCOF1T
compared with modeled curve. Bath exposure details as described in Figure
5-5. Data smoothed using 5-point moving average.
O)
c
O
'^
re
12
10
c o
o>
o
o
O 6
re
o>
CO
•9
LJJ
m
MTBE-d12: Subject BCOF1T
Measured Breath Decay
Modeled 1-Compartment Breath Decay
10 20
Elimination Time (min)
30
Figure 5-12. Measured MTBE-di2 exhaled air exposure uptake plot for Subject BCOF1T
compared with modeled curve. Bath exposure details as described in Figure
5-5. Data smoothed using 5-point moving average.
35
-------
20
^" 18
^>
3 16
•^ 14
o
o
C
O
O
n
o
^
CD
T>
111
CD
12
10
MTBE-d12: Subject BCOM2T
Measured Breath Uptake
Modeled 1-Compartment Breath Uptake
10 20
Exposure Time (min)
30
Figure 5-13. Measured MTBE-di2 exhaled air exposure uptake plot for Subject BCOM2T
compared with modeled curve. Bath exposure details as described in Figure
5-6. Data smoothed using 5-point moving average.
O)
o
o
O
n
o
16
14
12
10
m
LJ
CO
4
2
0
MTBE-d12: Subject BCOM2T
Measured Breath Decay
Modeled 1-Compartment Breath Decay
10 20
Elimination Time (min)
30
Figure 5-14. Measured MTBE-di2 exhaled air exposure decay plot for Subject BCOM2T
compared with modeled curve. Bath exposure details as described in
Figure 5-6. Data smoothed using 5-point moving average.
36
-------
E
^>
E
O
^3
o
o
C
O
O
n
o
m
T>
111
CD
16
14
12
10
8
6
4
I
2
MTBE-d12: Subject BCOF2T
Measured Breath Uptake
Modeled 1-Compartment Breath Uptake
10 20
Exposure Time (min)
30
Figure 5-15. Measured MTBE-di2 exhaled air exposure uptake plot for Subject BCOF2T
compared with modeled curve. Bath exposure details as described in
Figure 5-7. Data smoothed using 5-point moving average.
O)
16
14
12
o
•+*
n
~ 10
o
o
C
O
O
n
o
m
LJ
OQ
MTBE-d12: Subject BCOF2T
Measured Breath Decay
Modeled 1-Compartment Breath Decay
10 20
Elimination Time (min)
30
Figure 5-16. Measured MTBE-di2 exhaled air exposure decay plot for Subject BCOF2T
compared with modeled curve. Bath exposure details as described in
Figure 5-7. Data smoothed using 5-point moving average.
37
-------
O)
16
14
12
~ 10
n
o
o
C
O
O
n
o
m
m
CD
MTBE: Subject BCOM3T
Measured Breath Uptake
Modeled 1-Compartment Breath Uptake
0
10
20
30
Exposure Time (min)
Figure 5-17. Measured MTBE exhaled air exposure uptake plot for Subject BCOM3T
compared with modeled curve. Bath exposure details as described in
Figure 5-8. Data smoothed using 5-point moving average.
O)
16
14
12
•2 10
n
o
o
C
O
O
n
o
m
LJ
m
0
MTBE: Subject BCOM3T
Measured Breath Decay
Modeled 1-Compartment Breath Decay
0
10
20
30
Elimination Time (min)
Figure 5-18. Measured MTBE exhaled air exposure decay plot for Subject BCOM3T
compared with modeled curve. Bath exposure details as described in
Figure 5-8. Data smoothed using 5-point moving average.
38
-------
Table 5-2. Theoretical calculations of MTBE model parameters.
Parameter
Target Analyte
Nominal Water Concentration, Cwater ((ig/L)
Exposure (Uptake) Time, T (min)
Alveolar Ventilation Rate, AYR (L/min)a
/'(xlO3)
Max. Breath Cone. (ng/L)
Uptakeb
Decay0
Residence Time (min)
Uptake, Tuptate
Decay, TdecqyC
Adjusted R2d
Uptake
Decay
Amount Exhaled During Uptake (ng-min/L)e
Amount Exhaled During Decay (ng-min/L)f
Normalized Mass Excreted (|ig)8
Subj.
BCOM1T
MTBE-d12
150
34.1
6.10
0.19
One-Compartment
26.2
19.0
30.2
38.3
0.424
0.884
358
728
6.5
Subj.
BCOF1T
MTBE-d12
150
33.0
5.38
0.06
Subj.
BCOM2T
MTBE-d12
150
33.1
6.77
0.08
Subj.
BCOF2T
MTBE-d12
150
33.0
5.76
0.12
Subj.
BCOM3T
MTBE
150
29.5
6.60
0.10
Mean
—
150
32.5
6.12
0.11
Std Dev
—
0
1.8
0.58
0.05
Model (Uptake and Decay)
7.4
6.7
11.8
45.7
0.701
0.814
162
306
2.4
11.9
12.6
5.2
4.8
0.433
0.858
332
60
2.6
18.9
8.9
37.5h
78.7
0.827
0.462
209
700
5.3
14.4
9.6
21.5
39.8
0.930
0.785
194
382
3.8
15.8
11.4
21.2'
41.5j
—
—
251
435
4.1
7.2
4.8
13.1'
26.3j
—
—
88
281
1.8
a Alveolar ventilation rate assumed to be 67% of ventilation rate.
b All subjects, except Subject BCOM1T, had highly significant (p <0.0001) values.
0 All subjects had highly significant (p <0.0001) values.
d Adjusted R2 is the adjusted coefficient of determination, which takes into account the number of independent variables.
e Calculated from Equation (4-8).
f Calculated from Equation (4-9).
8 Calculated using measured ventilation rates, adjusted for alveolar contribution. Predicted dose normalized to 30 minutes decay period.
h Subject had significant (p <0.005) value.
1 Mean ± SD = 25.3 ± 11.1 when Subject BCOM2T is excluded.
J Mean ± SD = 50.6 ± 19.0 when Subject BCOM2T is excluded.
39
-------
indicating that the two-exponent equation was "over-parameterized" and less suitable than the
single-exponent equation. The adjusted R2 values for the uptake data ranged from 42% to 93%; the
adjusted R2 values for the decay data were quite similar, ranging from 46% to 88%.
Quality Control Data
The determination of the precision of a continuous real-time system, such as the breath
inlet/glow discharge/ion trap combination, is not well defined but, using a reasonably constant
source such as an environmental chamber, the variation in ion signal with time can be measured.
By averaging the results over a suitable time period, values of the means and standard deviations
for the target compounds can be found, to provide an overall measure of system stability and
reproducibility. Figure 5-19 shows the time course of the average signal for the MS/MS
fragment ion at m/z 55, obtained from a calibration standard of 2-butanone that was prepared in a
186-L glass chamber at a level of 866 |ig/m3 in zero-grade air. The ion current was sampled
every 6 s and, at fixed intervals, the signal was averaged for 5 min. The ion intensity is almost
constant over a 3!/2-h period, with a relative standard deviation of only 2.2%.
Quality control measures implemented in this study also included determining
background levels and limits of detection for the compounds of interest. Background levels were
estimated for the real-time breath measurements by passing humidified ultra-high purity air
through the entire breath analyzer and measuring the signals at the masses used to monitor the
target compounds. For the dermal exposure study, the mean background levels for MTBE-di2 at
40000
in
^ 35000
30000
25000
20000
50
100
Time (min)
150
200
Figure 5-19. Plot of average ion signal (and standard deviation) at m/z 55 as a
function of time, obtained from constant source of 2-butanone in
glass chamber at a concentration of 866 Hg/m3 in zero-grade air.
40
-------
Table 5-3. Limits of detection (LOD) for MTBE-dn and DBCM in exhaled
breath measured with the real-time breath analyzer (RTBA).
Subject
BCOM1T
BCOF1T
BCOM2T
BCOF2T
BCOM3T
Mean ± SD
RTBA
MTBE-d12
6.1
2.3
10.6
5.8
4.0a
5.8 ± 3.1
LOD (ng/m3)
DBCM
25.3
9.1
33.3
14.3
8.1
18.0 ± 10.9
m/z 82 and DBCM at m/z 129 were below the limits of detection, which were estimated by
47
taking three times the standard deviation of the background (blank) mean concentration. For
MTBE-di2, the detection limits averaged 5.8 ± 3.1 (SD) |ig/m3; for DBCM, the average
detection limit was 18.0 ± 10.9 |ig/m3. The individually-measured detection limits for the real-
time breath analyzer are summarized in Table 5-3.
41
-------
Chapter 6
Discussion
Breath Concentration/Time Profiles
Multiple measurements of breath concentrations were made during and after dermal-only
exposure to of MTBE-di2 and DBCM while bathing in tap water contaminated with these
chemicals at an elevated temperature. For MTBE-di2 and MTBE, the plots in Figures 5-4 to 5-7
and in 5-8, respectively, show that the dermal exposure of the subjects to a nominal level of 150
Hg/L for 30 minutes resulted in a relatively slow and small increase in the measured breath
concentration from pre-exposure levels of 2 - 9 |ig/m3 to peak levels of 7 - 15 |ig/m3. After
exposure ended, breath levels slowly decreased and tended toward the pre-exposure levels during
the 30-minute elimination monitoring period. In all cases, except for Subject BCOM2T, the
measured levels throughout the monitoring periods were above the limits of detection obtained
with the real-time breath analyzer. The pre-exposure levels were roughly equal to the detection
limits for MTBE-di2, which ranged from 2.3 to 10.6 |ig/m3.
Subjects also were dermally exposed at the same time to 40 jig/L of DBCM in water for
30 minutes. Detection limits for DBCM were significantly higher than for MTBE-di2, averaging
18.0 ± 10.9 |ig/m3 (range 8.1 - 33.3 |ig/m3). Background breath levels for DBCM were
approximately at or below the limits of detection. However, as noted earlier, the high initial
breath concentrations as well as the lack of agreement between the breath analyzer and canister-
GC/MS data in Figures 5-4 through 5-8 suggest that the measured breath analyzer signal at m/z
129 was probably due to an unknown contaminant with fragment ions at the same mass. We
were unable to monitor DBCM in the MS/MS mode because none of the precursor masses
examined (m/z 127, 129, and 131) fragmented by collision-induced dissociation in the glow
discharge/ion trap mass spectrometer.
The RTBA background levels for MTBE-di2 in pre-exposure breath samples were
between 2 and 9 |ig/m3. This concentration range is similar to that reported for background
levels in previous studies that relied on batch collection and GC/MS analysis for the
measurement of breath samples. As examples, in the inhalation exposure study of MTBE using
the single breath canister method, Lindstrom and Pleil11 obtained pre-exposure breath levels
between 5.6 and 7.8 |ig/m3. Similarly, in the inhalation exposure study conducted by Buckley et
al.,25 the background MTBE breath levels for two subjects were 3.6 and 12.6 ug/m3, and in the
78 7Q
more recent inhalation study reported by Lee et al., ' the mean pre-exposure breath level was
2.9 ± 4.3 |ig/m3.
42
-------
Breath Residence Times
The one-compartment model described by Equations (4-8) and (4-9) for the uptake and
decay phases, respectively, was fit to the background-corrected uptake and decay data for all five
subjects. The resulting curves are shown in Figures 5-9 to 5-18, and values obtained for/',
Tuptake-: and Tdecay are presented in Table 5-2. All of the Tuptake and Tdecay estimates, except the Uptake
value for Subject BCOM1T, were highly significant^ <0.0001). The adjustedR2 values associated
with the one-compartment model fits ranged from 42 to 93% for the uptake data and from 46 to
88% for the decay data.
The mean residence times for the decay phase were roughly twice as long as the mean
residence times for the uptake phase, viz., Tuptake = 21.2 ± 13.1 min and Tdecay = 41.5 ± 26.3 min
[mean ± standard deviation]. These values are much greater than the residence times obtained in
our earlier study of the dermal absorption of chloroform from bath water, for which the mean uptake
residence time was 8.2 ± 3.1 min and the mean decay residence time was 7.7 ±1.0 min.21 This may
be due to the greater solubility of MTBE in water, which is reflected by their respective Henry's
Law coefficients, namely, 1.6 mole/atm for MTBE vs. 0.26 mole/atm for chloroform.48 These
values also are significantly larger than the uptake and decay residence times for MTBE determined
in our companion inhalation study. As proposed in the earlier study,21 this may be due to the
obscuring effect that occurs as a result of continuous diffusion of MTBE through the stratum
corneum for a time after exposure ends in the dermal absorption case. Because of this diffusion, the
assumption of a single compartment is not strictly valid, and the continued influx of MTBE has the
effect of increasing the observed residence time in the compartment.
Steady-State Ratio f of Exhaled Breath to Water Concentration
The estimate of/', the fraction of exhaled MTBE-di2 to its water concentration, was fairly
comparable among the five subjects, and was equal to 1.1 (± 0.5) x 10"4. In one case (Subject
BCOM2T), the uptake breath concentration/time profile appeared to reach equilibrium rapidly (see
Figure 5-13) and the value for/' can be determined directly from the plot.
Our average value for/' is much smaller than the value calculated in our earlier inhalation
study (/= 0.29 ± 0.04), probably because of the more gradual dermal dose delivery and the fact that
steady-state conditions may not have been attained here. It is, however, of the same order as the/'
estimated by us in a similar experiment on the dermal absorption of chloroform from bath water,
namely, 5.4x 10"4.21
Although lacking physiological significance, the parameter/'nevertheless plays an
important role in compartmental models such as that used here to evaluate the data. From an
exposure assessment perspective, it may often be the case that humans engaged in normal everyday
activities are at or close to equilibrium with their immediate chemical environments. In these cases,
it has been found that simply multiplying the measured breath concentration by the reciprocal of the
parameter/'provides a reasonably good estimate of their average long-term normal exposure.49
43
-------
Total Exhaled Dose of MTBE
The total amount of MTBE-di2 exhaled during the exposure and post-exposure periods
was estimated by integrating the area under the curve. Measured ventilation rates (Table 5-1) for
the subjects were used, and the alveolar ventilation rates were assumed to be 67% of the
measured values. The mean amount of MTBE-di2 exhaled at an average temperature of 39.5°C
was 3.0 ± 1.1 (SD) jig (range: 1.7-4.6 jig). The mean exhaled amount obtained in our earlier
bath water study of chloroform absorption at roughly the same temperature was 7.0 ± 2.0 jig.
This indicates that the dermal uptake of MTBE from bath water is significantly smaller than that
of chloroform under similar exposure conditions.
44
-------
References
1. Squillace, P.J.; Zogorski, J.S.; Wilber, W.G.; Price, C.V. (1996). Preliminary assessment of
the occurrence and possible sources of MTBE in groundwater in the United States, 1993-
1994. Environ. Sci. Technol. 30: 1721-1730.
2. ATSDR (August 1996). Toxicological Profile for Methyl Tertiary-Butyl Ether. Agency for
Toxic Substances and Disease Registry, Centers for Disease Control (CDC), Atlanta, GA.
3. CalEPA (California Environmental Protection Agency). (June 1998). Public Health Goal
for Methyl Tertiary-Butyl Ether (MTBE) in Drinking Water (Draft). Pesticide and
Environmental Toxicology Section, Office of Environmental Heath Hazard Assessment,
California Environmental Protection Agency, Sacramento, CA.
4. U.S. EPA. (1993). Integrated Risk Information System (IRIS) on Methyl tert-Butyl Ether.
Environmental Criteria and Assessment Office, Office of Health and Environmental
Assessment, Office of Research and Development, U.S. Environmental Protection Agency,
Cincinnati, OH.
5. Rao, H.V.; Ginsberg, G.L. (1997). A physiologically-based pharmacokinetic model
assessment of methyl t-butyl ether in groundwater for a bathing and showering
determination. Risk Anal. 17: 583-598.
6. Williams, P.R.D.; Sheehan, PJ. (July/August 2002). Overview of MTBE and TEA
exposures and human health risk in the U.S. Contaminated Soil Sediment and Water 93-
103.
7. Johnson, M.L. Exposure of humans to MTBE from drinking water. In: Health and
Environmental Assessment of MTBE, Volume 5: Risk Assessment, Exposure Assessment,
Water Treatment and Cost-Benefit Analysis; Report to the Governor and Legislator of the
State of California as Sponsored by SB 521; November 1998. Available at:
http://tsrtp.ucdavis.edu/.
8. Wallace, L.A. (1997). Human exposure and body burden for chloroform and other
trihalomethanes. Crit. Rev. Environ. Sci. Technol. 27: 113-194.
9. Prah, J.D.; Blount, B.; Cardinal!, F.L.; Ashley, D.L.; Leavens, T.; Case, M.W. (2002). The
development and testing of a dermal exposure system for pharmacokinetic studies of
administered and ambient water contaminants. J. Pharmacol. Toxicol. Methods 47: 189-
195.
10. Lioy, P.J.; Weisel, C.P.; Jo, W.K.; Pellizzari, E.; Raymer, J.H. (1994). Microenvironmental
and Personal Measurements of Methyl-Tertiary Butyl Ether(MTBE) Associated with
Automobile Use Activities. J. Expos. Anal. Environ. Epidemiol. 4: 427-441.
11. Lindstrom, A.B.; Pleil, J.D. (1996). Alveolar breath sampling and analysis to assess
exposure to methyl tertiary butyl ether (MTBE) during motor vehicle refueling. J. Air &
45
-------
Waste Manage. Assoc. 46: 676-682.
12. Vayghani, S.A.; Weisel, C.P. (1999). The MTBE air concentration in the cabin of vehicles
while fueling. J. Expos. Anal. Environ. Epidemiol. 9: 261-267.
13. Mehlman, M.A. (2002). Carcinogenicity of methyl tertiary-butyl ether in gasoline. Ann.
N.Y. Acad. Sci. 982: 149-159.
14. Moolenaar, R.L.; Hefflin, B.J.; Ashley, D.L.; Middaugh, J.P.; Etzel, R.A. (1994). Methyl
tertiary butyl ether in human blood after exposure to oxygenated fuel in Fairbanks, Alaska.
Arch. Environ. Health, 49: 402-409.
15. Prah, J.D.; Goldstein, G.M.; Devlin, R.; Otto, D.; Ashley, D.; House, D.; Cohen, K.L.;
Gerrity, T. (1995). Sensory, symptomatic, inflammatory, and ocular responses to and
metabolism of methyl tertiary butyl ether in a controlled human exposure experiment.
Inhalation Toxicology, 6, 521-538.
16. Brown, S.L. (1997). Atmospheric and potable water exposures to methyl tert-butyl ether
(MTBE). Reg. ToxicolPharmacol. 25: 256-276.
17. Jo, W. K.; Weisel, C. P.; Lioy, P. J. (1990). Routes of Chloroform Exposure and Body
Burden from Showering with Chlorinated Tap Water. Risk Anal. 10: 575-580.
18. Weisel, C.P.; Jo, W.K. (1996). Ingestion, inhalation, and dermal exposures to chloroform
and trichloroethene from tap water. Environ. Health Per sped. 104: 48-51.
19. Giardino, N. J.; Andelman, J. B. (1996). Characterization of the emissions of
trichloroethylene, chloroform, and l,2-dibromo-3-chloropropane in a full-size, experimental
shower. J. Expos. Anal. Environ. Epidemiol. 6: 413-423.
20. Keating, G. A.; McKone, T. E.; Gillett, J. W. (1997). Measured and estimated air
concentrations of chloroform in showers: Effects of water temperature and aerosols. Atmos.
Environ. 31: 123-130.
21. Gordon, S.M.; Wallace, L.A.; Callahan, P.J.; Kenny, D.V.; Brinkman, M.C. (1998). Effect
of water temperature on dermal exposure to chloroform. Environ. Health Perspect. 106:
337-345.
22. Corsi, R. L.; Howard-Reed, C. (1998). Volatilization Rates from Water to Indoor Air,
Phase IIReport, US EPA Assistance Agreement No. CR 824228-01.
23. Moya, J.; Howard-Reed, C.; Corsi, R. L. (1999). Volatilization of chemicals from tap water
to indoor air while showering with contaminated water. Environ. Sci. Technol. 33: 2321-
2327.
24. Wester, R.C.; Maibach, H.I. (1994). Percutaneous absorption of chemicals from water
simulating swimming and bathing and from vapor exposure. Environ. Sci. Pollut. Control,
Ser9: 149-165.
25. Buckley, T.J.; Prah, J.D.; Ashley, D.; Zweidinger, R.A.; Wallace, L.A. (1997). Body
burden measurements and models to assess inhalation exposure to methyl tertiary butyl ether
(MTBE). J. Air Waste Manage. Assoc. 47: 739-752.
26. Nihlen, A.; Lof, A.; Johanson, G. (1998). Experimental exposure to methyl tertiary-butyl
46
-------
ether. I. Toxicokinetics in humans. Toxicol. Appl. Pharmacol. 148: 274-280.
27. Nihlen, A.; Walinder, R.; Lof, A.; Johanson, G. (1998). Experimental exposure to methyl
tertiary-butyl ether: II. Acute effects in humans. Toxicol. Appl. Pharmacol. 148: 281-287.
28. Lee, C.W. (1999). Biomonitoring of human exposure to methyl tertiary-butyl ether
following controlled exposures using alveolar breath, blood, and urine analysis. Doctoral
Dissertation, Rutgers University.
29. Lee, C.W.; Mohr, S.N.; Weisel, C.P. (2001). Toxicokinetics of human exposure to methyl
tertiary-butyl ether (MTBE) following short-term controlled exposures. J. Expos. Anal.
Environ. Epidemiol. 11: 67-78.
30. Gordon, S.M. (July 1997). Application of Continuous Breath Sampling to Determine VOC
Dose and Body Burden. Final Report under EPA Contract 68-D4-0023, Work Assignment
No. 1-05; National Exposure Research Laboratory, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, NC.
31. Gordon, S.M., Wallace, L.A., Pellizzari, E.D., O'Neill, H.J. (1988). Human breath
measurements in a clean air chamber to determine half lives for volatile organic compounds.
Atmos. Environ. 22: 2165-2170.
32. Raymer, J.H.; Pellizzari, E.D.; Thomas, K.W.; Cooper, S.D. (1991). Elimination of volatile
organic compounds in breath after exposure to occupational and environmental
microenvironments. J. Expos. Anal. Environ. Epidemiol. 1: 439-451
33. Kelly, T.J.; Kenny, D.V.; Spicer, C.W.; Sverdrup, G.M. (1989). Continuous Analysis of
Human Breath Using Atmospheric Pressure lonization MS/MS with a Novel Inlet Design.
In: Proceedings of the 1989 EPA/A&WMA International Symposium on Measurement of
Toxic and Related Air Pollutants, VIP-13; Air & Waste Management Association:
Pittsburgh, PA; 478-483.
34. Gordon, S.M.; Kenny, D.V.; Kelly, TJ. (1992). Continuous real time breath analysis for
the measurement of half lives of expired volatile organic compounds. J. Expos. Anal.
Environ. Epidemiol., Suppl. 1: 41-54.
35. McLuckey, S.A.; Glish, G.L.; Asano, K.G.; Grant, B.C. (1988). Atmospheric sampling
glow discharge ionization source for the determination of trace organic compounds in
ambient air. Anal. Chem. 60: 2220-2227.
36. McLuckey, S.A.; Glish, G.L.; Asano, K.G. (1989). The coupling of an atmospheric
sampling ion source with an ion trap mass spectrometer. Anal. Chim. Ada 225: 25-35.
37. Asano, K.G.; McLuckey, S. A.; Glish, G.L. (1990). Comparison of atmospheric sampling
glow discharge ionization with electron ionization. Spectroscopy 8: 191-209.
38. Gordon, S.M.; Callahan, P.J.; Kenny, D.V.; Pleil, J.D. (1995). Direct trace analysis of
volatile organic compounds in air using ion trap mass spectrometers with filtered noise
fields. In: Proceedings of the 1995 EPA/A&WMA International Symposium on Field
Screening Methods for Hazardous Wastes and Toxic Chemicals, Vol. 1, VIP-47; Pittsburgh,
PA: Air & Waste Management Association; 670-679.
39. Winberry, Jr., W.T.; Murphy, N.T.; Riggin, R.M. (1990). Methods for Determination of Toxic
47
-------
Organic Compounds in Air: EPA Methods, Noyes Data Corporation, Park Ridge, NJ.
40. Church, C.D.; Isabelle, L.M.; Pankow, J.F.; Rose, D.L.; Tratnyek, P.O. (1997). Method for
determination of methyl tert-butyl ether and its degradation products in water. Environ. Sci.
Technol. 31: 3723-3726.
41. Wallace, L.A.; Pellizzari, E.D.; Gordon, S.M. (1993). A linear model relating breath
concentrations to environmental exposures: application to a chamber study of four
volunteers exposed to volatile organic chemicals. J. Expo. Anal. Environ. Epidemiol. 3: 75-
102.
42. Pleil, J.D. and Lindstrom, A.B. (1997). Exhaled human breath measurement method for
assessing exposure to halogenated volatile organic compounds. Clin. Chem. 43: 723-730.
43. Lindstrom, A.B.; Pleil, J.D. (1996). A methodological approach for exposure assessment
studies in residences using volatile organic compound-contaminated water. J. Air & Waste
Manage. Assoc. 46: 1058-1066.
44. Yu, R. and Weisel, C.P. (1996). Measurement of benzene in human breath associated with an
environmental exposure. J. Expo. Anal. Environ. Epidemiol. 6: 261-277'.
45. Wallace, L.A.; Nelson, W.C.; Pellizzari, E.D.; Raymer, J.H. (1997). Uptake and decay of
volatile organic compounds at environmental concentrations: application of a four-
compartment model to a chamber study of five human subjects. J. Expo. Anal. Environ.
Epidemiol. 7: 141-163.
46. Gordon, S.M. (September 1999). Application of Continuous Breath Sampling to Determine
VOC Dose and Body Burden: Dermal and Inhalation Exposure to Chloroform. Final
Report under EPA Contract 68-D4-0023, Work Assignment No. 3-09; National Exposure
Research Laboratory, Office of Research and Development, U.S. Environmental Protection
Agency, Research Triangle Park, NC.
47. Long, G.L.; Winefordner, J.D. (1983). Limit of detection. Anal. Chem. 55: 712A-724A.
48. Sander, R. (July 2001). "Henry's Law Constants" in NIST Chemistry WebBook, NIST
Standard Reference Database Number 69, Eds. P. J. Linstrom and W.G. Mallard, National
Institute of Standards and Technology, Gaithersburg MD, 20899 (http://webbook.nist.gov).
49. Wallace, L.; Buckley, T.; Pellizzari, E.; Gordon, S. (1996). Breath measurements as
volatile organic compound biomarkers. Environ. Health Perspect. 104 (Suppl. 5): 861-869.
48
------- |