praeger handbook of environmental health robert h. … · praeger handbook of environmental health...
TRANSCRIPT
1
Praeger Handbook of Environmental Health
Robert H. Friis, Editor
Volume III: Water Quality, Air Quality, and Solid Waste Disposal
Chapter 8
Potential Health Effects of Exposure to Diesel Engine Exhausts
Dr. Thomas W. Hesterberg, MA, PhD, MBA
Director, Product Stewardship and Environmental Health
Navistar
4201 Winfield Road
Warrenville, IL 60555
Phone: 312-927-2697
Email: [email protected]
Dr. William B. Bunn, MPH, MD, JD
Vice President, Health, Safety, Security and Productivity
Navistar
4201 Winfield Road
Warrenville, IL 60555
Phone: 630-753-2301
Email: [email protected]
Dr. Peter A. Valberg, MA, MS, PhD
Gradient
20 University Road
Cambridge, MA 02138-5756
Phone: 617-395-5570
Email: [email protected]
Dr. Christopher M. Long, SM, ScD
Gradient
20 University Road
Cambridge, MA 02138-5756
Phone: 617-395-5532
Email: [email protected]
2
Abstract
Diesel exhaust (DE) is a complex mixture of particulate matter, condensible vapors, and
gases, with a composition that can vary depending upon engine type, fuel type, and operating
conditions. Elevated exposure levels of DE have been linked with both cancer and non-cancer
health risks, primarily in studies of exhaust from diesel technology typical of the engines, fuels,
and lubricants in use prior to 1988 when diesel-engine emissions were not regulated in the
United States. Prompted by increasingly stringent emission standards implemented by the US
Environmental Protection Agency over the last two decades, major advances have occurred in
diesel technology that have resulted in quantitative and qualitative changes in diesel-engine
emissions, including dramatic reductions in emitted diesel exhaust particulate (DEP), nitrogen
oxides (NOx), and other components.
1.0 Diesel-Engine Exhaust: Introduction, Nature, and Human Exposure Potential
Diesel engines differ from spark-ignition, gasoline engines in that the fuel-air mixture is
ignited by the heat of compression. Diesel engines combust hydrocarbon fuels with oxygen to
produce mechanical energy, and thus, at the fundamental level, the products of combustion found
in "diesel exhaust" (DE) are gaseous carbon dioxide (CO2) and water (H2O). Because
combustion is generally incomplete, and because diesel fuel contains some level of impurities,
many other chemical compounds are present in DE, including a small quantity of airborne
particulate matter (PM), called "diesel exhaust particulate matter" (DEP).
3
At the outset, it should be pointed out that diesel-engine exhaust, its composition, and its
potential health effects have been the subject of frequent review. Among the major reviews is
the 2002 US EPA review entitled "Health Assessment Document for Diesel Exhaust," a 671-
page analysis (1). Additional, contemporary reviews include Hesterberg et al. 2006, 2009a,
2009b, 2010; Gamble, 2010; Institute of Medicine, 2005; Mauderly and Garshick, 2009; Pronk et
al. 2009; and Wichmann, 2006 (2-10). Older major reviews include the 1989 International
Agency for Research on Cancer (IARC) monograph (11), the 1995 report by the Health Effects
Institute (12), and the health-assessment documents developed by the California EPA (13).
In practice, DE is a complex mixture of particulate aerosol – DEP, condensible vapors,
and gases. DE composition varies widely depending upon engine type, fuel type, and operating
conditions. Data on the potential health effects of DE inhalation are available mostly for what
has been termed "traditional diesel exhaust," or TDE (2, 3, 14). TDE refers to the exhaust from
diesel technology typical of the engines, fuel injection systems, fuels, and lubricants in use prior
to 1988, when exhaust emissions from diesel were not regulated in the US.
Stimulated by progressively more stringent DE regulatory standards, major advances
have occurred in diesel technology over the past two decades that have resulted in quantitative
and qualitative changes in diesel-engine emissions, including dramatic reductions in emitted
DEP, nitrogen oxides (NOx), and other components. Present-day engines emit "new technology
diesel exhaust" (NTDE), where NTDE refers to the diesel exhaust from modern integrated
systems (engines, fuel injection systems, ultra-low-sulfur fuels, lubricants, and exhaust after-
treatment devices) manufactured and sold in the post-2006 era to meet the stringent US
4
Environmental Protection Agency (US EPA) emissions standards for heavy-duty highway diesel
engines. Both DE from post-2006 diesel engines, as well as DE from engines retrofitted with a
diesel particulate filter (DPF) and operated with ultra-low sulfur diesel fuel, are considered to be
representative of NTDE, providing that they can achieve the 2007 US EPA emissions standard
for DEP.
The US EPA-mandated changes in DEP and NOx emissions over time are illustrated in
Figure 1. In addition to > 90% reductions in DEP mass, the chemical composition of the DEP
and gases released from NTDE are qualitatively and quantitatively different from TDE (15, 16).
With NTDE, emissions of DEP and NOx are over 99% lower than emissions from engines prior
to regulations. Other aspects of NTDE are summarized elsewhere (15, 16). It is important to
note that most of the available health-effects research does not provide accurate information for
assessment of human health effects that might be associated with current and future exposures to
NTDE.
5
Figure 1. Emissions reductions due to US EPA standards for DEP from heavy-duty diesel
trucks (t) or urban buses (ub), relative to pre-1988 emissions. Panel A, DEP; Panel B,
NOx (data from (1); figures adapted by permission from Informa Healthcare: Critical
Reviews in Toxicology (2)).
US EPA standards for particulate emissions from heavy duty diesel trucks (t) or urban buses (ub),
calculated as grams particulate matter emitted per brake-horsepower-hour (g/b hp-hr) and adjusted
relative to pre-1988 unregulated engine emissions. From: US EPA Health Assessment Document for
Diesel Engine Exhaust, May 2002. Table 2-4, P. 2-16.
Part
icula
tes E
mis
sio
ns,
g/b
hp
-hr
(rela
tive t
o u
nre
gula
ted)
100%
60%
25%
10%5%
1%
Unregulated 1988 t 1991 t 1994 t 1996 ub 2007 t
Fig. 1. Reductions in Diesel Particulate Matter Emissions in the US
Traditional Diesel Transitional Diesel New Technology
Exhaust (TDE) Exhaust Diesel Exhaust (NTDE)
Panel A
NO
x (g
/bh
p-h
r)
15
6
5
4
2
0.2
1977 1990 1991 1998 2004 2010
US EPA standards for NOx emissions from heavy duty diesel engines, calculated as grams NOx
emitted per brake-horsepower-hour (g/b hp-hr). From: USEPA Health Assessment Document for
Diesel Engine Exhaust, May 2002, Table 2-4, p. 2-16.
Model Year
Fig. 2. Reductions in Diesel Nitrogen Oxide (NOx) Emissions in the US
Panel B
6
The majority of our review thus relates to historical and present-day exposures to TDE,
given that most of the available DE toxicological data are for studies of pre-2006 diesel engines
lacking modern aftertreatment systems. TDE is composed of a gas-and-vapor phase, which is
typically composed of about 98% carbon dioxide and water vapor, and also includes NOx, sulfur
dioxide, carbon monoxide, and methane plus non-methane volatile organic carbon compounds.
The particulate phase of TDE, i.e., DEP, from a traditional diesel engine running on high sulfur
fuel typically represents less than 1% of the mass of total diesel exhaust emissions (17).
Exposures to TDE are generally described by giving only the DEP concentration, which may
leave the erroneous impression that any observed health effects are due exclusively to the DEP
alone. In fact, several studies have shown that the gaseous components of engine exhausts may
be more important than the particulate components (18-20). In any case, DEP is often used as a
surrogate measure for all the components in the DE mixture.
A major problem in estimating DEP exposure is that most areas where diesel engines are
in use also include airborne particles from many other non-diesel sources, including carbon
compounds from, e.g., tobacco smoke, gasoline engine exhaust, tire-wear dust, combustion of
wood, paper and waste, meat-cooking fumes, hydrocarbon solvents, deposited and resuspended
pollen, and asphalt dust. The exhausts of engines (both gasoline- and diesel-powered) share
similar physical and chemical characteristics with each other and with airborne materials from
many other combustion sources. There is no known marker for distinguishing DEP from other
types of carbon-based dust. Thus, it has been difficult, if not impossible, to quantify the portion
of an individual's total airborne PM exposure that derives from vehicle exhaust generally, and
even more difficult to quantify the portion that is specifically related to DE. Indeed, DE and
7
gasoline engine exhaust exposures are generally present together and cannot be clearly separated
(21).
US EPA has collected data on environmental concentrations of DEP derived from
extrapolations of measured elemental carbon (EC) and other markers, and the agency has also
generated estimates of DEP levels using a variety of source apportionment strategies (1, 22).
The agency has estimated that U.S. long-term average urban and rural exposure concentrations
from on-road vehicles and stationary sources range between approximately 0.2 and 3.0 µg/m3.
Historically, DEP concentrations in occupational environments have been considerably higher
than the ambient levels, as illustrated in Table 1.
Table 1. Approximate DEP concentrations in ambient and occupational environments where
TDE is, or was, historically, present (9, 1, 23, 24).
Exposure Environment DEP (µg/m3)
Long-term Average Ambient Levels < 0.2 – 3.0
Truckers 7 – 10
Railroad workers 40 – 70
US surface miners 90 – 100
US underground coal miners 500 – 700
US underground metal/mineral
miners
800 – 1,000
For the general public, short-term DEP exposure levels can be considerably higher than
long term average exposure levels, and in fact, many human controlled-exposure studies use
8
DEP exposure levels in the range of 100 to 300 µg/m3. The range of typical DEP concentrations
for exposures to humans (both in the laboratory and ambient settings) is illustrated in Figure 2
(note logarithmic scale of DEP concentrations).
Figure 2: Examples of short-term and long-term DEP concentrations relevant to general public
exposure (figure adapted by permission from Informa Healthcare: Critical Reviews in
Toxicology (3)). The Fruin et al. (25) data (7 – 23 µg/m3) represent measurements made
inside vehicles during highway driving. The McCreanor et al. (26) data (EC
concentrations, 4 – 16 µg/m3) represent 2-hr averages during weekday periods along
London's heavily trafficked Oxford Street. (Note logarithmic scale of DEP
concentrations.)
DE
P C
on
ce
ntr
atio
n (
g/m
3)
0.1
1
10
100
1000
Short-term GeneralPopulation ExposureLevels
Typical Range of DEP Exposure Levels in RecentHuman Controlled Exposure Studies
Fruin et al. (25)
US EPA(1); Hesterberget al. (2)
US EPA(22)
Long-term GeneralPopulation ExposureLevels
McCreanor et al.(26)
2.0 Health Effects of Diesel-Engine Exhaust: Potential for Cancer Risk
In 1989, IARC (11) found limited evidence from studies of humans for carcinogenicity of
DE (evidence primarily derived from studies of railroad workers). The IARC panel noted in the
monograph that, in the epidemiologic studies they reviewed, there were no direct data for the
workers' DE exposures; historical exposures were either assumed based on job title or were
9
estimated from more recent exposure assessments (11, p. 132). The IARC finding of sufficient
evidence from animal studies for carcinogenicity of DE was based primarily on studies in which
rats (but not mice or hamsters) developed tumors after lifetime inhalation of very high
concentrations of DE ( ≥ 2,200 μg/m3 DEP). At the time of the 1989 IARC review, the Working
Group was not able to consider the strong evidence that developed subsequently regarding the
fact that the lung tumors in rats are due to a rat-specific lung-clearance-overload mechanism
triggered by long-term elevated exposures to PM (2).
The US EPA reviewed the science regarding health risks to humans from DE in 2002, in
their "Health Assessment Document for Diesel Exhaust." This document included an extensive
analysis of "Carcinogenicity of Diesel Exhaust" (Chapter 7), with a primary focus on a possible
link to lung cancer risk. The agency concluded that the weight of the evidence supports a
"likely" role for DE in the risk of lung cancer, but assessment of the DE database led to the
conclusion that neither the existing epidemiological studies nor the laboratory animal data were
adequate to quantitatively predict potential human health effects from exposure to DE, or to link
DE to increases in lung cancer (1, 2, 10). When evaluating the evidence for causal associations
between DE exposure and cancers to sites other than the lungs, the US EPA concluded: "Quite a
few studies have examined DE for other effects such as bladder cancer, leukemia,
gastrointestinal cancers, prostate cancer, etc. The evidence for these effects is inadequate" (1, pp.
7-80).
The Institute of Medicine of the National Academies also reviewed the science regarding
health risks to humans from fuels and fuel combustion products (7). Although the IOM did not
10
draw a conclusion specific to DE, it did offer the conclusion that: "there is sufficient evidence of
an association between exposure to combustion products and lung cancer."
Of the occupations listed in Table 1, truckers and railroad workers have been the focus of
most epidemiology studies regarding DE-exposed populations. A significant problem with the
data on truckers is that increases in lung cancer were seen in this occupation prior to dieselization
(See Table 9 in (2)). As discussed subsequently, studies of underground miners have generally
been negative for lung cancer risk. Consequently, U.S. railroad workers have formed the basis
of most studies regarding DE-exposure and its possible relationship to lung cancer risk. These
include case-control and retrospective cohort mortality studies reported by Garshick and
collaborators (27-30) and a reanalysis of the epidemiologic data by Crump (31). The railroad
epidemiologic studies were based on computerized work records maintained since 1959 by the
U.S. Railroad Retirement Board (RRB). By 1959, the transition from coal-powered to diesel-
powered locomotives was 95% complete in the U.S. However, one of the issues in the railroad
worker data is that the lung cancer mortality results do not show a clear trend with increasing
DEP concentration when the cohort is examined by job category. This is summarized in Table 2,
and additional details are available in Hesterberg et al. (2).
11
Table 2: Railroad-worker personal exposures, by job category, to estimated DEP a (n = number
of measurements) versus lung cancer mortality relative risk (n = number of lung cancer
deaths), based on U.S. lung cancer mortality rates (31, 32).
Exposure Lung cancer mortality
Job Category
n
Estimated DEP a
μg/m3, geometric
mean
n
Relative Risk (RR)
Unexposed
Clerks 59 17 315 b 0.98
b
Signal men 13 49
Exposed
Engineers/Firemen 128 39 – 73 298 1.23
Conductors/Brakemen 158 52 – 92
437 1.20 c
Hostlers 8 191
Shop Workers 174 114 – 134
318 1.08 a For each air sample, estimated fraction of cigarette smoke was subtracted from total
respirable particulate matter; adjusted data are presumed to reflect the concentration of
airborne DEP (32). b
Clerks and signal men combined. c
Conductors/brakemen and hostlers combined.
In the late 1990s, the Health Effects Institute (HEI) convened a "Diesel Epidemiology
Expert Panel" (33) to review the railroad worker data and the various analyses of these data. The
Panel was assisted by leading investigators who had conducted epidemiologic research on DE,
and by expert analysts who had conducted critical reviews of that research. The Panel noted that
lung cancer mortality for train workers/riders (engineers, conductors) was higher than for
clerks/signalmen (unexposed), with shop workers (highest DEP exposure) exhibiting
intermediate risks (See Table 2, above). However, the Panel's analyses also demonstrated that
within each category of worker, the risk of lung cancer decreased with increasing duration of
employment, and, further, that the decrease was statistically significant for clerks/signalmen and
train workers. HEI's Diesel Epidemiology Expert Panel concluded that the data: "are not
12
consistent with a steadily increasing association between cumulative diesel exposure and lung
cancer risk." The Panel noted that the negative exposure-response relationship could be due to a
number of possible reasons, including unmeasured confounding variables and/or "other sources
of pollution" that could have been responsible for the observed effect. The HEI Panel also found
that the conclusions initially reached by Garshick and co-workers (i.e., a positive exposure-
response relationship) resulted entirely from baseline differences in risk between the two job
categories (train workers versus clerks/signalmen). The Panel concluded: "These patterns are
not consistent with a monotonically increasing association between cumulative exposure to
diesel exhaust and lung cancer risk. If risk increased consistently with increasing exposure, a
positive trend with duration of employment would be expected for the exposed groups (including
train workers), even if exposure magnitudes were incorrect." That is, the weight of evidence
suggested that, in the railroad-worker studies, any occupational increase in lung cancer risk
among train workers was not due to DE exposures.
Laden et al. (34) published a report that used historical data on dieselization of individual
railroads and emission factors for locomotives in each railroad for an innovative exposure
intensity characterization. These investigators calculated annual railroad-specific probabilities of
worker exposure to DE, going back to 1945. As expected, RRs for lung cancer remained
elevated, but there was no evidence of an exposure-response relationship using these improved
measures of exposure intensity. Another innovative approach to RR-worker data is a case-
control analysis of lung-cancer mortality (1981-1982) by Lee et al. (35), using a new type of
Kaplan-Meier survival plot in which the time scale represents a measure of disease progression
rather than mortality over calendar time. The authors reported that workers who had been
13
engineers or brakemen had a better initial health status, but a steeper rate of health decline than
workers who had never been engineers or brakemen. This steeper rate of decline was attributed
by the authors to DE exposure, however, no quantitative measures of DE exposure were used
other than the "job categories" from the original study (28), which were shown to be problematic
in the HEI (33) analysis.
In a coal-dust analysis relevant to DEP, IARC reviewed studies of coal miners and
determined that evidence was inadequate to show any lung cancer risk from coal dust exposure;
IARC classified coal dust as Group 3, i.e., "cannot be classified as to its carcinogenicity to
humans" (36). This conclusion is important with regard to DEP for two reasons: (1) The studies
in the IARC review included coal miner cohorts of workers who historically inhaled some of the
highest occupational concentrations of total airborne particulates among all working
environments, and this potential "lung overlead" did not lead to lung cancer in humans as it does
in rats. (2) Hundreds of underground coal mines, particularly outside the US, had used diesel
equipment for many decades, exposing those coal miners to considerable DEP as well as to coal
dust. As illustrated in Table 1, and stated in US EPA's HAD for diesel exhaust, "The highest
occupational exposures to DEP are for workers in coal and non-coal mines using diesel-powered
equipment" (1, pp. 2-107). Yet, as IARC found, lung cancer did not appear to be elevated.
Studies of underground miners have been recently reviewed by Hesterberg and
colleagues (2), and the results indicate that between the high levels of DEP exposure and the
adequacy of latency periods, lung cancer risk, if any, should have been readily identified. That
is, the underground mining studies are potentially much more powerful than studies of other
14
occupational groups. However, while not definitive, the underground miner studies provide no
convincing evidence of a risk of lung cancer associated with DEP, and are generally consistent
with no increased risk. Thus, even with DEP exposures that were an order of magnitude higher
than those in either the trucking or railroad industries studies, the mining studies are, on balance,
consistent with no detectable increase in risk.
For more than 10 years now, a long-standing collaboration between the National Institute
of Occupational Safety and Health (NIOSH) and the National Cancer Institute (NCI) has been
evaluating mortality from lung cancer and other diseases among U.S. nonmetal miners in relation
to quantitatively measured exposure to DE, using a cohort and nested case control study (37).
NIOSH researchers (38, 39) just recently reported findings characterizing current and past levels
of surrogates of diesel exhaust, deriving historical estimates of exposure to respirable elemental
carbon (REC). These exposures are being used to investigate potential exposure-response
relationships with lung cancer, but as of this writing (late 2010), no epidemiologic results have
been published by NIOSH or NCI.
Laboratory studies of exposure to TDE, both in vivo and in vitro, have limited relevance
in assessing the carcinogenic potential of TDE in humans. Laboratory rats, when exposed for a
lifetime to high levels of TDE (> 2,200 μg/m3), develop excess lung tumors; however such lung
tumor increases are consistently observed in rats exposed to overload levels of other types of fine
particles (TiO2, talc, and carbon black). Other species (mice and hamsters) exposed at high DEP
levels do not show an excess of lung tumors, nor do rats exposed at lower DEP levels. In rats,
prolonged and elevated exposures to a variety of different particulates result in lung overload,
15
lung inflammation, lung epithelial cell proliferation, and eventually lung tumors. This
mechanism is not DEP-specific and did not occur in the rats at DEP exposure concentrations
below 600 μg/m3 (40), a concentration level that is 10-fold greater than TDE DEP levels to
which railroad and trucking industry workers might have been exposed, and 100-fold above
ambient concentrations. Thus, the tumorigenic effect of high levels of TDE in rats is considered
to be a non-specific particle effect that results from a unique rat-lung overload mechanism (14,
41, 42). In fact, if any occupation might have resulted in "lung overload" in humans,
underground coal miners might be the most likely in this regard. As described earlier, IARC did
not find evidence of lung cancer risk among coal-miner populations. Thus, the rat "lung
overload" phenomenon should not be considered relevant to humans exposed either to DEP in
occupational environments or to even lower ambient levels.
A final aspect of the laboratory-animal studies relates to the potential mutagenicity of
DEP organic extracts, and reviews of these data are available elsewhere (2, 8, 43, 44). Although
the organic compounds extracted from DEP using strong solvents like dichloromethane are
capable of damaging DNA in vitro, such damage has not been established to occur under the
conditions of the DEP inhalation bioassay. Moreover, DEP organic compounds are poorly
bioavailable (12), and the fact that lung tumors can be induced in rats exposed by lifetime
inhalation of non-DEP particles with virtually no adsorbed organics (e.g., carbon black, titanium
dioxide) supports the conclusion that PM overload per se, and not the organics bound to DEP,
are responsible for lung tumors in rats exposed to overloading levels of DEP.
16
Conclusions on Potential Cancer Risks of Inhaled DE
A number of careful analyses of the DE epidemiologic data have concluded that existing
epidemiological studies are unable to quantitatively link DE exposure levels to increases in lung
cancer (2, 6, 33, 45-48). Several factors that support this conclusion are: (1) the epidemiologic
database lacks consistency, with some studies showing a weak association between presumed
DE exposure and lung cancer and other studies showing no association; (2) there is an overall
lack of dose-response among DE-exposed populations, with truckers at low exposures showing
greater risks than underground miners at high DE exposures (49); (3) some studies show
negative exposure-response relationships, and for those with weak positive associations with DE
exposure, the result may be attributable to residual confounding (particularly by smoking); (4)
many of the DE epidemiologic studies suffer from inadequate latency periods; (5) given the
negative mutagenicity data on DEP per se, and a negative animal database (aside from lung-
overloaded rats), biological plausibility remains an issue; and (6) the epidemiological studies
lack adequate DEP exposure information, without which scientists cannot establish a quantitative
estimate of human cancer risk.
3.0 Health Effects of Diesel-Engine Exhaust: Potential for Non-Cancer Health Effects
Laboratory-Animal Data
Numerous non-cancer health endpoints for DE have been investigated in animal studies.
Compared with observational and experimental human studies, laboratory animal studies offer
several unique advantages, including the study of both healthy and diseased animals (e.g.,
17
spontaneously hypertensive rats, atherosclerotic mice, lung-compromised mice) over a range of
well-defined exposure levels and controlled study conditions. Importantly, laboratory studies
allow for the assessment of serious health impacts, including longer-duration, rare, and
permanent health effects as well as those that require invasive measurement methods (e.g., multi-
organ pathology), not possible in human studies. Through the use of elevated exposure levels,
large numbers of study animals, sensitive animal species, and animal models of disease,
laboratory animal studies can be designed to increase the likelihood of detecting adverse effects
from DE inhalation. In fact, sometimes specific genetic strains are used to discover possible
effects of DE on, say, resistance to infection (50) or endothelial function (51). However,
extrapolation of conclusions derived from animal species to humans can be highly uncertain
given that laboratory experiments are typically conducted at extremely high exposure levels,
experimental routes of administration may differ from physiological, real-life exposures (e.g.,
intratracheal instillation is not representative of real-life inhalation exposures), and there may be
large interspecies differences in sensitivity and mode of action.
The 2002 US EPA "Health Assessment Document for Diesel Engine Exhaust" (Diesel
HAD) examined evidence regarding potential non-cancer health effects of both long-term and
short-term exposure to DE and DEP. In terms of elevated, short-term exposures, the agency
stated that DE at sufficient levels can cause transient irritation, inflammatory symptoms, and
may exacerbate asthma symptoms. For long-term exposures, US EPA identified a DEP
reference concentration (RfC), representing a lifetime exposure concentration not expected to
cause adverse non-cancer health effects, of 5 μg/m3 (1). This RfC was based on exposure-
response data for inflammatory and histopathological changes in lungs of rats exposed to high
18
levels of DE over extended periods of time. However, as noted earlier, as cleaner NTDE engines
replace a substantial number of existing, traditional diesel engines, the applicability of the US
EPA RfC analysis will need to be reevaluated.
With regard to non-cancer effects of DEP exposure, Hesterberg et al. (3) provide a
critical evaluation of over 100 published articles on experimental research. It is important to
note that even recent studies continue to use DE emissions from a wide variety of old, traditional
diesel engines and fuels, and hence the results likely have limited relevance to the modern fleet
of vehicles emitting new technology diesel exhaust (NTDE). For example, out of all of the DE
studies, very few have used DE from an engine running on diesel fuel meeting the 2007 US EPA
standard, and most other studies have used engines or fuels no longer commercially available.
Also, animal studies were often carried out at elevated TDE concentrations, sometimes reaching
DEP levels as high as 20,000 to 100,000 μg/m3.
As reviewed by Hesterberg et al. (3), several large-scale experiments with animal species
inhaling DEP have been completed since the US EPA Diesel HAD (1). These data show that
highly elevated DEP doses (DEP concentration exposure duration) can lead to chronic lung
inflammation, but that at smaller doses, still much higher than typical ambient levels of DEP,
little has been reported in the way of adverse or irreversible effects. In fact, one group of
investigators suggested a no-observable-adverse-effect level (NOAEL) in the range between 200
to 1,000 μg/m3 DEP (52), and other investigators point out that rat exposure levels turn out to be
roughly equal to human exposure concentrations (HEC) (within a factor of 2) by taking into
account dose per lung (alveolar) surface area, relative lung deposition, and relative lung
19
clearance (53). Thus, more recent data, subsequent to US EPA setting the RfC at 5 μg/m3,
suggest that the 5 μg/m3 is quite conservative and health protective.
The McDonald et al. (17) laboratory animal study provides some of the few available
experimental data for a diesel exhaust mixture representative of NTDE. This study investigated
the relative toxicity of acute inhalation exposures (6 hrs per day over 7 days) for a baseline
uncontrolled, TDE emissions case (approximately 200 μg/m3 DEP) versus an emissions-
reduction, NTDE case (low sulfur fuel, catalyzed ceramic trap, near background levels for all
emissions but NOx) on a suite of sensitive measures of acute lung toxicity in mice, including
lung inflammation, RSV resistance, and oxidative stress. For the baseline TDE case, McDonald
et al. (17) observed statistically significant DE-induced effects for each class of responses, while
these effects were either nearly or completely eliminated for the NTDE case.
With its well-characterized exposure atmosphere and its assessment of a suite of sensitive
measures of acute lung toxicity, the McDonald et al. (17) study provides some of the strongest
experimental evidence of the reduced toxicity of NTDE. However, as a single study that
addressed only acute lung toxicity in a single animal species for a single engine and
aftertreatment configuration, there is clearly a need for more comprehensive toxicological
investigations of NTDE to confirm these findings of reduced NTDE toxicity for a broader range
of aftertreatment configurations and operating conditions and for other classes of health
endpoints (e.g., cardiovascular effects, allergenic effects). On this note, it is expected that the
comprehensive health effects components of the ongoing Advanced Collaborative Emissions
Study (ACES) will provide a wealth of information for assessing the carcinogenicity, subchronic,
20
and chronic non-cancer toxicity of NTDE. A core component of ACES is a chronic rat bioassay
where rats are exposed via inhalation for 24 or 30 months, with interim sacrifices at 1, 3, 12, and
24 months, to three dilutions of whole emissions from a 2007-compliant diesel engine with
advanced emission control technologies (and clean air controls). Health endpoints of interest
include not only carcinogenicity but also pulmonary function, pulmonary inflammation,
oxidative damage, lung cell proliferation, histopathological changes, and hematological effects.
Exposure of Human Volunteers to DE
Controlled-exposure studies with human volunteers have several major advantages,
including the direct study of human subjects; the use of well-defined, continuously measured
exposure concentrations and durations; the absence of confounding exposures to other
chemicals; and the use of sophisticated research equipment to simultaneously and precisely
measure a suite of physiological endpoints potentially relevant to health, including both subtle
biological responses and small functional decrements. Although exposures via nasal masks or
mouthpieces have been used in some studies, large state-of-the-art inhalation chambers (e.g., 25
to 100 m3 whole-body chambers with control of humidity, temperature, ventilation, etc.) are
currently used, wherein small numbers of volunteers receive whole-body exposures to one or
more pollutants while either exercising or at rest. Some controlled human exposure studies have
been performed using adults representative of potentially susceptible subpopulations, including
those with asthma, chronic obstructive pulmonary disease, and cardiovascular disease.
21
Studies on human volunteers also have limitations. Namely, (1) small groups of healthy
volunteers may not be representative of larger populations; (2) investigation of only acute effects
from short-duration exposures may not extrapolate to long-term exposures; and (3) use of
exposure protocols and pollutant concentrations expected to elicit only transient, clinically mild
health responses may not extrapolate to higher-level, worker exposures (54, 55). In addition,
there is generally no control of the recent exposure history of volunteers, which can be an
important modifier of study findings. To increase the likelihood of detecting effects among
small groups of healthy subjects, human exposure studies often use relatively high DE
concentrations, compared to actual real-world exposure levels, yet, of course, below those that
are suspected to increase the risk of long-term or irreversible health effects. Because of these
limitations, human controlled exposure studies may be underpowered to detect some health
responses that are of health significance.
Because of the mild nature of the responses measured (often with subjects reporting no
perceptible symptoms), the question arises as to whether the response is an "adverse health
effect." Although physiologic impairment or clinically significant decrements may reach
adverse levels, the American Thoracic Society (56) has pointed out that not all "effects"
measured in clinical-exposure studies reflect "adverse health" outcomes warranting regulatory,
preventive measures. Specifically, ATS (56) concluded that "not all changes in biomarkers
related to air pollution should be considered as indicative of an injury that represents an adverse
effect." Similarly, ATS (56) concluded that "a small, transient loss of lung function, by itself,
should not automatically be designated as adverse." ATS (56) further distinguished adverse
22
symptoms as those that are associated with "a diminished quality of life or with a change in
clinical status."
Since the preparation of the Diesel HAD, a number of new human controlled exposure
studies have been published, with several of these studies following up on previous studies of
lung and systemic inflammatory responses, and other recent studies addressing cardiovascular
health responses including cardiac, vasomotor, and fibrinolytic function (3). Studies of human
volunteers have used elevated concentrations of DE (about 100 to 300 μg/m3), markedly above
what would be experienced in typical non-occupational environments. An illustration of the
recent cardiovascular-related results that have been found in humans is given in Figure 3, where
the vertical axis gives the concentration of DEP, and the horizontal scale lists the type of studies
that have been done. Cardiovascular health responses have been a focus of a number of recent
DE human clinical studies, and as shown in Figure 3, these studies have generally reported
mixed findings with respect to various subclinical measures of acute cardiovascular health
responses. However, none of these studies have examined NTDE, the low emission technology
that is required for all diesel on-road vehicles starting in 2007. In fact, preliminary data are
available from two studies (57, 58) showing a reversal of effects on vasomotor function and
thrombus formation with addition of a commercially available retrofit particle trap to the test
heavy-duty diesel engine.
23
Figure 3: Graphical summary of key findings from recent controlled human exposure studies of
the cardiovascular-related health effects of inhaled DE (both particles and gases), with
Panel A addressing systemic inflammatory and fibrinolytic/thrombogenic responses and
Panel B showing effects on subclinical markers of cardiovascular disease (e.g., heart rate,
blood pressure, heart rate variability, etc.), effects on vascular function, and changes in
indicators of endothelial dysfunction. Green circles with – signs represent negative (null)
findings, red squares with + signs represent positive findings, and yellow triangles
represent equivocal findings.
Ba
rath
et a
l. (
61)
Blo
mb
erg
et a
l. (
62)
Ca
rlste
n e
t a
l. (
63)
Luckin
g e
t a
l. (
64)
Mill
s e
t a
l. (
65)
Mill
s e
t a
l. (
66)
Sa
lvi e
t a
l. (
67)
To
rnqvis
t e
t a
l. (
68)
Blo
mb
erg
et a
l. (
62)
Ca
rlste
n e
t a
l. (
63)
Ca
rlste
n e
t a
l. (
69)
Luckin
g e
t a
l. (
64)
Mill
s e
t a
l. (
65)
Mill
s e
t a
l. (
66)
Sa
lvi e
t a
l. (
67)
DE
P E
xposure
Level (
g/m
3)
50
100
150
200
250
300
350
400
NegativeFindings
PositiveFindings
Inflammatory Cells/ Pro-InflammatoryMediators
+
-
KEY
Fibrinolytic/Thrombogenic Response
Panel A
24
Bara
th e
t al. (
61)
Langrish e
t al. (
70)
Lundback e
t al. (
71)
Mill
s e
t al. (
65)
Mill
s e
t al. (
66)
Pere
tz e
t al. (
72)
Pere
tz e
t al. (
73)
Torn
qvis
t et al. (
68)
Mill
s e
t al. (
66)
Pere
tz e
t al. (
73)
Bara
th e
t al. (
61)
Langrish e
t al. (
70)
Lundback e
t al. (
71)
Mill
s e
t al. (
65)
Mill
s e
t al. (
66)
Pere
tz e
t al. (
72)
Torn
qvis
t et al. (
68)
Blo
mberg
et al. (
62)
Carlste
n e
t al. (
63)
Carlste
n e
t al. (
69)
Langrish e
t al. (
70)
Mill
s e
t al. (
65)
Pere
tz e
t al. (
72)
DE
P E
xpo
sure
Level (
g/m
3)
0
100
200
300
400
NegativeFindings
PositiveFindings
Equivocal/MixedFindings
HR/BP Vascular Function,Arterial Compliance
+
-
KEY
EKG/HRVIndicators of EndothelialDysfunction (e.g., VWF, ET-1)
Panel B
Overall, given the relatively small number of statistically significant DE-induced changes
observed in these recent human-exposure studies for some test parameters among a larger
number of non-significant findings, as well as some conflicting findings among studies (Figure
3), it remains difficult to interpret the broader health implications of what currently remains a
disparate body of findings from studies of small numbers of subjects and different study designs
and measurements. Although animal studies have provided some findings suggestive of
25
potential mechanisms (e.g., the Wong et al. (59) findings suggesting a neurokininergic
mechanism for DE-induced lung inflammation), our mechanistic understanding remains limited.
This is particularly true for low-level ambient DE concentrations, given that most animal studies
have been conducted at concentrations vastly higher than those used in controlled human
exposure studies. Broader interpretation of these human clinical data is limited by the fact that
all but a few of the available studies were conducted in the same exposure laboratory for freshly-
generated emissions from the same engine type under the same operating conditions (idling
Volvo TD45, model year 1991, 4.5-liter, 4 cylinder, 680 rpm, diesel engine). This places limits
on generalizing the study findings to emissions from other engines and operating conditions, and
to environmentally-aged diesel emissions. As summarized in the 2002 Diesel HAD (1) and Ris
(60), it is well-established that DE emissions vary both in chemical composition and particle size
distributions for different types and ages of diesel engines, and within engine types, depending
on operating conditions (fuel composition, load characteristics, lube oil composition, emission
control devices), with atmospheric aging also serving to modify DE properties.
The question regarding potential health effects of "aged" DE emissions might be best
addressed by studies such as that of McCreanor et al. (26), where both health effects and PM
levels were assessed for 2-hour weekday exposure periods between November 2003 and March
2005 along London's heavily-trafficked Oxford Street (Figure 2, EC concentrations, 4 – 16
µg/m3, median PM2.5 concentration 28 μg/m
3). The Oxford Street location was chosen to
represent a busy city street impacted by diesel-vehicle emissions, because only diesel-powered
buses and taxicabs are permitted on this heavily-trafficked street, while Hyde Park (EC
concentrations, 0.4 – 7 μg/m3, median PM2.5 concentration, 12 μg/m
3) is a traffic-free area of
26
London. Ultrafine-particle concentrations, in terms of 1,000's of particles per cm3, were 64 on
Oxford Street and 18 in Hyde Park.
The McCreanor et al. (26) study included 60 participants with mild to moderate asthma,
and each participant walked for 2 hours along a heavily trafficked street (Oxford Street) and, on
a separate occasion, through a nearby, traffic-free park (Hyde Park). The investigators observed
small, statistically significant, "asymptomatic but consistent" reductions in FEV1 (up to 6.1%)
and FVC (up to 5.4%) for the Oxford Street exposures compared to those for the Hyde Park
exposures. These mild, reversible lung function changes for the Oxford Street exposures
coincided with statistically significant increases in sputum myeloperoxidase levels, a biomarker
of neutrophilic inflammation, and airway acidification. However, between the two sites, there
were no statistically significant changes in FEF25-75%, mean FENO, sputum neutrophil counts,
interleukin-8, sputum eosinophil counts, or eosinophil cationic protein levels. Using pollutant-
specific, exposure-response analyses, the study investigators linked the observed health
responses with the significantly greater air pollutant exposure concentrations measured during
the Oxford Street exposure period (e.g., 5.7-fold higher EC concentrations and 3.5-fold greater
ultrafine particle count concentrations), noting that, in two-pollutant models, the effects of
ultrafine particles and elemental carbon retained statistical significance and were most consistent.
Although the study authors suggest elevated exposures to DE on Oxford Street may underlie
their study findings, they do acknowledge the possibility that other unmeasured pollutants
associated with roadside diesel-traffic exposure, namely road dust and engine or tire debris, may
instead be the causal agents. Likewise, noise, temperature (2°C hotter on Oxford Street), and
other stresses may have also played a role in the measured differences.
27
Although not specific to DE, a number of observational epidemiology studies have linked
cardiovascular and respiratory health effects to traffic-related air pollution (74-76). The HEI
Panel on the Health Effects of Traffic-Related Air Pollution (76) conducted one of the more
comprehensive reviews of the health effects literature related to traffic-related air pollution,
concluding that "the evidence is sufficient to support a causal relationship between exposure to
traffic-related air pollution and exacerbation of asthma." In addition, the HEI panel concluded
that there was "suggestive evidence of a causal relationship" with onset of childhood asthma,
nonasthma respiratory symptoms, impaired lung function, total and cardiovascular mortality, and
cardiovascular morbidity. Importantly, studies of traffic-related air pollution have generally
relied upon surrogate measures of exposure to traffic-related pollution, including both traffic-
pollutant surrogates (e.g., CO, NO2, EC) and proximity-based surrogates (e.g., distance of
residence to nearest road, and traffic density). As a result, the role of DE and DEP in these
associations cannot be clearly assessed due to the non-specificity of the pollutant surrogates, and
due to many potential confounding factors associated with surrogates based on proximity, such
as gasoline-engine exhaust, noise, fugitive road dust, socioeconomic status, and so forth (77).
Furthermore, as acknowledged in HEI (76), the available epidemiology studies are primarily for
past time periods and older vehicles, meaning that they are of uncertain, and possibly little,
relevance to today's modern engine technologies and fuels.
Conclusions on Potential Non-Cancer Health Effects of Inhaled DE
28
Human controlled-exposure studies provide evidence suggestive of lung inflammatory
effects and thrombogenic and ischemic effects of inhaled DE, albeit for older model diesel
engines and concentrations that are much higher (~300 μg/m3) than typical ambient or even
occupational levels. Recent animal studies provide insights on the potential mechanisms
underlying observed respiratory and cardiovascular health responses, but because of
unrealistically high DE concentrations, it is unclear whether the mechanisms elucidated in these
studies are relevant at lower DE exposure levels. A mechanism of action that allows reliable
prediction of adverse health impacts at DE exposure levels typical of the present-day ambient
and occupational environment has not emerged. Because of changing diesel-engine technology,
inhalation studies using realistic environmental and occupational exposures of new technology
diesel exhaust (NTDE) are of critical importance.
4.0 Conclusions
Much remains to be understood in terms of the constituents of TDE and NTDE that have
the greatest potential for eliciting health effects at adequately high exposure concentrations and
durations. There are important differences in mass emission rates, particle size distributions,
elemental carbon vs. organic carbon content, ratios of 3- and 4-ring polycyclic aromatic
hydrocarbons (PAHs), and other constituent concentrations, not only between TDE and NTDE,
but also among various types of engines within the two classes (15, 16). In fact, it cannot be
clearly stated whether DE is of greater or lesser toxicity than other combustion sources such as
gasoline-engine exhaust, wood smoke, fossil-fuel power plants, compressed-natural-gas engines,
and other combustion sources. These issues are crucial both for DEP and ambient PM, where
there is disagreement between observational epidemiology and toxicology as to the sufficient
29
dose and toxic role of chemical constituents and physical characteristics causing biologic
activity.
Although DE-exposed worker populations have been studied a great deal, both
inadequate estimates of DE exposure as well as poorly-understood exposure-response
relationships have prevented development of quantitative estimates of lung-cancer risk. In fact,
there does not appear to be an exposure-response relationship over different occupations that
have considerably different exposure potential for DE. A high priority is the reporting of results
from the longstanding NIOSH/NCI studies of US underground miners with historically elevated
DE exposures. These results need to be completed, analyzed, and reported in detail in the open
literature.
Emissions of DEP nanoparticles (i.e., with diameters < 100 nm) have received increased
attention in recent times, due to reports that nanoparticle emissions could be increased in NTDE,
as well as due to the intense interest in the toxicity of engineered nanoparticles. Nano-sized
particles, including individual nuclei mode particles and carbonaceous agglomerates, are well
known to dominate particle number concentrations of DEP (78). Hesterberg et al. (5) examined
findings from the DE human clinical studies to identify insights relevant to potential NP human
health hazards, concluding that the available DE human clinical data do not give evidence of a
unique toxicity for NPs (at least in the DEP context) as compared to other small particles. Given
that particle number and surface area concentrations are recognized as more relevant exposure
metrics for nanoparticle health effects than particle mass concentration, there is a real need for
DE health effect studies to quantify these exposure metrics (in addition to mass concentrations).
30
Recent studies of DE exposures to human volunteers have provided useful human
evidence of the potential respiratory and cardiovascular health hazards of short-term exposures to
elevated DE exposures, but there is a need to better understand the human clinical significance of
these findings and their relevance to lower, ambient levels of DE and a wider range of engine
types, operating conditions, and population subgroups. In addition, there is a need for more
comprehensive toxicological investigations of NTDE to confirm the toxicological differences
between NTDE and TDE indicated by the distinctions in their chemical and physical
characterization properties. Furthermore, with recent research indicating that other combustion
emissions (e.g., gasoline engine emissions) and ambient particle types can elicit similar
biological responses as DE, further study is also needed to understand how DE health risks
compare to those from other common air contaminants. With further study and improvements in
our understanding of not only DE hazard assessment, but also dose-response for realistic
inhalation exposures, it can be hoped that newly-collected data will stimulate continuing
progress toward a cleaner-burning, increasingly safer diesel engine technology.
31
References:
1. United States Environmental Protection Agency (US EPA). Health Assessment Document
for Diesel Engine Exhaust. National Center for Environmental Assessment, Office of
Research and Development; 2002. (EPA/600/8-90/057F).
2. Hesterberg TW, Bunn W, Chase GR, et al. A critical assessment of studies on the
carcinogenic potential of diesel exhaust. Crit Rev Toxicol. 2006;36(9):727-776.
3. Hesterberg TW, Long CM, Bunn WB, et al. Non-cancer health effects of diesel exhaust
(DE): A critical assessment of recent human and animal toxicological literature. Crit Rev
Toxicol. 2009a;39(3):195-227.
4. Hesterberg TW, Valberg PA, Long CM, et al. Laboratory studies of diesel exhaust health
effects: Implications for near-roadway exposures. EM, Air & Waste Manage Assn Pub
Environ Managers. August 2009b:13-16.
5. Hesterberg TW, Long CM, Lapin C, et al. Diesel exhaust particulate (DEP) and
nanoparticle (NP) exposures: What do DEP human clinical studies tell us about potential
human health hazards of nanoparticles? Inhal Toxicol. 2010;22:679-694.
6. Gamble, J. Lung cancer and diesel exhaust: A critical review of the occupational
epidemiology literature. Crit Rev Toxicol. 2010;40:189-244.
7. Institute of Medicine (IOM). Gulf War and Health – Volume 3: Fuels, Combustion
Products, and Propellants. Washington, DC: National Academies Press; 2005.
32
8. Mauderly JL, Garshick E.. Diesel exhaust. In: Lippman M, ed. Environmental Toxicants,
3rd
Ed. Hoboken, New Jersey: John Wiley & Sons, Inc.; 2009:551-630.
9. Pronk A, Coble J, Stewart PA. Occupational exposure to diesel engine exhaust: A
literature review. J Expo Sci Environ Epidemiol. 2009;19:443-57.
10. Wichmann H-E. Environmental pollutants: Diesel exhaust particles. In: Laurent GJ,
Shapiro SD, eds. Encyclopedia of Respiratory Medicine. Oxford: Elsevier; 2006:96-100.
11. International Agency for Research on Cancer (IARC). IARC Monographs on the
Evaluation of Carcinogenic Risks to Humans: Diesel and Gasoline Engine Exhausts and
Some Nitroarenes (Volume 46). Lyon, France: World Health Organization; 1989.
12. Health Effects Institute (HEI). Diesel Exhaust: A Critical Analysis of Emissions,
Exposure, and Health Effects. Cambridge, MA: Health Effects Institute; 1995. (A Special
Report of the Institute's Diesel Working Group).
13. California Environmental Protection Agency (Cal EPA). Health Risk Assessment for
Diesel Exhaust Part 6: Proposed Identification of Diesel Exhaust as a Toxic Air
Contaminant. Sacramento, CA: Office of Environmental Health Hazard Assessment,
California Air Resources Board; 1998.
14. Hesterberg TW, Bunn WB, McClellan RO, et al. Carcinogenicity studies of diesel engine
exhausts in laboratory animals: A review of past studies and a discussion of future
research needs. Crit Rev Toxicol. 2005;35(5):379-411.
33
15. Hesterberg TW, Lapin CA, Bunn WB. A comparison of emissions from vehicles fueled
with diesel or compressed natural gas. Environ Sci Technol. 2008;42(17): 6437-6445.
16. Hesterberg TW, Long CM, Sax SN, et al. Particulate matter in new technology diesel
exhaust (NTDE) is quantitatively and qualitatively very different from that found in
traditional diesel exhaust (TDE). 2011; Submitted to the Journal of the Air & Waste
Management Association.
17. McDonald JD, Harrod KS, Seagrave J, et al. Effects of low sulfur fuel and a catalyzed
particle trap on the composition and toxicity of diesel emissions. Environ Health
Perspect. 2004;112:1307-1312.
18. Campen MJ, Babu NS, Helms GA, et al. Nonparticulate components of diesel exhaust
promote constriction in coronary arteries from ApoE-/- mice. Toxicol Sci. 2005;88(1):95-
102.
19. Seagrave JC, Berger I, Zielinska B, et al. Comparative acute toxicities of particulate
matter (PM) and semi-volatile organic compound (SVOC) fractions of traftic tunnel air.
Toxicologist 2001;60:192.
20. McDonald JD, Reed MD, Barren EG, et al. Health effects of inhaled gasoline engine
emissions. Inhal Toxicol. 2007;19:107-116.
21. Lee BK, Smith TJ, Garshick E, et al. Exposure of trucking company workers to
particulate matter during the winter. Chemosphere 2005;61:1677-90.
34
22. United States Environmental Protection Agency (US EPA). (). Technology Transfer
Network: 1999 National-scale Air Toxics Assessment. 2006.
(http://epa.gov/ttn/atw/nata1999/).
23. Mine Safety and Health Administration (MSHA). Diesel Particulate Matter Exposure of
Underground Metal and Nonmetal Miners; Proposed Rule. 1998. (MSHA, 63 Fed Reg
58104-58270).
24. Mine Safety and Health Administration (MSHA). Diesel Particulate Matter Exposure of
Underground Metal and Nonmetal Miners; Final Rule. 2006. (MSHA, 71 Fed Reg
28924-29012).
25. Fruin SA, Winer AM, Rodes CE. Black carbon concentrations in California vehicles and
estimation of in-vehicle diesel exhaust particulate matter exposures. Atmos Environ.
2004;38:4123-4133.
26. McCreanor J, Cullinan P, Nieuwenhuijsen MJ, et al. Respiratory effects of exposure to
diesel traffic in persons with asthma. N Engl J Med. 2007;357:2348-58.
27. Garshick E, Schenker MB, Muñoz A, et al. A case-control study of lung cancer and
diesel exhaust exposure in railroad workers. Am Rev Respir Dis. 1987;135(6):1242-1248.
28. Garshick E, Schenker MB, Muñoz A, et al. A retrospective cohort study of lung cancer
and diesel exhaust exposure in railroad workers. Am Rev Respir Dis. 1988;137(4):820-
825.
35
29. Garshick E, Laden F, Hart JE, et al. Lung cancer in railroad workers exposed to diesel
exhaust. Environ Health Perspect. 2004;112(15):1539-1543.
30. Garshick E, Laden F, Hart JE, et al. Smoking imputation and lung cancer in railroad
workers exposed to diesel exhaust. Am J Ind Med. 2006;49(9):709-718.
31. Crump KS. Lung cancer mortality and diesel exhaust: reanalysis of a retrospective cohort
study of U.S. railroad workers. Inhal Toxicol. 1999;11(1):1-17.
32. Woskie SR, Smith TJ, Hammond SK, et al. Estimation of the diesel exhaust exposures of
railroad workers: II. National and historical exposures. Am J Ind Med. 1988;13(3):395-
404.
33. Health Effects Institute (HEI). Diesel Emissions and Lung Cancer: Epidemiology and
Quantitative Risk Assessment. Boston, MA: Health Effects Institute; 1999. (Special
Report of the Diesel Epidemiology Expert Panel).
34. Laden F, Hart JE, Eschenroeder A, et al. Historical estimation of diesel exhaust exposure
in a cohort study of U.S. railroad workers and lung cancer. Cancer Causes Control
2006;17:911-19.
35. Lee ML, Whitmore GA, Laden F, et al. A case-control study relating railroad worker
mortality to diesel exhaust exposure using a threshold regression model. J Stat Plan
Inference. 2009;139(5):1633-1642.
36. International Agency for Research on Cancer (IARC). Silica, Some Silicates, Coal Dust
and Para-Aramid Fibrils (Volume 68). Lyon, France: World Health Organization; 1997.
36
37. Attfield M. A cohort mortality study with a nested case control study of lung cancer and
diesel exhaust among nonmetal miners. Division of Respiratory Disease Studies, NIOSH
and National Institutes of Health Clinical Center, NCI; 1999.
(http://clinicaltrials.gov/ct2/show/record/NCT00342264;
http://www.cdc.gov/niosh/programs/mining/projects.html).
38. Stewart PA, Coble JB, Vermeulen R, et al. The diesel exhaust in miners study: I.
Overview of the exposure assessment process. Ann Occup Hyg. 2010;54(7):728-46.
39. Vermeulen R, Coble JB, Lubin JH, et al. The diesel exhaust in miners study: IV.
Estimating historical exposures to diesel exhaust in underground non-metal mining
facilities. Ann Occup Hyg. 2010;54(7):774-88.
40. Valberg PA, Crouch EAC. Meta analysis of rat lung tumors from lifetime inhalation of
diesel exhaust. Environ Health Perspect. 1999;107:693-699.
41. Watson AY, Valberg PA. Particle-induced lung tumors in rats: Evidence for species
specificity in mechanisms. Inhal Toxicol. 1996;Suppl 8: 227-257.
42. Stinn W, Teredesai A, Anskeit E, et al. Chronic nose-only inhalation study in rats,
comparing room-aged sidestream cigarette smoke and diesel engine exhaust. Inhal
Toxicol. 2005;17:549-76.
43. Valberg PA, Watson AY. Comparative mutagenic dose of ambient diesel engine exhaust.
Inhal Toxicol. 1999;11:215-28.
37
44. Mauderly JL. Diesel exhaust. In: Lippman M, ed. Environmental Toxicants: Human
Exposures and Their Health Effects. NY, New York: Wiley-Interscience; 2000:193-241.
45. Muscat JE, Wynder EL. Diesel engine exhaust and lung cancer: an unproven association.
Environ Health Perspect. 1995;103(9):812-818.
46. Stöber W, Abel UR. Lung cancer due to diesel soot particles in ambient air? A critical
appraisal of epidemiological studies addressing this question. Int Arch Occup Environ
Health 1996;68(Suppl.):S3-61.
47. Cox LA. Does diesel exhaust cause human lung cancer? Risk Anal. 1997;17(6):807-829.
48. Morgan WK, Reger RB, Tucker DM. Health effects of diesel emissions. Ann Occup Hyg.
1997;41(6):643-658.
49. Valberg PA, Watson AY. Lack of concordance between reported lung-cancer risk levels
and occupation-specific diesel-exhaust exposure. Inhal Toxicol. 2000;12(Suppl. 1):199-
208.
50. Harrod KS, Jaramillo RJ, Rosenberger CL, et al. Increased susceptibility to RSV
infection by exposure to inhaled diesel engine emissions. Am J Respir Cell Mol Biol.
2003;28(4):451-463.
51. Hansen CS, Sheykhzade M, Moller P, et al. Diesel exhaust particles induce endothelial
dysfunction in apoE-/- mice. Toxicol Appl Pharmacol. 2007;219(1):24-32.
38
52. Ishihara Y, Kagawa J. Chronic diesel exhaust exposures of rats demonstrate
concentration and time-dependant effects on pulmonary inflammation. Inhal Toxicol.
2003;15(5):473-492.
53. Reed MD, Gigliotti AP, McDonald JD, et al. Health effects of subchronic exposure to
environmental levels of diesel exhaust. Inhal Toxicol. 2004;16:177-93.
54. Utell MJ, Frampton MW. Toxicologic methods: Controlled human exposures. Environ
Health Perspect. 2000;108(Suppl. 4):605-613.
55. McDonnell WF. Utility of controlled human exposure studies for assessing the health
effects of complex mixtures and indoor air pollutants. Environ Health Perspect.
1993;101(S4):199-203.
56. American Thoracic Society (ATS). What constitutes an adverse health effect of air
pollution: The official statement of the American Thoracic Society. Am. J. Respir. Crit.
Care Med. 2000;161:665-673.
57. Barath S, Lucking AJ, Lundbäck M, et al. Retrofit particle traps reduce exposure to fine
particulate air pollution and prevent increased thrombogenesis in man. Am J Respir Crit
Care Med. 2009;179:A1634.
58. Lundbäck M, Lucking AJ, Barath S, et al. Retrofit particle traps reduce exposure to fine
particulate air pollution and prevent vascular dysfunction in man. Am J Respir Crit Care
Med. 2009;179:A1633.
39
59. Wong SS, Sun NN, Keith I, et al. Tachykinin substance P signaling involved in diesel
exhaust-induced bronchopulmonary neurogenic inflammation in rats. Arch Toxicol.
2003;77(11):638-650.
60. Ris C. US EPA health assessment for diesel engine exhaust: A review. Inhal Toxicol.
2007;19(Suppl. 1):229-239.
61. Barath S, Mills NL, Lundbäck M, et al. Impaired vascular function after exposure to
diesel exhaust generated at urban transient running conditions. Part Fibre Toxicol.
2010;23;7:19.
62. Blomberg A, Törnqvist H, Desmyter L, et al. Exposure to diesel exhaust nanoparticles
does not induce blood hypercoagulability in an at-risk population. J Thromb Haemost.
2005;3:2103-2105.
63. Carlsten C, Kaufman JD, Peretz A, et al. Coagulation markers in healthy human subjects
exposed to diesel exhaust. Thromb Res. 2007;120:849-55.
64. Lucking AJ, Lundbäck M, Mills NL, et al. Diesel exhaust inhalation increases thrombus
formation in man. Eur Heart J. 2008;29:3043-3051.
65. Mills NL, Törnqvist H, Robinson SD, et al. Diesel exhaust inhalation causes vascular
dysfunction and impaired endogenous fibrinolysis. Circulation 2005;112: 3930-3936.
66. Mills NL, Törnqvist H, Gonzalez MC, et al. Ischemic and thrombotic effects of dilute
diesel-exhaust inhalation in men with coronary heart disease. New Engl J Med.
2007;357:1075-1082.
40
67. Salvi S, Blomberg A, Rudell B, et al. Acute inflammatory responses in the airways and
peripheral blood after short-term exposure to diesel exhaust in healthy human volunteers.
Am J Respir Crit Care Med. 1999;159:702-709.
68. Törnqvist H, Mills NL, Gonzalez M, et al. Persistent endothelial dysfunction following
diesel exhaust inhalation in man. Am J Respir Crit Care Med. 2007;176:395-400.
69. Carlsten C, Kaufman JD, Trenga CA, et al. Thrombotic markers in metabolic syndrome
subjects exposed to diesel exhaust. Inhal Toxicol. 2008;20:917-21.
70. Langrish JP, Lundbäck M, Mills NL, et al. Contribution of endothelin 1 to the vascular
effects of diesel exhaust inhalation in humans. Hypertension 2009;54:910-915.
71. Lundbäck M, Mills NL, Lucking A, et al. Experimental exposure to diesel exhaust
increases arterial stiffness in man. Part Fibre Toxicol. 2009;6:7.
72. Peretz A, Sullivan JH, Leotta DF, et al. Diesel exhaust inhalation elicits acute
vasoconstriction in vivo. Environ Health Perspect. 2008;116:937-942.
73. Peretz A, Kaufman JD, Trenga CA, et al. Effects of diesel exhaust inhalation on heart
rate variability in human volunteers. Environ Res. 2008;107:178-184.
74. Brunekreef B, Beelen R, Hoek G, et al. Effects of long-term exposure to traffic-related air
pollution on respiratory and cardiovascular mortality in the Netherlands: the NLCS-AIR
study. Res Rep Health Eff Inst. 2009;139:5-71.
75. Gan WQ, Tamburic L, Davies HW, et al. Changes in residential proximity to road traffic
and the risk of death from coronary heart disease. Epidemiology 2010;21:642-649.
41
76. Health Effects Institute (HEI). Traffic-related Air Pollution: A Critical Review of the
Literature on Emissions, Exposure, and Health Effects. Boston, MA; 2010. (Special
report of the HEI Panel on the Health Effects of Traffic-related Air Pollution).
77. Havard S, Deguen S, Zmirou-Navier D, et al. Traffic-related air pollution and
socioeconomic status: A spatial autocorrelation study to assess environmental equity on a
small-area scale. Epidemiology 2009;20:223-30.
78. Kittelson DB. Engines and nanoparticles: A review. J Aerosol Sci. 1998;29:575-588.