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1
Introduction
Breathing fulfills the vital function
of exchanging the gases of oxygen and car-
bon dioxide. With oxygen, breathing
brings in common toxic air pollutants,
such as nitrogen dioxide, sulfur dioxide,
ozone, carbon monoxide, and particulate
matter. Because of concern for the poten-
tial impacts of these and other pollutants
on public health, the National Heart, Lung,
and Blood Institute, the Office of Health
Research of the Environmental Protection
Agency (EPA), the National Institute of
Environmental Health Sciences, and the
Agency for Toxic Substances Disease Re~is-
try asked the Board on Environmental
Studies and Toxicology (BEST) in the
National Research Council's Commission
on Life Sciences to conduct a study of the
scientific basis, potential use, and cur-
rent state of development and validation
of biologic markers in the respiratory
system. BEST organized the Committee on
Biologic Markers to examine the use of
biologic markers in environmental health
research. Three specific biologic
systems or fields of research were chosen
for study: the reproductive system, the
respiratory system, and the immune sys-
tem. This is the report of the Subcom-
mittee on Pulmonary Toxicology, which was
charged to review potential biologic mark-
ers in the respiratory tract.
11
Biologic markers, broadly defined, are
indicators of variation in cellular or
biochemical components or processes,
structure, or function that are measurable
in biologic systems or samples. For most
purposes in environmental health re-
search, the reason for interest in
biologic markers is a desire to identify
the early stages of disease and to under-
stand basic mechanisms of exposure and
response in research and medical practice.
The growth of molecular biology and bio-
chemical approaches to medicine has re-
sulted in the rapid development of markers
for understanding disease, predicting
outcome, and directing treatment. Many
diseases are now defined, not by overt
signs and symptoms, but by the detection
of biologic markers at the subcellular
or molecular level. For example, liver
and kidney diseases are often diagnosed
by measuring enzymes in blood or proteins
in urine; lead poisoning can be diagnosed
on the basis of blood lead concentrations
and such biologic changes as increases
in heme biosynthesis components in red
cells and urine; and many inborn errors
of metabolism, such as phenylketonuria,
are diagnosed on the basis of cell biochem-
ical findings, rather than expressed dys-
functions. The identification, valida-
tion, and use of markers in medicine and
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12
biology depend fundamentally on increased
understanding of mechanisms of action and
the role of molecular and biochemical proc-
esses in cell biology.
It is important to recognize that markers
represent signals on a continuum between
health and disease and that their defini-
tions might shift as knowledge of the fun-
damental processes of disease progression
increases. That is, today's markers of
exposure might become tomorrow's markers
of early biologic effect. What are per-
ceived at first to be early signals of risk
could come to be considered health impair-
ments themselves because the predictive
relationship is so strong; i.e., an early
signal could represent an effect at a stage
in the progression at which it is difficult
to prevent a disease. Thus, biologic mark-
ers can be valuable in the prevention,
early detection, and early treatment of
disease.
There is growing interest in the use of
biologic markers to study the health ef-
fects of exposure to environmental toxi-
cants in clinical medicine, epidemiology,
toxicology, and related biomedical
fields. Clinical medicine uses markers
to allow earlier detection and treatment
of disease; epidemiology uses markers as
indicators of exposure, internal dose,
or health effects; toxicology uses mark-
ers to help determine underlying mechan-
isms of diseases, develop better estimates
of dose-response relationships, and im-
prove the technical bases for assessing
risks at lower levels of exposure.
TYPES OF BIOLOGIC MARKERS
The Biologic Markers Committee has de-
fined the following concepts related to
biologic markers. Biologic markers are
indicators of events in biologic systems
or samples. It is useful to classify bio-
logic markers into three types-markers
of exposure, of effect, and of suscepti-
bility-and to describe the events peculi-
ar to each type. A biologic marker of ex-
posure is an exogenous substance or its
metabolite or the product of an interaction
between a xenobiotic agent and some target
molecule or cell that is measured in a com-
partment within an organism. A biologic
hL9R=RS IN PULMONARY TOXICOLOGY
marker of effect is a measurable biochemi-
cal, physiologic, or other alteration
within an organism that, depending on mag-
nitude, can be recognized as an established
or potential health impairment or disease.
A biologic marker of susceptibility is an indi-
cator of an inherent or acquired limitation
of an organism's ability to respond to the
challenge of exposure to a specific xenobi-
otic substance. Biologic markers of sus-
ceptibility are discussed in this report
only insofar as they can also serve as mark-
ers of exposure or effect.
Once exposure has occurred, a continuum
of biologic events can be detected. These
events may serve as markers of the initial
exposure, administered dose (circulating
peak or cumulative dose), biologically
effective dose (dose at the site of toxic
action, dose at the receptor site, or dose
to target macromolecules), altered struc-
ture or function with no ensuing pathologic
effect, or potential or actual disease.
Even Bet ore exposure occurs, biologic
differences among humans might cause some
individuals to be more susceptible to en-
vironmentally induced disease. Thus,
biologic markers are tools that can be used
to clarify the relationship, if any, be-
tween exposure to a xenobiotic substance
and disease.
c
Markers of Exposure
Exposure is the sum of xenobiotic mater-
ial presented to an organism, whereas dose
is the amount of the material that is ac-
tually absorbed into the organism or
reaches a target tissue or organ.
Blood flow, capillary permeability,
transport into an organ or tissue, the num-
ber of receptor sites, and route of admin-
istration (which determines the path of
the parent material or its metabolites
in the body) all can influence absorbed
dose or biologically effective dose. An
inhaled carcinogen might produce tumors
in the lung; if the same material were in-
gested and eliminated via the kidney,
renal tumors might be produced. If the
parent material is responsible for the
observed toxicity, the amount of metabo-
lite that reaches the target might be of
no importance. If metabolites are respon
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INTRODUCTION
sible, however, metabolism in the liver,
in another target organ, or elsewhere as
a result of metabolic cooperation between
several tissues is an important determin-
ant of absorbed dose and biologically ef-
fective dose.
Markers of Effect
For present purposes, the effects of
an exposure on an organism (the responses
of an organism to an exposure) are consid-
ered in the context of the relationship
of exposure to disease or to the probabili-
ty of disease. An effect is defined as a
health impairment, a precursor that indi-
cates a likelihood of health impairment,
or an event peripheral to any disease proc-
ess, but correlated with one and thus pre-
dictive of development of disease.
A biologic marker of an effect or re-
sponse, then, can be any change that is
qualitatively or quantitatively indica-
tive of health impairment or potential
impairment (disease process) associated
with exposure. Biologic markers are also
useful to identify endogenous components
or system functions that are considered
to signify normal health. It is important
to recognize, however, that the magnitude
of such a component or function represents
points on a continuum. Therefore, the
boundaries between health and disease can
change as knowledge increases.
Markers of Susceptibility
Some biologic markers indicate individ-
ual or population differences that affect
the biologically effective dose of or the
response to environmental agents indepen-
dentlY of the characteristics of a particu
lar exposure. An intrinsic genetic or
other characteristic or a pre-existing
disease that results in an increase in the
absorbed dose, the biologically effective
dose, or the target-tissue response after
an exposure can be a marker of increased
susceptibility. Such markers include
inborn differences in metabolism, varia-
tions in immunoglobulin concentrations,
low organs reserve capacity, and other
identifiable genetically determined or
environmentally induced variations in
13
absorption, metabolism, and response to
environmental agents. Other factors that
can affect individual susceptibilities
include the nutritional status of the or-
ganism, the role of the target site in con-
trolling overall body function, the
condition of the target tissue (whether
disease is or was present), and compensa-
tion by homeostatic mechanisms during and
after exposure. The reserve capacity of
an organ to recover from an insult at the
time of exposure can play an important role
in determining the extent of an impairment.
VALIDATION OF BIOLOGIC
MARKERS
The usefulness of a biologic marker must
be validated by establishing the existence
of a relationship between an environmental
exposure and the biologic change of inter-
est. Two characteristics of assessment
determine the validity of a marker: sen-
sitivity and specificity. Sensitivity
is the extent to which a biologic marker
indicates that a particular characteris-
tic is present when it is present. If sen-
sitivity is high, the probability of ob-
taining false-negative results is low.
Specificity is the extent to which a bio-
logic marker indicates that a particular
characteristic is absent when it is absent.
If specificity is high, the probability
of obtaining false-positive results is
low.
It is desirable for a marker to be as spe-
cific and as sensitive as possible. Speci-
ficity is needed to be able to associate
a biologic marker with exposure to a speci-
fic pollutant. Sensitivity is required
because many environmental exposures are
airborne pollutants at low concentra-
tions. The ideal biologic marker of an
environmental exposure would be pollu-
tant-specific, available for analysis
with noninvasive techniques, detectable
in trace concentrations or at very low
activities, inexpensive to detect, and
quantitatively relatable to the degree
of exposure. Very rarely will all those
qualities be available in a biologic
marker. Most markers discussed in this
report lack at least one of the attributes.
Furthermore, many, if not most, diseases
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14
can be due to multiple causative agents,
only some of which are environmental.
Nevertheless, biologic markers provide
valuable information that can improve our
ability to determine the extent of environ-
mentally induced respiratory disease.
Before many markers can be used for large
epidemiologic field studies, efforts must
be directed toward both the miniaturiza-
tion of laboratory techniques and the pre-
servation and banking of appropriate spe-
cimens. Those efforts initially must be
carried out by laboratory scientists de-
veloping new biologic markers and-because
of the intensity of the developmental ef-
forts-will usually be of only second-
order interest. DelaYs in taking the new
_
techniques from the laboratory and apply-
ing them to population-based field studies
will be inevitable.
A useful approach to the validation of
biologic changes as markers is to use ex-
perimental studies in animals and clinical
(human) studies to develop a matrix of
information that enables one to make es-
timates for humans (Table 1-1~. For ex-
ample, markers of acute effects of short-
term, low-concentration exposures to a
pollutant can be detected in both animals
and humans. A comparison of this informa-
tion with markers of chronic effects re-
sulting from long-term exposure of animals
to the same pollutant could lead to the
development of markers that are more pre-
dictive of health effects in chronically
exposed humans (McClellan, 1986~.
Numerous instances of clinical research
and animal toxicology studies have both
used and provided validation of biologic
MARKERS IN PULMONARY TOXICOLOGY
markers. Analysis of bronchoalveolar-
lavage fluid is used to detect markers of
an inflammatory response in the respira-
tory tract (Hunninghake et al., 1979b;
Henderson et al., 1985a; Utell et al.,
1985; Reynolds, 1987~. Those markers have
proved useful in diagnosing, staging, and
planning therapeutic approaches to pul-
monary disease in humans (Reynolds, 1987~;
in screening for pulmonary toxicity of
inhaled pollutants in animals (Henderson
et al., 1 985a); and in detecting human
responses to inhaled pollutants in short-
term clinical studies (Utell et al., 1985~.
From such studies has come information
on potential biologic markers of both the
magnitude and the respiratory effects of
environmental exposure.
It is important to distinguish between
physiologic responses that represent
normal defense mechanisms and responses
that are predictive of disease. An organ-
ism might have a continuum of responses
to a noxious agent-from responses that
lead to removal of the agent or repair of
initial injury to responses that indicate
that irreversible damage has occurred or
is destined to occur. Markers are needed
to indicate where a given response lies
on the continuum.
USE OF BIOLOGIC MARKERS IN THE
RESPIRATORY TRACT
The potential usefulness of markers
applies to all organ systems and tissues.
In this report, discussion is limited to
use of markers in the respiratory tract.
The respiratory tract, as a portal of
TABLE 1-1 Example of a Matrix for Determining the Validity of a Biologic Marker
Nature of External Internal Health
Species Exposure Exposure Dose Effect
A Acute X X X
Chronic X X X
B Acute X - X
Chronic
Human Acute X X X
Chronic ? ? ?
X = Marker determined.
- = Marker not yet determined.
? = Not yet tested.
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INTRODUCTION
entry for airborne pollutants into the
body (and as a route of exit of some materi-
als), should be advantageous for detecting
pollutant-specific markers. If tissues
or cells of the respiratory tract react
chemically with an inhaled pollutant, it
might be possible to detect reaction prod-
ucts in the lumen of the respiratory tract
or in cells washed from it. Gaseous pol-
lutants or the volatile metabolites of
pollutants might be detected in the exhaled
breath of exposed people.
A disadvantage of attempting to assess
toxicant-induced changes in the respira-
tory tract, with respect to potential bio-
logic markers of effects of environmental
exposures, is the lack of specificity of
pulmonary responses in relation to etio-
logic agents. The lung can respond to in-
haled toxic materials in only a few ways:
· Altered breathing patterns and airway
constriction. Altered breathing patterns
are receptor-mediated responses; airway
constriction can result from the direct
action of a variety of stimuli or be mediat-
ed through neurogenic reflexes. Besides
pollutants, potential stimuli include
such agents as various antigens (in sen-
sitized persons), infection, exercise,
cold, and psychogenic factors.
· Cell injury leading to inflammation.
The inflammatory response is character-
ized by an influx of inflammatory cells
and an increased permeability of the al-
veolar-capillary barrier, which might
lead to edema. Such an inflammatory re-
sponse can also be induced by immunologic
responses in a sensitized lung or by infec-
tious agents.
· Persistent alteration of lung struc-
ture, such as fibrosis, chronic obstruc-
tive pulmonary disease (such as chronic
bronchitis or emphysema), granulomatous
disease, or neoplasia. None of these con-
ditions or responses has a specific etiolo-
gy; each can be a response to a variety of
causative agents or conditions.
15
Thus, although biologic markers, such
as changes in respiratory function, can
be used to detect some structural altera-
tions, it is not readily possible to as
sociate a single functional alteration
with a single causative agent. In the same
manner, it might be easy to detect an in-
flammatory response in the respiratory
tract by analyzing bronchoalveolar-lavage
fluid or nasal-ravage fluid, but without
additional information it is not easy to
associate inflammation with a particular
environmental exposure.
The following chapters discuss poten-
tial biologic markers of environmentally
induced pulmonary disease. Some of the
markers represent new techniques made
possible by recent technologic advances.
Others represent new uses of technique
or procedures that have been used in other
fields of research.
STRUCTURE OF THE REPORT
Chapter 2 examines markers of exposure.
The deposition and clearance of inhaled
material is discussed. New methods for
monitoring inhaled material are reviewed
as well as clinical techniques for assess-
ing exposure. Chapter 3 examines current
methods for assessing respiratory func-
tion. In addition, methods for assessing
airway hyperactivity and injury to alveo-
lar and vascular tissues are described.
Chapter 4 discusses methods for structural
assessment of whole lung, airways, and
parenchyma.
Chapter 5 describes the mechanisms of
inflammatory and immune response in the
respiratory system and the associated
markers. Chapter 6 continues the discus-
sion developed in Chapter 5 but focuses
on the cellular and biochemical responses
observed as the lung responds to chemical
insult. Finally, Chapter 7 provides the
recommendations of the Subcommittee on
Pulmonary Toxicology.
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Representative terms from entire chapter:
respiratory tract
