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OCR for page 1
Executive Summary
In the course of a year, an adult breathes
approximately 7 million liters of air.
Industrial workers breathe about 20
liters/minute, and runners can create
up to 80 liters/minute. As part of the
body's autonomic processes, breathing
fulfills the vital function of exchanging
the gases of oxygen and carbon dioxide.
Along with air, respiration can bring in
common air pollutants, such as toxic pol-
lutants, respirable particulate matter,
and the "criteria" air pollutants-nitro-
gen dioxide, sulfur dioxide, ozone, and
carbon monoxide.
Original interest in reducing the
intake of these pollutants came directly
from episodes of severe air pollution that
were clearly linked with immediate in-
creases in deaths related to respiratory
disorder, such as those in the Meuse Val-
ley, Belgium, in 1930 and in Donora, Penn-
sylvania, in 1948. By December 1952, the
"great fog" of London had killed an esti-
mated 4,000 residents, many of whom were
elderly persons who already had heart
and lung problems. Sobered by such epi-
sodes, the United States developed an
aggressive program for reducing air
pollutants.
Still, subtle differences in pulmonary
performance can occur and chronic pulmon-
ary problems afflict one of every five
persons; exposure even of healthy persons
to environmental pollutants, even at their
current magnitudes, plays a role. Such
problems include reductions in the
maximal amount of air that can be expelled,
increases in chest tightness, wheezing,
and possibly even cancer. Young children,
elderly persons, and those with chronic
diseases are likely to be especially vul-
nerable to pollution; respiratory symp-
toms can occur in them when concentrations
of air pollutants increase even slightly.
In light of these longstanding and con-
tinuing concerns and corresponding con-
cerns for other elements of public health,
the Board on Environmental Studies and
Toxicology (BEST) of the National Research
Council's Commission on Life Sciences
undertook a major investigation of the
use of biologic markers in health research.
At the request of the Office of Health Re-
search of the U.S. Environmental Protec-
tion Agency (EPA), the National Institute
of Environmental Health Sciences, and the
Agency for Toxic Substances and Disease
Registry, the Committee on Biologic
Markers was formed to clarify the concepts
and definitions of biologic markers. After
completion of its task, the committee or-
ganized two subcommittees: the Subcom-
mittee on Reproductive and Neurodevelop-
mental Toxicology (with individual panels
on male reproduction, female reproduc-
tion, pregnancy, and neurodevelopment),
OCR for page 2
2
and the Subcommittee on Pulmonary Toxicol-
ogy, which developed this report.
This executive summary encapsulates
each of the seven chapters in the body of
the report and presents a summary of the
major conclusions and recommendations.
Preceding the summary of the chapters are
introductory sections that present con-
cepts, definitions, and selected applica-
tions of biologic markers.
CONCEPTS AND DEFINITIONS
The committee has defined, as described
in Chapter 1, the following concepts re-
lated to biologic markers. Biologic mark-
ers in the context of environmental health
are indicators of events in biologic sys-
tems or samples. It is useful to classify
biologic markers into three types-markers
of exposure, of effect, and of suscepti-
bility-and to describe the events peculiar
to each type. A biologic marker of expo-
sure is an exogenous substance or its me-
tabolite 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
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
indicator of an inherent or acquired limit-
ation of an organism's ability to respond
to the challenge of exposure to a specific
xenobiotic substance. Biologic markers
of susceptibility are discussed in this
report only insofar as they also can serve
as markers 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 patho-
logic effect, or potential or actual
health impairment. Even before exposure
occurs, biologic differences among
humans might cause some to be more suscep
AL4RKERS IN PULMONARY TOXICOLOGY
tible to environmentally induced disease.
Thus, biologic markers are tools that can
be used to clarify the relationship, if
any, between exposure to a xenobiotic com-
pound and health impairment.
Markers of Exposure
Exposure is the sum of xenobiotic mater-
ial presented to an organism, whereas dose
is the amount of the xenobiotic compound
that is actually absorbed into the
organism.
Blood flow, capillary permeability,
transport into an organ or tissue, the
number of receptor sites, and route of
administration (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 that is retained in
the lung might produce tumors in the lung;
if the same material were ingested and
eliminated via the kidney, renal tumors
might be produced. If the parent material
is responsible for the observed toxicity,
the amount of metabolite that reaches the
target might be of no importance. If metab-
olites are responsible, however, metabo-
lism in the liver, another target organ,
or elsewhere as a result of metabolic coop-
eration between several tissues is an im-
portant determinant of absorbed dose and
biologically effective 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 health impairment or to
the probability of health impairment.
An effect is defined as an actual health
impairment or recognized disease, an
early precursor of a disease process that
indicates a potential for health im-
pairment, or an event peripheral to any
disease process, but correlated with one
and thus predictive of development of
health impairment.
A biologic marker of an effect or re-
sponse, then, can be any change that is
qualitatively or quantitatively predic
OCR for page 3
EXECUTED: sentry
live of health impairment or potential
impairment associated with exposure.
Biologic markers are also useful to iden-
tify endogenous components or system
functions that are considered to signify
normal health, e.g., blood glucose. It
is important to recognize, however, that
the concentration or presence of such mark-
ers represents points on a continuum.
Therefore, the boundaries between health
and disease can change as knowledge in
creases.
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 an exposure under study. An in-
trinsic genetic or other characteristic
or a pre-existing disease that results
in an increase in the absorbed dose, the
biologically effective dose, or the tar-
get-tissue response can be a marker of
increased susceptibility. Such markers
include inborn differences in metabolism,
variations in immunoglobulin concentra-
tions, low organ reserve capacity, or
other identifiable genetically deter-
mined or environmentally induced varia-
tions in absorption, metabolism, and re-
sponse to environmental agents. Other
factors that can affect individual sus-
ceptibilities include nutritional status
of the organism, the role of the target
site in controlling overall body func-
tion, the condition of the target tissue
(whether disease is or was present), and
compensation 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 ex-
tent of an impairment.
EXTRAPOLATION FROM ANIMALS
TO HUMANS
Extrapolations of data from animals
to humans should be based on the most sen-
sitive animal species tested, barring
clear evidence that that species is toxi-
cologically distinct from humans. Recent
3
ly, EPA issued guidelines for evaluating
exposure studies and other guidelines
concerning various toxic effects (e.g.,
reproductive mutagenicity). Those guide-
lines provide a means to estimate data
quality and stipulate the types of data
that are necessary to estimate exposure
for assessment evaluations.
Laboratory animals and humans can dif-
fer in structure, physiology, and phar-
macokinetics. Thus, data from animals
must be used carefully in determining
health risks in humans. Important similar-
ities and differences in relation to par-
ticle deposition and clearance between
laboratory animals and humans must be con-
sidered when animal data are used to model
human diseases. It has been particular-
ly difficult to model asthma and emphy-
sema. Furthermore, animal models of ef-
fects of suspected human carcinogens-such
as radon, cigarette smoke, and arsenic-
have been difficult to develop.
The toxicity of some chemicals is medi-
ated by activation or detoxification bio-
transformation reactions. Inasmuch as
biotransformation differs among species,
it is important to establish whether the
routes and rates of human and animal meta-
bolic pathways are similar.
Health risks often are associated with
combinations of effects in humans. For
example, cardiovascular disease in humans
can encompass atherosclerosis and hyper-
tension. Although swine provide the most
suitable animal model for studying spon-
taneous atherosclerosis, young rats might
be most appropriate for studying hyper-
tension. Estimating human risks neces-
sarily would entail some appropriate
combination of the relevant animal test
systems.
A common source of uncertainty in risk
assessment is the dose-response relation-
ship at low doses or for rare effects.
It is often impractical to conduct animal
studies of effects at low doses, because
large numbers of animals are required to
detect a low incidence of an effect. Dem-
onstrable health effects in humans, given
the limits of epidemiology, often are as-
sociated with high doses. Sensitive molec-
ular markers being developed will permit
study of the relationship between exposure
OCR for page 4
4
to chemicals at low ambient concentrations
and the formation of a molecular marker
predictive of human risk. The development
of biologic markers might enable scien-
tists to make better use of laboratory-
animal data in estimating the effects of
chemicals in humans.
As a 1986 National Research Council
study on drinking water and health ob-
served, the timing of exposure and the
dose-response patterns in animal studies
have important implications for extrapo-
lating the resulting data to humans.
MARKERS OF EXPOSURE
As the portal of entry for airborne pol-
lutants, the respiratory tract should
be an excellent site for detecting pollu-
tant-specific markers. From the fine
cilia and mucosa of the nasal passages,
through the trachea, to the bronchi, bron-
chioles, and moist alveolar membranes,
the respiratory anatomy may be considered
a system for detecting and identifying
a variety of markers. Investigators seek
markers of general pulmonary function
or toxicity that reflect such deviations
from normal conditions as altered
breathing patterns and airway constric-
tion. Specific exposure markers can be
devised by sampling and examining tissue
in the nose and lung (e.g., with nasal or
bronchoalveolar ravage) and noting con-
centrations of pollutants of interest,
such as diesel-exhaust particles, chryso-
tile asbestos, wood dust, fiberglass,
wollastonite, iron, silica, and volcanic
ash.
This report assesses various respira-
tory phenomena as markers of exposure,
disease, and in some cases predisposition
to disease. The respiratory system can
respond to inhaled toxicants in only a
few ways. Pollutants, antigens, infec-
tion, exercise, cold, and psychologic
factors can all alter breathing patterns
and lead to airway constriction; and per-
sistent alteration of lung structure can
occur in persons with chronic obstructive
pulmonary disease (such as chronic
bronchitis or emphysema, fibrosis, granu-
lomatous disease, or neoplasia). None
of those responses can be associated with
WIRERS IN PULMONARY TOXICOLOGY
a specific etiology; each can result from
a variety of causative agents or condi-
tions. Yet some markers could be chosen
as peculiar to a specific disease state
and could be quantitatively relatable to
the degree or stages of the disease.
Chapter 2 describes several new ap-
proaches to the use of biologic markers
for providing information on respiratory
tract dosimetry. The development of bio-
logic markers of exposure to xenobiotics
offers much promise. New molecular bio-
logic techniques permit the measurement
of such molecular markers as adducts form-
ed with macromolecules in the body, the
techniques can be used to detect adducted
material in blood, urine, and tissue
samples and are sensitive enough for the
measurement of adducts formed with DNA
or protein in cells washed from the respir-
atory tract or collected in sputum.
Innovative procedures, such as magneto-
pneumography, allow estimation of the
lung burdens of some types of particles.
Refined histologic techniques have re-
vealed the cellular sites of deposition
of inhaled particles in the lung and thus
created the potential for calculating
the dose to critical cells. And techniques
for analyzing markers are well advanced;
e.g., new techniques allow analysis of
exhaled air, sputum, nasal ravage fluid,
and bronchoalveolar ravage fluid for
chemical evidence of exposure to specific
pollutants. The field of mathematical
modeling has advanced to the point where
models now include physiologic measure-
ments, such as blood flow rates, ventila-
tion rates, metabolic rates, and both
blood-air and blood-tissue partition
coefficients. The models have made it
much easier to extrapolate data from ani-
mal pharmacokinetic studies to predicted
deposition and distribution in humans.
To make optimal use of the new tech-
niques, we must determine the relation-
ship between markers of exposure and the
characteristics of the exposures that
generate them. The markers usually yield
only yes-no answers; that is, a particular
exposure did or did not occur. But we need
to determine the kinetic relationships
between formation and breakdown of mark-
ers, so that we can use mathematical
OCR for page 5
EXECUTM? SPRY
models to answer the question, "Given this
amount of this marker in this tissue, what
exposures could have produced the marker?"
In addition, there is a need to explore such
readily available respiratory tract flu-
ids as nasal fluids and sputum for chem-
ical markers of exposure to specific
pollutants.
Chapter 2 briefly summarizes methods
for collecting clinical information.
The standardized questionnaire on respir-
atory disease can play an important role
in identifying markers of potential res-
piratory disease. Neither the clinical
history of a patient nor information ob-
tained from a population with a stand-
ardized questionnaire constitutes bio-
logic material, but such information is
important in identifying the potential
for respiratory disease. For instance,
severe respiratory illness before the
age of 2 years implies a likelihood of res-
piratory illness in later childhood;
and persistent wheezing in childhood pre-
dicts abnormal pulmonary function in
adulthood. Since the early 1950s, efforts
to develop standardized procedures for
gathering clinical and epidemiologic data
on pulmonary health status have been in
place. One of the most successful ques-
tionnaires has been the one developed by
the British Medical Research Council and
adopted by the American Thoracic Society.
This questionnaire is used widely in the
United States and throughout the world.
Chapter 2 shows the importance of deter-
mining the mechanisms by which environ-
mental pollutants induce lung disease.
What are the sites of toxic actions? How
much of a given pollutant is required at
a given site to produce a given toxic re-
sponse? Knowledge of the mechanisms by
which toxicity occurs should provide
the most pertinent information on poten-
tial early markers of exposure to environ-
mental pollutants and initial stages of
response to them.
MARKERS OF PHYSIOLOGIC
EFFECTS IN INTACT ORGANISMS
Chapter 3 describes the role of physio-
logic measurements of the functional sta-
tus of the respiratory tract, which are
s
applicable for use in intact humans and
animals. These measurements range from
commonly used clinical tests of respira-
tory function to currently developing
assays of the integrity of tissue bar-
riers. Most of the measurements described
in this chapter are relatively noninvas-
ive and do not require anesthesia, cath-
eterization, or collection of tissue sam-
ples. Several are readily adaptable to
large-scale epidemiologic studies; how-
ever, some that require extensive or high-
ly sophisticated equipment are best suit-
ed to studies of small groups.
The physiologic markers of early biolog-
ic effects in intact organisms can be de-
scribed in four general categories:
· Markers of changes in respiratory
(gas-exchange) function of the lung.
These are derived from measurements of
ventilation and its control, lung mechan-
ical properties, intrapulmonary gas dis-
tribution, and alveolar-capillary gas
exchange. A wide variety of such measure-
ments have been developed and are in common
use.
· Markers of increased airway reactivi-
ty, both to specific environmental agents
and to standardized physiologic provoca-
tion. These are usually indexes of respir-
atory function. They are distinct from
markers in the first category, in that
the focus is not on gas exchange.
· Markers of change in clearance of par-
ticles. Measurement is used to examine
an important set of respiratory defense
mechanisms, and alterations of the mech-
anisms at times provide an early indica-
tion of an adverse effect of inhaled
environmental agents.
· Markers of increased permeability
of the air-blood barrier and of increased
uptake of potentially injurious materials
in the lung. Increase in permeability
is sometimes an early feature of lung in-
jury due to inhaled particles.
MARKERS OF ALTERED
STRUCTURE OR FUNCTION
Chapter 4 describes two of the simplest
methods of assessing alterations in lung
structure: examination with the naked
OCR for page 6
6
eye and microscopic examination. Of
course, access to relevant materials in
vivo is problematic, requiring in most
cases direct access to lung tissue during
surgical procedures. Lung tissue at
autopsy is very helpful in establishing
the burden of inhaled particles. Separate
autonomic regions can be sampled, and quan-
titative data obtained. Apart from gross
examination of lung tissue, both light
and electron microscopic examination can
be useful. Light microscopy has the ad-
vantages of speed, accuracy, and low cost.
It also has some limitations, in that the
types of measurements of tissue compart-
ments are restricted. Such measurements
are more easily made with electron micros-
copy. However, electron microscopy re-
quires expensive equipment and more
highly trained personnel. Newer
techniques using electron and x-ray
microscopy can also identify elements such
as silica, cobalt, and nickel in human
lung.
The proliferation of epithelial cells,
fibroblasts, and macrophages can be meas-
ured microscopically. Proliferation
of those cells can serve as markers of lung
damage. For example, oxidant gases and
chrysotile asbestos fibers cause rapid
incorporation of tritiated thymidine into
bronchiolar and alveolar cells. Detec-
tion and analysis of inhaled particles
are possible with microscopic techniques.
The size and distribution of particles
in pulmonary tissue can be assessed with
current morphometric techniques.
MARKERS OF INFLAMMATORY AND
IMMUNE RESPONSE
Chapter 5 discusses markers associated
with the inflammatory and immune responses
of the respiratory tract. Inflammation
in the lungs starts with the macrophage,
the resident cell in the lower respiratory
tract. The macrophage response is usually
followed rapidly by an influx of neutro-
phils, which can damage tissue directly.
Neutrophils are, however, most effective
for destroying bacteria, and their pres-
ence constitutes a primary response to
injury in any part of the body. The presence
and timing of the neutrophil influx are
MARKERS IN PULMONARY TOPOLOGY
good markers of inflammatory response in
the respiratory tract. Neutrophils are
seen in nasal washings and in other biolog-
ic samples from the respiratory system
after exposure.
Another inflammatory cell, which is
less commonly seen, is the eosinophil.
It is attracted to the lung by chemotactic
factors released during an inflammatory
response. Like neutrophils, eosinophils
can release chemotactic factors for other
cells. They can also release several
potential irritants, including oxygen
radicals and leukotrienes.
The influx of neutrophils and eosino-
phils is usually seen in the first 3-7 days
of an inflammatory response. If the in-
flammatory response is sustained, it is
usually accompanied by a specific immune
response. The immune response is general-
ly mediated by lymphocytes, which migrate
into the inflamed area within days of the
original insult.
Apart from cells in the inflamed area
that serve as markers, proteins and other
products of cells can be detected. Those
products often appear in predictable pat-
terns that allow one to estimate the dura-
tion and intensity of the inflammatory
response. Increases in proteins and other
products in biologic fluids, such as bron-
choalveolar ravage fluid, can serve as
sensitive markers of the inflammatory
response.
The human respiratory tract contains
a complex array of host defenses-anatom-
ic barriers, mucociliary clearance, phag-
ocytic cells, and various components of
cellular and humoral immunity-that col-
lectively cleanse inhaled air and inac-
tivate infectious and other injurious
agents that are inhaled. In particular,
the mucosal lining of the small airways
and alveolar airspaces contains many com-
ponents of the immune system that are im-
portant in protecting the normal lung.
However, some of the components also play
an important role in immunologic lung
disease.
Antigen-antibody complexes are the
basis of immune response. The initial
phase of the immune response usually be-
gins with antigen processing by phago-
cytes, such as macrophages. That includes
OCR for page 7
EXECVTM: SPRY
degradation of foreign substances and
exposure of lymphocytes to antigens, which
stimulate the production of antibody,
sensitized cells, or both. Chapter 5
describes the mechanisms of the immune
response and the different cells and fac-
tors involved in the immune response that
can be used as markers.
MARKERS OF CELLULAR AND
BIOCHEMICAL RESPONSE
Chapter 6 discusses current and devel-
oping cellular and biochemical techniques
that provide a possible source of markers
peculiar to the lung and upper respiratory
tract. The most important of the new tech-
niques are bronchoalveolar ravage and
nasal ravage. The predominant cell in
bronchoalveolar ravage fluids from
healthy people is the macrophage. Howev-
er, in an inflammatory state, neutrophils,
eosinophils, and mast cells might be pres-
ent. Macrophages play an important role
in the regulation of the immune cellular
response, acting as both promoters and
suppressors of events during inflamma-
tion. Thus, bronchoalveolar ravage fluid
is ideally suited to the study of cells from
respiratory tract and their response to
chemical insult in both laboratory ani-
mals and humans. For example, alveolar
macrophages secrete interleukin- 1; the
role of interleukin- 1 as a mediator of
inflammation is uncertain, and broncho-
alveolar ravage is providing important
mechanistic information on it.
Biochemical markers of pulmonary dis-
ease processes are also present in ravage
fluid. Lactate dehydrogenase, a cytoplas-
mic enzyme released from damaged or lysed
cells, can be used as a marker of cytotox-
icity. An increase in this enzyme ac-
tivity can be used to distinguish between
toxic events and physiologic responses.
An increase in serum proteins in the ravage
fluid serves as an indicator of increased
permeability of the alveolar-capillary
barrier. The activity of hydrolytic and
proteolytic enzymes released into the epi-
thelial lining fluid has been shown to
be correlated with the toxicity of inhaled
particles. Biochemical and cellular mark-
ers of inflammation are useful in animal
7
toxicity studies to rank the toxicity of
a series of compounds and to study the mech-
anisms of development of late-occurring
lung diseases, such as fibrosis and
emphysema.
Testing for immune cellular response
has often used whole animals or humans.
The interaction of several components
of the immune system can be tested, and
body responses can be measured, so one
need not rely on extrapolation from results
obtained in vitro. The examination of
individual cellular components is de-
scribed in detail in Chapter 6.
Exposure to environmental toxicants
can cause damage in individual cells at
the level of DNA and other cellular com-
ponents. New techniques are now available
to measure molecular markers of damage
to cell components. Molecular markers
have proved useful in the detection and
diagnosis of some infectious diseases
and in sickle-cell anemia and alpha- and
beta-thalassemia, and they are being de-
veloped for other diseases, such as
Duchenne muscular dystrophy, cystic fi-
brosis, Lesch-Nyhan syndrome, phenylke-
tonuria, antithrombin III deficiency,
and alpha,-antitrypsin deficiency. The
development and use of molecular markers
to identify cellular responses to en-
vironmental toxicants will be important
in increasing understanding of the mech-
anisms involved in pulmonary disease.
RECOMMENDATIONS
The recommendations of the Subcommittee
have been divided into four major groups:
exposure dosimetry, physiologic measure-
ments, structural and functional meas-
urements, and cellular and biochemical
measurements.
Exposure Dosimetry
More information is needed on factors
that affect the dosimetry of inhaled toxi-
cants at specific sites along the respira-
tory tract. Specifically needed is infor-
mation on the following:
· Regional deposition of inhaled pol-
lutants at various sites along the respir
OCR for page 8
8
atory tract. Considerable information
is available on regional deposition of
inhaled particles larger than 0.1 ,um in
aerodynamic diameter, but relatively
little is known about factors that govern
the deposition of inhaled gases, vapors,
and ultrafine particles (smaller than
0.1 Em in aerodynamic diameter). Specific
factors that affect deposition, particu-
larly airway structure, need to be assess-
ed in both laboratory animals and humans.
· Pollutant effects on clearance of
deposited material. Dosimetry at speci-
fic sites in the respiratory tract depends
both on how much is deposited at the site
and on how quickly it is removed. Inter-
species studies of regional clearance are
required.
· The capacity of tissues at the site
of deposition to metabolize a pollutant
to a more toxic or a less toxic form. The
toxicity of an inhaled organic compound
might be increased by metabolic activity
at some sites of deposition.
· Effects of chemical and physical char-
acteristics of pollutants on the site
of sequestration and on the induction of
injury in the respiratory tract.
Physiologic modeling of the pharmacoki-
netics of inhaled materials in animals
and humans shows promise for allowing ex-
trapolation of dosimetry data between
species, sexes, and regimens. Extension
of that approach to the active metabolites
of inhaled compounds would greatly in-
crease our understanding of the toxicity
of inhaled materials. Physiologic model-
ing also requires information on deposi-
tion, clearance, and metabolism.
One region of the respiratory tract that
has received little attention, but is read-
ily accessible for sampling, is the nose.
The analysis of nasal rinses or sputum to
detect exposures to specific pollutants
could be useful. It must be applied with
appropriate knowledge of dosimetry dif-
ferences between the nose and the rest of
the respiratory tract when different toxi-
cants are inhaled.
Macromolecular adduct formation offers
a promising new method of measuring expo-
sure to organic chemicals that are reac-
tive or can be metabolized to reactive
MARKERS IN PULMONARY TOXICOLOGY
forms. Further research on the kinetics
of adduct formation and clearance is
required to determine the relationship
between exposure history and the concen-
tration of adducts in blood or tissue samp-
les. Most research has been on formation
of adducts with DNA and hemoglobin. Ad-
ducts with other macromolecules, particu-
larly those with site specificity, should
be explored as markers of dose.
Physiologic Measurements
Existing physiologic tools need to be
extended and new tests need to be developed
and evaluated to focus on specific sites
of action of environmental pollutants
and specific effects of given pollutants.
That requires evaluation of pathophysio-
logic correlates assessed initially in
animals and later in humans, both in con-
trolled exposure settings and in popula-
tion-based samples.
Further research is required on the role
~ · · · ~. ~
OI lIlCreaSeS In llOIlSpeC11 1C airway reac-
tivity in identifying persons susceptible
to environmental agents and on the role
of increases in airway reactivity in the
natural history of chronic obstructive
pulmonary disease (COPD). The role of
transient changes in airway reactivity
in response to specific environmental
agents needs to be assessed in regard to
risk of development of COPD.
Links among alterations in particle
clearance, environmental exposures, and
development of lung disease need to be
studied further to determine the useful-
ness of clearance as a marker of suscep-
tibility and response.
Markers of early endothelial changes
that would identify persons likely to de-
velop acute or chronic vascular injury
are needed. Markers of endothelial dys-
function that demonstrate toxicant speci-
ficity should be sought. More information
is needed on how endothelial barrier func-
tion is correlated with nonbarrier
functions. Refinements in techniques are
needed to render them applicable to the
screening of large numbers of people for
vascular function.
Immunologic, biochemical, cytologic,
and structural markers identified as re
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EXECUTED? SPRY
lated to specific lung injury need to be
correlated with physiologic measures
of respiratory function, airway reactivi-
ty, particle clearance, and indexes of
air-blood barriers. Understanding of
those relationships could be important
in developing methods for assessing risks
associated with environmental exposures.
Structural and Functional Measurements
Animal studies are needed for increasing
understanding of the pathologic sequelae
of particle disposition at specific sites
in the lung. Examples of some analytic
methods that can be made highly site-spe-
cific and cell-specific are morphometry,
immunocytoche mistry , his to c hem is try ,
and in situ hybridization (i.e., formation
of RNA-DNA hybrids).
Research is required on the specific
cell kinetics of response to injury.
Labeling indexes determined by autoradi-
ography are not adequate for describing
cell kinetics. New techniques, such as
a combination of autoradiography with
morphometry to measure cell pool sizes
before and after injury, can make it pos-
sible to determine changes in the entire
cell cycle during lung injury.
Three-dimensional reconstruction of
cells and tissues could establish changes
in intracellular organelles and cell-cell
relationships that result from exposure
and injury. Such techniques as computer-
assisted tissue reconstructions, time-
lapse photography, and high-voltage elec-
tron microscopy can be applied to obtain
data on cell function and cell regulation.
Lavage fluids should be analyzed to de-
termine whether exposure to particles
or gases changes chemotactic activity.
Alterations could be due to depletion or
activation of pulmonary C5, oxidants,
arachidonic acid metabolites, growth
factors, and other chemotactic factors
that might be important markers of
response.
Cell- and organ-culture models should
be developed for extrapolating animal
data on histologic changes to humans.
9
Findings on early histologic markers of
exposure and injury in animals are diffi-
cult to apply to humans, because they re-
quire invasive techniques. New ways to
maintain and use human cells obtained by
bronchoalveolar ravage, transbronchi-
al lung biopsy, and tracheal exploration
need to be developed.
Cellular and Biochemical Measurements
Bronchoalveolar ravage has proved use-
ful for evaluating lung inflammation,
but further research is required to deter-
mine its utility for assessing pollutant
exposure. Interspecies studies are needed
to determine relationships between
changes in bronchoalveolar-lavage fluid
constituents and site-specific and pol-
lutant-specific injury. Where applic-
able, clinical studies should be used for
confirmation of results.
Cell and mediator changes found in bron-
choalveolar and nasal-ravage fluid need
to be related to physiologic and patho-
logic changes to assess their utility as
biologic markers.
Nasal ravage needs to be investigated
as a means of evaluating pollutant expo-
sure and as an epidemiologic tool. The
characteristics of bronchoalveolar-
lavage fluid, nasal-ravage fluid, and
whole-lung specimens need to be correlated
in humans and animal models.
Monoclonal antibodies and molecular
genetic techniques need to be applied to
characterize types and functions of cells
of the respiratory tract. As those tech-
niques are introduced, relationships
between phenotypic changes, pollutant
exposure, and cell function should be
established.
It would be of value to identify markers
of susceptibility. Changes in cells and
mediators in ravage fluid should be
examined as possible markers of
susceptibility.
Markers of the early events leading to
late-stage disease should be developed
to serve as molecular probes of mechanisms
of disease.
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Representative terms from entire chapter:
biologic markers
