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OCR for page 133
7
Conclusions and Recommendations
The potential health effects of exposure
to environmental pollutants constitute
a problem of great concern, because of the
quantities of pollutants in question and
the large numbers of people involved. But
the problem is difficult to assess, because
exposures to the pollutants and their
mixtures are generally small. The use of
biologic markers as objective measures
of exposure or response to environmental
pollutants offers a promising new approach
to this problem. Biologic markers poten-
tially can be used to obtain evidence of
exposure to specific chemicals and of
responses to exposure.
The study and use of biologic markers
are growing rapidly. The list of macro-
molecular adducts formed because of ex-
posures to chemicals is expanding daily.
Since the drafting of this report itself,
research on the functions of adhesive
proteins, such as fibronectin and laminin,
and of cellular integrins, which bind to
receptor sites on these proteins, has
exploded, providing potential new markers
for following the progress of normal and
abnormal processes of repair of pollutant-
caused damage.
Listed below are recommendations for
research that offers the best opportunity
to enhance the use of biologic markers in
the study of environmental health effects
on the respiratory tract. Recommendations
aimed at increasing the use of biologic
markers in the dosimetry of inhaled materi-
als are listed first and are followed by
recommendations regarding the use of
such markers in detecting structural,
physiologic, and biochemical responses
to inhaled pollutants.
DOSIMETRY
1. More information is needed on factors
that affect the dosimetry of inhaled toxins
at specific sites along the respiratory
tract. Specifically needed is information
on:
· Regional deposition of inhaled pol-
lutants at various sites along the respira-
tory tract. Considerable information is
available on regional deposition of in-
haled particles larger than .01 ,um in aero-
dynamic diameter, but relatively little
is known about factors that govern the
deposition of inhaled gases, vapors and
ultrafine particles (smaller than .01 ,um
in aerodynamic diameter). Specific fac-
tors that affect deposition, particularly
airway structure, need to be assessed in
both laboratory animals and humans.
· Pollutant effects on clearance of
deposited material. Dosimetry at specific
133
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134
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 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
characteristics of pollutants on the site
of sequestration and on the induction of
injury in the respiratory tract.
2. Physiologic modeling of the phar-
macokinetics of inhaled materials in ani-
mals and humans shows promise for allowing
extrapolation of dosimetrv 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 described
in Recommendation 1 above.
3. One region of the respiratory tract
that has received little attention but
is readily accessible for sampling is the
nose. The analysis of nasal rinses or spu-
tum to detect exposures to specific pol-
lutants could be useful. It must be applied
with appropriate knowledge of dosimetry
differences between the nose and the rest
of the respiratory tract when different
toxicants are inhaled.
4. Macromolecular adduct formation of-
fers a promising new method of measuring
exposure to organic compounds that are
or can be metabolized to reactive forms.
Further research on the kinetics of adduct
formation and clearance is required to
determine the relationship between ex-
posure history and the concentration of
adducts in blood or tissue samples.
5. Most research has been on formation
of adducts with DNA and hemoglobin. Adducts
with other macromolecules, particularly
those with site specificity, should be
explored as markers of dose.
MARKERS IN PULMONARY TOXICOLOGY
PHYSIOLOGIC MEASUREMENTS
1. Existing physiologic tools need to
be extended and new tests need to be de-
veloped and evaluated to focus on specific
sites of action of environmental pollut-
ants and specific effects of given pollut-
ants. That requires evaluation of patho-
physiologic correlates assessed initially
in animals and later in humans, both in con-
trolled exposure settings and in popula-
tion-based samples.
2. Further research is required on the
role of nonspecific airway reactivity in
identifying persons susceptible to en-
vironmental agents and on the role of air-
way 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 increased risk of development
of COPD.
3. Linkages among altered 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.
4. 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 func-
tions. Refinements in techniques are need-
ed to render them applicable to the screen-
ing of large numbers of people for vascular
function.
5. Immunologic, biochemical, cyto-
logic, and structural markers identified
as related 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.
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CONCLUSIONS AND RECOMMENDATIONS
STRUCTURE AND FUNCTION
1. Animal studies are needed for in-
creasing understanding of the pathogenic
sequelae related to particle dose at spe-
cific sites in the lung. Examples of some
analytic methods that can be made highly
site-specific and cell-specific are mor-
phometry, immunocytochemistry, histo-
chemistry, and in situ hybridization.
2. Research is required on the specific
cell kinetics of response to injury. La-
beling indexes determined by autoradiog-
raphy 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.
3. 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 reconstruc-
tions, time-lapse photography, and high-
voltage electron microscopy can be applied
to obtain data on cell function and cell
regulation.
4. Cell and organ culture models should
be developed for extrapolating animal data
on histologic changes to humans. Findings
on early histologic markers of exposure
and injury in animals are difficult to
apply to humans, because they require in-
vasive techniques. New ways to maintain
and use human cells obtained by BAL, trans-
bronchial lung biopsy, and tracheal ex-
planation need to be developed.
CELLULAR AND BIOCHEMICAL
RESPONSE
1. Bronchoalveolar ravage (BAL) has
proved useful for evaluating lung inflam-
mation,but further research is required
135
to determine its utility for assessing
pollutant exposure. Interspecies studies
are needed to determine relationships
between changes in BAL constituents and
site-specific and pollutant-specific
inj ury. Where applicable, clinical
studies should be used for confirmation
of results.
2. Cell and mediator changes found in
BAL and nasal-wash fluid need to be related
to physiologic and pathologic changes to
assess their utility as biologic markers.
Furthermore, ravage fluids should be ana-
lyzed to determine whether exposure to
particles or gases changes chemotactic
activity. Alterations could be due to
depletion or activation of pulmonary CSa,
oxidants, arachidonic acid metabolites,
growth factors, and other chemotactic
factors that might be important markers
of response.
3. Nasal ravage needs to be investigat-
ed as a means of evaluating pollutant ex-
posure and as an epidemiologic tool. The
characteristics of BAL-fluid, nasal-
lavage fluid, and whole lung specimens
need to be correlated in humans and animal
models.
4. 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 be-
tween phenotypic changes, pollutant ex-
posure, and cell function should be es-
tablished.
5. It would be of value to identify mark-
ers of susceptibility. Changes in cells
and mediators in ravage fluid should be
examined as possible markers of suscep-
tibility.
6. Early markers of late-stage dis-
ease should be developed to serve as molec-
ular probes of mechanisms of health im-
pairment.
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Representative terms from entire chapter:
biologic markers
