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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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