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Motor Vehicle Emissions: A Strategy for Quantifying Risk RICHARD R. BATES ANN Y. WATSON Health Effects Institute Automotive Emissions: A Brief Perspective / 19 Understanding the Components of Risk / 19 Chemical and Physical Properties of Pollutants / 20 Pollutant Exposure and Dose to Biological Tissues / 22 Biological Responses to Pollutants / 23 Sensitive Individuals / 24 Research Approaches / 24 Epidemiology / 24 Experimental Methods / 25 Mathematical Models / 26 Physical Models / 26 Pursuing Quantitative Toxicology: A Strategy for Research / 26 Highlights of the Authors' Recommendations / 27 Criteria for Prioritization / 27 A Proposed Research Strategy / 28 Summary 1 34 Conclusion / 34 Air Pollution, the Automobile, and Public Health. @) 1988 by the Health Effects Institute. National Academy Press, Washington, D.C. 17

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18 A Strategy for Quantifying Risk The ultimate objective of a regulatory- oriented research program that focuses on air pollution from mobile sources is to identify and quantify any effects that those emissions may have on human health. But before we invest intellectual and financial resources, we must first understand the limitations of current information and methodologies that preclude accurate esti- mates of risk to human health. Future research programs should be justified by their promise to overcome these limita- tions. The goal of this volume, then, is to identify issues and select a research agenda that will be most effective in advancing our ability to quantify the health risks associ- ated with air pollution. To understand risk, it is essential to understand the relation between the amount or dose of pollutants, and the response, in terms of human illness, to those pollutants (National Research Coun- cil 1983~. Yet the obstacles that challenge our understanding of that relation are for- midable. Biologists ask, "To what sub- stances are people exposed, and what dose levels are most relevant for experimental studies?" Engineers and physical chemists inquire, "Which of the hundreds of com- pounds and chemical reactions are biologi- cally important?" This volume alone cannot answer these questions, but its discussions are critical to beginning a dialogue among the . . . , . . various sclentl~lc commumtles. The first part of this book addresses research about the exposure of humans to vehicular emissions and their reaction products. The first three chapters examine the nature of automotive emissions John- son), their chemical transformation (At- kinson), and the mechanisms of their trans- port through the atmosphere (Samson). Subsequent chapters explore the use of ambient measurements (Graedel) and math- ematical models (Russell) as ways of de- scribing pollutant concentrations, which in turn are key descriptors of human exposure (Sexton and Ryan). The remaining chapters discuss the principles and mechanisms by which, during exposure, particulate (Schle- singer; Sun, Bond, and Dahl) or gaseous (Overtop and Miller; Ultman) pollutants are inhaled and distributed throughout the respiratory tract. In the second half of this book, the chapters examine whether specific biologi- cal responses to airborne pollutants consti- tute a health hazard. The problem is ap- proached trom two complementary points of view. One view starts with the chemical constituents of automotive emissions and their transformation products and investi- gates their effects on human health. In this approach, oxidants (Bresnitz and Rest), polycyclic aromatic hydrocarbons (PAHs) and nitro-PAHs (Hecht), and alcohols and aldehydes (Marnett) are discussed. In contrast, the second view begins with a set of human diseases and investigates whether automotive emissions or their de- rivatives play a role in disease develop- ment. Attention is given to health effects of obvious relevance to airborne contaminant exposure. Thus, asthma (Bromberg), res- piratory infection (Pennington), cancer (Kaufman), fibrosis (Last), and emphysema and small airways disease (Wright) are con- sidered. Coronary heart disease (Clarkson) is examined because cigarette smoke in- creases mortality, and it is not known if other combustion products affect morbidity and mortality rates. Neurobehavioral effects (Wood) of hazardous substances, which may not be an obvious health effect, also warrant investigation. One's perception of, and re- sponse to, the environment may be just as significant for the "health" of society as clin- ical presentations of organic disease. Thus, this book examines the existing evidence about risks from automotive emissions and evaluates the methodologies presently available to quantify human risks. However, not all possibilities are explored. Areas for which the evidence was lacking or the rationale for associating automotive emission exposure with health risks was not compelling were omitted; examples include the role of automotive-derived pol- lutants in the etiology of reproductive dis- orders or renal dysfunction. By the same token, we did not want to duplicate previ- ous analyses; for example, numerous pol- lutants are described in the U.S. Environ- mental Protection Agency (EPA) Criteria Documents. Unfortunately, even though human exposure is not to a single material or even to a uniform mixture, we were unable to properly explore the issue of

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Richard R. Bates and Ann Y. Watson 19 complex mixtures. Many of the chapters stress the necessity of acquiring better in- formation about atmospheric constituents and quantitative markers of human disor- ders before a research protocol can be for- mulated to test, within the scope of limited resources, the bioactivity of such mixtures. Although the primary focus of this book is automotive emissions a focus fully jus- tified by the omnipresence of motor vehi- cles in our society the scientific principles underlying many of the discussions are applicable to other air pollutants and even to other sources of exposure. First, auto emissions and their derivatives are not the only source, or even the predominant - ~ ized. source, ot ~ auman exposure to many ot these chemical substances. Second, air pol- lutants, whether they originate from auto- mobiles, power plants, or wood-burning stoves, are all governed by similiar princi- ples of transport through the atmosphere and into the body. Finally, the research needed to identify people who are suscep- tible to emphysema, pulmonary fibrosis, or lung cancer is similar whether the causative agents derive from auto emissions, occupa- tional exposures, or cigarettes. The primary purpose of this overview chapter is threefold: (1) to describe the issues and difficulties involved in providing reliable scientific data for risk assessment; (2) to highlight and integrate the authors' recommendations into the issues raised; and (3) to propose a research strategy. We start with putting into perspective the au- tomobile as a source of potentially harmful substances. We next describe components that determine risk of injury and discuss the strengths and weaknesses of various research approaches. We then summarize the authors' choices of future research directions. Finally, after having carefully read the authors' sug- gestions, we conclude with an attempt to translate their individual priorities into a fea- sible, cross-disciplinary research strategy. Automotive Emissions: a Brief Perspective Motor vehicles contribute significantly to . . . . . . . ,- emlsslon Inventories In certain regions ot the United States, particularly in urban areas. Table 1 shows the relative contribu- tion of various emission sources to the total inventory of five pollutants for the country as a whole and for two metropolitan areas. Typically, in urban areas, motor vehicle emissions dominate carbon monoxide in- ventories and can contribute up to 50 per- cent or more of nitrogen oxides and hydro- carbons. It is, however, important to remember that these figures reflect outdoor pollutant concentrations. Most people in industrialized societies spend more time indoors than outdoors, and the contribu- tion of motor vehicles to pollution of in- door air has not been adequately character l wo additional points are worth noting. First, volatile organic compounds and total suspended particulates are broad categories that include many individual compounds of divergent toxicologic importance. Thus, table 1 may not adequately portray the relative impact of these emission sources on human health. Second, comparable data are not available for unregulated emissions which include many compounds of possi- ble toxicologic interest. Therefore, even though motor vehicles emit numerous chemical species into the environment, we cannot determine, with current data bases, the relative contribution of mobile sources to the health risks of our society. Understanding the Components of Risk Pollutants and their derivatives cause harm by interacting with, and impairing, mol- ecules crucial to the biochemical or phys- iological processes of the human body. Figure 1 illustrates the pathways from pol- lutant sources to toxic effects. Clearly, it is difficult to link a specific pollutant to a particular ill effect until the processes in between are understood. The risk of toxic injury from a substance depends on three factors: the chemical and physical proper- ties of the substance, the dose of the mate- rial that reaches critical tissue sites, and the responsiveness of these biological sites to the substance. The relationship of each

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20 A Strategy for Quantifying Risk Table 1. Relative Contribution of Various Sources to Emissions of Regulated Pollutants United States: 1984a 106 tons/year (%) Volatile Total Carbon Nitrogen Organic Suspended Sulfur Source Monoxide Oxides Compounds Particulates Oxides Transportationb 48.5 (69) 8 7 (44) 7 2 (33) 1.3 (19) 0.9 (4) Fuel combustionC 8 3 (12) 10.1 (51) 2 6 (12) 2 0 (29) 17.3 (81) Industrial process 4.9 (7) 0.6 (3) 8 4 (39) 2 5 (36) 3 1 (15) Solid waste disposal 1.9 (3) 0.1 (1) 0.6 (3) 0.3 (4) 0.0 (0) Other 6.3 (9) 0.2 (1) 2 7 (13) 0.9 (13) 0 0 (0) Metropolitan Los Angeles: 1981 103 tons/year (%) Transportationb 3,859 (92) 399 (62) 406 (44) 431 (59) 57 (26) Fuel combustionC 45 (1) 193 (30) 27 (3) 20 (3) 64 (29) Industrial process 110 (3) 48 (7) . 223 (24) 31 (4) 97 (44) Solid waste disposal 116 (3) 2 (I) 39 (4) 16 (2) 0 (0) Other 76 (2) 1 (1) 239 (26) 235 (32) 0 (0) New Jersey-New York-Connecticut: 1981 103 tons/year (%) Transportationb 4,248 (94) 349 (58) 397 (38) 361 (53) 50 (12) Fuel combustionC 91 (2) 229 (38) 26 (2) 42 (6) 315 (75) Industrial process 26 (1) 9 (2) 276 (27) 194 (29) 47 (11) Solid waste disposal 125 (3) 10 (2) 31 (3) 41 (6) 7 (2) Other 24 (1) 1 (1) 311 (30) 39 (6) 0 (0) a From U.S. Environmental Protection Agency (1986). b Includes motor vehicles, rail, aircraft, vessels. c Includes stationary sources such as residential, electric generation, industrial, commercial-institutional. ~ From U.S. Environmental Protection Agency (1984). component to the scheme presented in fig- ure 1 is discussed below. Chemical and Physical Properties of Pollutants Exhaust from the tailpipe of motor vehicles is a complex mixture that contains hun- dreds of chemicals in the form of gases as well as solid and liquid aerosols. The com- position of the mixture depends on the fuel, the type and operating conditions of the engine, and the effects of any emission control devices. Upon their release, emit- ted substances are transformed by complex atmospheric chemical reactions. Airborne pollutants, therefore, consist of primary tailpipe emissions (for example, carbon monoxide, nitric oxide), and new chemical species formed as a result of atmospheric reactions (for example, nitrogen dioxide, ozone); the opportunity for chemical diver- sity is immense. In addition, the chemical composition is dynamic; the air we breathe today is different than the air we breathed 10 years ago. Therefore, a changing con- stituency must be recognized in any evalu- ation of chronic health effects. The physical form of airborne contami- nants will influence their distribution both in the atmosphere and in biological tissues. As emissions cool, some vapors are ad- sorbed onto particles or condensed into droplets, and fine particles and droplets coalesce into large ones. Upon inhalation, the regional tissue distribution of gases or aerosols depends on such physical proper- ties as size and solubility. In addition, the deposition, metabolism, and clearance of volatile organic compounds are dramati- cally altered if they are adsorbed onto respirable particles. Eventual dose, there

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Richard R. Bates and Ann Y. Watson 21 Fuel Engine characteristics Emission controls Other sources Mobile source emlsslons, , Sinks r~ GENETIC AND I ENVIRONMENTAL I MODIFIERS 1 Detoxification Primary pollutants Atmo. Ph. uric r r ; I Ind oor | pollutants | ) I Dose to pulmonary tissues l Metabolism Dose to / \ I target tissues | Cellular and | molecular cascade l l | toxic agents 1 t: - Figure 1. Pathways from pollutant sources to toxic effects. fore, is intimately associated with the phys- ical properties of the airborne contami- nants. Because chemical structure and physical characteristics are important determinants of toxicity, an improved understanding of these properties is essential. For example, slight modifications of functional groups on PAHs can markedly alter the mutagenic potential. Nasal, but not bronchial, tumors have been found in rats after prolonged exposure to formaldehyde, which, because of its solubility, is absorbed in the nasal cavity. In addition, some compounds have

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22 A Strategy for Quantifying Risk similar properties but different biological effects. Ozone and nitrogen dioxide are oxidants, but only nitrogen dioxide pro- duces emphysema in laboratory animals. Other as-yet-unidentified factors must in- fluence outcome. Information about struc- ture and toxicity is available for some classes of closely related materials that have been studied extensively. For most sub- stances in the environment, however, data necessary for quantitative prediction of toxicity based on chemical or physical . . . properties are Sac Equate or unavailable. Pollutant Exposure and Dose to Biological Tissues Pollutants derived from vehicular exhaust are transported away from their sites of release by wind and diffusion. Once air- borne, they mix both with pollutants from other sources and with materials of natural origin, and they may be chemically trans- formed into other species. Ultimately, at- mospheric pollutants are removed from the air either by rain or by dry deposition to the earth's surface. Highly reactive chemicals may be transformed or removed within a few minutes; stable substances may persist for years. Meteorological conditions and physical structures can also profoundly in- fluence atmospheric concentrations. Thus, individual exposure is determined by the location a person occupies in relation to emission sources, as well as by patterns of atmospheric transport, transformation, and dilution. Airborne pollutants that are inhaled may deposit onto surfaces of the respiratory tract. Deposited insoluble material is moved (either intra- or extracellularly) toward the pharynx by mucociliary action and then swallowed. Alternatively, particles may be sequestered for long periods within pulmo- nary tissue or in adjacent lymph nodes. Inhaled chemicals that dissolve in body fluids may pass from the respiratory tract into the bloodstream and circulate through- out the body. As a result, air pollutants may affect extrapulmonary organs. Pollutants may be chemically trans- formed within the body by metabolic en- zymes. The liver is particularly active in the metabolism of foreign chemicals, but the lung and other organs also have this capac- ity. In general, metabolism facilitates ex- cretion of pollutants from the body and thus reduces pollutant levels in body tis- sues. In addition the toxic potential of some parent compounds may be reduced by met- abolic conversion. Paradoxically, though, metabolism may also generate products with increased toxicity. The balance be- tween metabolic processes that increase toxicity, decrease toxicity, or favor elimi- nation is an important factor in the sensi- tivity of an individual to a toxic chemical. The definition of "dose" may vary widely. It may be based on the concentra- tions of inhaled pollutants at any point from their deposition on respiratory tract surfaces, to the concentrations of reactive material at "target sites," where damage occurs. The latter is the most valuable definition of dose and the most difficult to determine. Dose-to-target measurements require identification of the sites of dam- age, understanding the mechanisms by which the toxic material produces damage, and knowledge of the reactive materials responsible for toxicity. Obtaining such information from laboratory animals or tissue cultures is not trivial and is seldom feasible in living human beings. Instead, for most practical purposes, we must rely on some surrogate measurement of dose-to-target sites. This may be the dose to some other, but more accessible body tissues, such as the blood or respira- tory tract. Alternatively, it may be a mea- sure of exposure, or even of atmospheric concentration. The more removed the sur- rogate measurement is from the target site in humans, the more the approximation is confounded by intervening environmental and biological variables. Nevertheless, sur- rogate measurements may be fully ade- quate for some applications. In other cases, mathematical models of the relationships between exposure and dose can extend the applicability of surrogate measures. Do- simetry models that correlate dose between laboratory animals and humans also broaden the use of surrogate measures. Surrogate measures of dose are com- monly used in experimental and epidemio

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Richard R. Bates and Ann Y. Watson 23 logic studies. Dose/response studies of tox- icity in laboratory animals usually measure exposure, not dose. But differences in the respiratory tract anatomy and ventilation of humans and rodents mean that identical exposure may not result in identical dose. Such studies, however, may nevertheless become increasingly important in predict- ing human health effects as mathematical models capable of supporting interspecies extrapolations are developed; these models aim to relate, in rodents and humans, the physical and chemical properties of pollu- tants to the sites and amounts of pollutant deposited. Interspecies comparisons of ac- tive metabolite dose or extrapulmonary dose-to-target sites will require additional studies of the species-specific pharmacoki- netics (absorption, metabolism, distribu- tion, and excretion) of the chemical. Epidemiologic investigations of the health effects of air pollutants often exam- ine the relationships between the health of people in a community and the concentra- tions of pollutants at a few stationary mon- itoring sites within the community. The people studied are not congregated around the monitoring stations but are widely sit- uated, indoors as well as outdoors. A1- though more localized measurements of subjects' exposure levels would provide better data, such measurements are expen- sive and, for some pollutants, not techni- cally feasible at this time. Mathematical models of the dispersion and transforma- tion of pollutants from their sources, cou- pled with a better understanding of time/ . . activity patterns wit nin the community, would provide an alternative approach for making better exposure estimates. Im- proved accuracy in exposure data for the study population would aid in the applica- tion of the conclusions to other popula- tions. Another area of considerable interest is the development of indices that reflect the actual amount of pollutants that reach tar- get tissues. Although it may not be tech- nically feasible to measure levels of the original substance, quantification of metab- olites or reaction products may be possible. The discovery that carcinogenic metabo- lites covalently bind to macromolecules such as DNA or protein, which in turn can be measured, has stimulated extensive re- search in this area. It should be noted, however, that the use of such approaches for vehicular emissions is complicated by the fact that many of the pollutants of interest are present in very low concentra- tions. Therefore, more sensitive analytical techniques for measuring molecular dosim- eters are needed than are currently being used. Biological Responses to Pollutants The interaction of pollutants with biologi- cal molecules (often called receptors) trig- gers the mechanisms of toxic response. Some responses are direct, the immediate result of the effect on the receptor. For example, some forms of asthma may be precipitated by the direct stimulation of airway irritant receptors by an inhaled pol- lutant. In contrast, some other manifesta- tions of toxicity are highly indirect and, hence, poorly understood; this is frequently true of chronic or delayed effects of toxic- ity. In these cases, the initial interaction of the toxic chemical with a target site recep- tor may trigger a cascade of molecular and cellular events that ultimately damage tis- sue other than the original target site. Pul- monary fibrosis and emphysema illustrate such indirect manifestations of toxicity. Damage to the pulmonary connective tis- sue, the hallmark of these diseases, does not result from the direct actions of inhaled toxic pollutants, but rather, it results from a complex, multistep process: pollutant ex- posure initiates an inflammatory response, which in turn stimulates excessive produc- tion of connective tissue or causes the en- zymatic digestion of elastic tissue. Through a self-enhancing process, damaged tissue and inflammatory cells release chemical mediators that stimulate the recruitment and proliferation of more inflammatory cells. Products of these cells include highly reactive and toxic oxygen-derived radicals, digestive enzymes, and growth factors. In addition to the complexity of cellular and molecular events, it is not clear what regulates the balance between normal de- fense or repair functions and abnormal pro

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24 A Strategy for Quantifying Risk cesses. Components of the inflammatory system, which include macrophages, neu- trophils, and complement, are essential fac- tors in the defense against infectious agents and inhaled dusts. These components, in proper balance under biological control mechanisms, kill invading microorganisms and help to prevent or repair tissue damage. Yet under certain pathological circum- stances, they produce pulmonary diseases. Two inferences can be drawn from such complex and poorly understood mecha- nisms of toxicity. First, a research strategy useful for evaluating exposures that is, tracing the path of a pollutant from its source to sites of human exposure, and vice versa-cannot be used for many biological problems. We simply know too little about the "middle phase" of most chronic dis- eases to follow the molecular path from pollutant deposition to aberrant tissue structure or function. The situation is fur- ther complicated because a single pollutant may trigger a variety of immediate bio- chemical and physiological actions as it passes through the body. Many, if not most, are inconsequential, but it is impos- sible to recognize the few of toxicologic importance without understanding the chronic disease process. The second implication of the preceding discussion is that a combination of factors, including genetics, nutrition, and other en- vironmental chemicals, influence each of the multiple stages in the development of adverse effects, as well as the interactions of enhancing or inhibiting agents at each stage. These factors undoubtedly deter- mine the sensitivity of any person to the toxic effects of a pollutant. The definition and enumeration of sensitive individuals could be pursued more effectively if the steps between the initial interaction of toxic substances with their target sites and the ultimate manifestations of chronic toxicity were better understood. Sensitive Individuals The ability to identify population sub- groups particularly vulnerable to health ef- fects induced or exacerbated by hazardous substances is a critical aspect in the assess- ment of human exposure to automotive emissions. In particular, the young or the elderly may be especially susceptible to deleterious effects; persons with asthma may experience aggravated symptoms upon exposure. We currently cannot determine whether differential responses in sensitive individu- als result from a greater delivered dose or from inherent biological differences. Im- proved measurements of exposure and dose will aid in the identification of people who exhibit greater responses primarily because they receive more of the pollutant. The challenge, however, is to identify those in- dividuals who are inherently more prone to disease states. Most likely, the genetic background of individuals contributes sig- nificantly to their biological response. The multiple cellular and biochemical processes . . . . set into motion in response to reactive materials are under complex genetic con- trol. Taken together, such processes deter- mine individual sensitivity and, hence, the outcome from exposure to toxic sub- stances. Research Approaches The utilization of multiple approaches will most likely enable us to make reasonable predictions about the risk of toxic injury from automotive emissions or their constit- uents. An effective research strategy will consist of epidemiologic studies, experi- mental studies, and/or model systems. The advantages and limitations of these ap- proaches are described below. Epidemiology Epidemiology represents the most direct approach to demonstrate in humans that exposure to a particular substance results in an increase in the incidence of a specific disease. Limitations in the methodologies that assess exposures and biological effects, however, prevent better use of epidemio- logical approaches. Although epidemio

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Richard R. Bates and Ann Y. Watson 25 logic studies are valuable for detecting ex- acerbations of existing chronic disease or the occurrence of acute respiratory disease, their use for revealing causes of chronic respiratory disease is limited. The time lag between exposure to automotive emission products and the appearance of a chronic disease makes it difficult to prove a causal relationship unless early markers of the disease are known. It is highly desirable, therefore, to determine that adducts or other proposed molecular dosimeters are indeed reliable indices of exposure and to identify early markers of chronic disease. People who should be examined in epidemiologic studies include those with well-defined exposures, specific diseases, or inherent factors of sus- ceptibility. Selection of high-risk groups pro- vides a more sensitive basis for the detection of any increase in disease. Experimental Methods Clinical. Two important advantages of human clinical studies are controlled expo- sure and data derived from human subjects. The use of exposure chambers permits the delivery of known quantities of pollutants. Construction of dose/response curves de- mands, though, that careful attention be given to pollutant generation and measure- ment. Numerous methods that cover a range of human response, from physiolog- ical to biochemical effects, are available. Traditionally, pulmonary function tests have been used to assess functional capabil- ities of the lung. Some of these tests form the clinical definition of disease, such as asthma or chronic obstructive pulmonary disease. Because pulmonary function tests reflect end points of respiratory malfunc- tion, they have limited value in detecting the onset of chronic disease. A more recent innovation, the fiber-optic bronchoscope, permits access to human tissues by biopsy and to human cells by ravage. Sampling of Cell Culture. Cell cultures can be used for human tissues will be of central importance ~r . ~ at a. to confirm animal studies. Although bron choscopy can be performed with minimal risk, it is not ideal for large-scale screening; therefore, the development of noninvasive techniques should also be pursued. Animal. Several issues must be consid- ered for proper implementation of labora- tory investigations. Animal studies should address three components of experimental design: exposure conditions, disease state, and extrapolation to humans. Ideally, ani- mal exposure should mimic conditions of human exposure. Pollutant concentration should be low and administered by inhala- tion. To establish links between acute and chronic effects, wide ranges of exposure . . . . . . regimes are necessary. Once It IS not always feasible or practical to conduct chronic, low-dose, inhalation studies, deviations from these parameters should be validated. Sedation of laboratory animals should be avoided, since anesthesia will alter their ventilatory parameters. An improved un- derstanding of the influence of chemical structure on toxicity is necessary to help guide the choice of appropriate mixtures of compounds that should be tested. Experimentally induced disease should be similar to the human counterpart. In some cases, it may be necessary to develop more appropriate animal models for some forms of toxicity, as well as for susceptible populations. In addition, if relevant cofac- tors exist in human ailments, these must be considered. For example, research on the effects of air pollutants on morbidity or mortality from atherosclerosis cannot ig- nore the role of diet. Likewise, studies on the susceptibility to infection should use infectious organisms that are appropriate models of human pathogens. Finally, before accurate dose/response relationships in animal studies can be ap- plied to human risk evaluation, it will be necessary to develop reliable extrapolation or scaling factors. This will require more extensive baseline information on the rele- vant anatomy, histology, physiology, and metabolism in the various species. ~7 the Isolation ot metabolltes or mediators, as well as for the elucidation of biochemical mechanisms of toxicity. The use of culture systems allows compounds or complex mixtures to be quickly screened for toxic effects. It is essential. however, that results

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26 A Strategy for Quantifying Risk from in vitro studies be related to in viva outcomes; for example, the generation of DNA adducts in culture must ultimately be correlated with tumor formation in the whole organism. Mathematical Models Mathematical models can be used to esti- mate or predict emission levels, air quality, human exposure, and respiratory tract dis- tribution of inhaled particles and gases. As alluded to above, the primary asset of these mathematical models is their potential to provide a surrogate measure of dose. In addition, models can be used to distinguish individual contributions from various sources to the total pollutant load. Several models have been developed for these pur- poses. Such models, though, are only as good as the chemical and physical data upon which they are based. There is a need to improve data bases and to perform model validation studies. New models also need to be developed, as well as incorpo- rating additional concepts into current sys- tems; of primary importance is the inclu- sion of indoor air quality into exposure assessment and source apportionment models. In addition, predictions of noncri- teria pollutant concentrations could be im- proved if better mathematical descriptions of atmospheric chemical reactions were used. With respect to dosimetry models, reactive gas uptake in the upper respiratory tract and particle deposition In regional areas are inadequately developed. Physical Models Some research questions are poorly suited to analysis by mathematical modeling methods. In such cases, it is often easier to construct a small-scale physical analogy to the problem of interest, and then test that scale model to learn how the system be- haves. Physical models of atmospheric fluid mechanics problems, such as the dilution of pollutants near buildings, can be built and tested in wind tunnels. Atmospheric chem- ical reactions can be studied in smog cham- bers that are constructed to replicate the irradiation of pollutant mixtures by the sun. Physical models of the geometry of the human respiratory tract can be used to study the patterns of aerosol deposition or gas transport in the lung. Pursuing Quantitative Toxicology: A Strategy for Research Armed with the knowledge of what is known about the components of risk, and of what research approaches are available, we can focus our attention on how to go about supplying the missing pieces be- tween the point of pollutant emission and the generation of toxic response. Returning to figure 1, we see that the investigator can link chemical substances to toxic biological responses by starting at either end of the puzzle. In other words, the hypothesis can be posed in either of two ways: (1) Can automotive emissions adversely affect hu- man health under conditions of human exposure? (2) Do human ailments or phys- iological malfunctions result from exposure . . ~ to automotive emlss1ons' Numerous factors complicate the design and interpretation of any experiment. For example, pursuit of the first hypothesis can be confounded by the transformation of primary pollutants and the generation of new chemical species; the "molecule of interest" and its concentration are not al- ways readily identifiable. With respect to the second hypothesis, the contribution of other agents capable of inducing disease makes the assignment of attributable risk to automotive emissions more difficult. Such factors cannot be ignored, and any research strategy must take their presence into ac- count. Regardless of the number of chemicals that might be tested for toxicity or the number of toxic effects that might be sought, the evaluation of health effects lacks a satisfying sense of unity. No satis- factory paradigm provides a coherent ex- planation of the relationships between chemical structure, dose, and toxic effects. Perhaps such a paradigm could be said to have existed when the principal concern of

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Richard R. Bates and Ann Y. Watson 27 toxicology was with immediate and readily observable toxic actions. For these, the maxim of the sixteenth century Swiss phy- sician and alchemist, Paracelsus, applied: "In all substances there is a poison, and there is nothing without a poison. It de- pends only upon the dose whether a poison is poison or not" (Paracelsus 1958~. Ac- cording to this guidance, chemicals could be categorized into groups on the basis of the magnitude of dose required to cause death or some other toxic end point (Klaas- sen and Doull 1980~. Although this precept served a useful purpose, it is insufficient for evaluating health effects of automotive emissions and their derivatives. For health effects that occur with low frequency or low magnitude, which are the more likely result of these materials, the poison is not only in the dose but also in the genetics, environment, and lifestyle of the exposed individual. An unfortunate consequence of the lack of a unifying theoretical framework for toxicology is the phenomenological ap- proach used for investigating health risks of pollutants. The battery of tests that should be done to assess each important type of health hazard is large and still growing. The task is magnified immensely when the pollutant is as complex and as variable in its composition as automotive emissions and their transformation prod- ucts. It is impractical to study the effects of each chemical individually; nor could such an approach adequately assess the synergis- tic and antagonistic influences of the mix- ture on the toxicity of each component. On the other hand, it is equally impractical to test all possible variants of the complex mixture that would be produced under differing conditions of fuel, engine opera- tion, and climate. Moreover, no single set of conditions can be assumed that might result in a representative exhaust emission mixture, which, in turn, could serve as a toxicity testing standard for experimental work. This dilemma will most likely exist for some time into the future. In the short term, we can look toward the scientific developments that provide guidance on the most important applications of phenome nological toxicology. Perhaps the develop- ment of batteries of inexpensive, short- term tests for the most important toxic hazards will direct attention to a small number of the components most in need of thorough evaluation. Alternatively, such tests might be applied to varied samples of the complete mixture to define subsets with distinctly different toxicological character- istics. Each subset might then be more fully investigated. It is possible, however, to speculate on directions of research that may eventually lead to improved quantification of human exposure and risk. Well-defined and well- focused investigation can provide some of the necessary information. But the puzzle will not be solved tomorrow, or all at once. We must take it one piece at a time, and if we choose our pieces wisely, the picture can be visualized sooner. Highlights of the Authors' Recommendations Within each chapter, authors provide their interpretations of the most important re- search directions in their fields of expertise. Their recommendations can be placed within the context of the various compo- nents of risk of injury, and the distillation of their suggestions are represented in ta- bles 2-5. However, any comprehensive re- search agenda will be severely limited by resource constraints; major choices will have to be made. Before outlining a strat- egy for action, we must first outline our . . . . . . criteria tor pnor~t~zat~on. Criteria for Prioritization To achieve the primary objective of im- proving our ability to quantify risks, mul- tiple criteria were used to guide our selection of future research efforts. Consid- eration must be given to the relative impor- tance of the information sought and the feasibility of obtaining it. Importance may be related to the seriousness of the health risk or to the likelihood that it may result from exposures near ambient levels. Im- portance is also linked to societal needs. Before industry utilizes a new technology

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28 A Strategy for Quantifying Risk Table 2. Chemical and Physical Properties Topic Formation and Transformation of Unregulated Pollutants Vehicle exhaust Formaldehyde: There is a need for real-time concentration data under various driving conditions in methanol-fueled vehicles operated with and without catalysts. Nitro-polycyclic aromatic hydrocarbons (nitro-PAHs): Kinetics of formation in the exhaust system and dilution tunnel for diesel emissions should be determined. Diesel exhaust: Detailed characterization of particulate and gas-phase hydrocarbons is needed. Diesel particulates: Research on particulate control technology is needed. Data on particle size distribution, metal species, adsorbed hydrocarbons; and effects of additives should be collected. Atmospheric reactions Oxides of nitrogen: Further investigation of the transformations of oxides of nitrogen under atmospheric conditions is needed. This topic is important for indoor . Author(s) Johnson Atkinson environments as well. PAHs and nitro-PAHs: Atmospheric transformation products of PAHs in gaseous as well as adsorbed phases require study. Quantitative information on reaction pathways leading to nitro-PAHs and on removal processes for nitro-PAHs is needed. Aromatic hydrocarbons: The products arising from hydroxyl radical-initiated reactions of the aromatic hydrocarbons should be identified. Aerosol Processes Data are needed on aerosol formation, particle size distribution, chemical compost- Graedel; Russell lion, and chemical transformations. Instrumentation and Analytical Methods Real-time measurement methods should be refined in order to more accurately quantify emission constituents. Analytical techniques for the nondestructive, nonintrusive, in situ study of transformation products of gaseous as well as particle-associated chemical species should be improved. or government agencies formulate regula tory policies, certain scientific knowledge may be desirable. Finally, some pieces of information must be obtained before other ideas can be pursued. For example, the application of dosimetry models requires that crucial input data be representative. Some research topics are extremely im portant, but unfortunately, with current knowledge or methodology, their near term solutions are not very feasible. For example, it is essential that the science of toxicology evolve to the point where com plex mixtures can be analyzed for their toxicity. A prerequisite will be the devel opment of quantitative markers associated with the onset of disease. If sufficient knowledge and adequate methodologies are available, then long-range research goals should be pursued. Johnson Atkinson A Proposed Research Strategy If we cross-stitch the recommendations from the various authors with the criteria for prior- itization, we can begin to chart a course for future research. Two major themes emerge that appear to be at the heart of our objective of generating an adequate scientific data base for risk assessment: (1) an increased emphasis on the quantification of exposure and dose, and (2) an improved understanding of basic disease processes. Quantification of Exposure and Dose. The development of molecular dosimeters should constitute a long-range research ob- jective. Currently, the formation of ad- ducts has been exploited the most for our purposes; however, validation of specific adducts and identification of different do

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Richard R. Bates and Ann Y. Watson 29 Table 3. Exposure Characterization T. OplC Author(s) Air Quality Atmospheric evaluation The chemistry of atmospheric aerosol particles should be monitored in Graedel more detail. Chemical differences as a function of particle size should be determined. Routine monitoring of alcohol and aldehyde levels should be done in areas where alcohol-based fuels are or will be in heavy use. Better mathematical descriptions of appropriate chemical reactions for use in models should be made. Improved descriptions of pollutant transport and dispersion are needed for street canyons and other complex situations in which air movement is restricted. Inclusion of chemical reactions within a street canyon model is also needed. The potential exposure of passengers in closed and open vehicles along Samson roadways should be examined. Research should continue to focus on the role of vehicular turbulence in initial dispersion of exhaust. Indoor evaluation Indoor pollutants should be measured and their sources identified. Models should be improved for apportioning specific emission sources to individual exposures and for relating outdoor to indoor air quality. Exposure Assessment Studies should be undertaken to provide information on the spatial and temporal distributions of human populations as they relate to exposure. To obtain this information, valid and reliable questionnaires should be developed. Instrumentation Development and use of more suitable instruments for indoor and personal monitoring are needed. A reliable, sensitive formaldehyde or aldehyde monitor should be developed. Dosimeters Sensitive methods to detect adducts should be developed. Available biological measurement techniques should be adapted to air pollution monitoring. The relationship among exposure, dose, and health outcome requires better understanding. Model Validation Detailed and accurate sets of input data should be used to assess the adequacy of current air quality and exposure models. Graedel; Marnett Russell Russell; Samson Graedel; Sexton and Ryan Russell; Sexton and Ryan Bresnitz and Rest; Sexton and Ryan Bresnitz and Rest; Graedel; Sexton and Ryan Graedel Hecht; Kaufman; Marnett Sexton and Ryan Russell; Sexton and Ryan simeters associated with other disease pro- cesses are needed. To accomplish these goals, more knowledge about the molecu- lar events related to the onset of disease should be obtained. Furthermore, if molec- ular dosimeters are to serve as an effective link between pollutant exposure and subse- quent health effects, the quantitative rela- tionship among exposure, dosimeter levels, and effects will have to be established. Therefore, until we are able to identify and validate molecular dosimeters, more emphasis should be placed on refining sur- rogate measures of dose. For this, better characterizations of exposure, as well as improved models for dose assessment are needed. It is becoming increasingly appar- ent, however, that exposure estimation is not as straightforward as initially supposed and may have uncertainties as great as, or greater than, those associated with dose/re- sponse estimates. We need more informa- tion about environmental levels of most unregulated pollutants, indoor exposure levels, and how to integrate indoor and outdoor levels into a comprehensive pic- ture of human exposure. This information is also needed to conduct and interpret experimental studies as well as to validate dosimetry models.

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30 A Strategy for Quantifying Risk Table 4. Dose Assessment Topic Author(s) Expanded Data Bases Comparative analyses in normal species Morphometric measurements at all levels of the respiratory tract Schlesinger should be done in adult humans and laboratory animals. Comparisons among and within species should be made and statistical variability determined. More emphasis should be placed on the upper respiratory tract, including the development of dosimetry models for this region. Description of the liquid lining of the lung in humans and laboratory animals is needed. Data on deposition and clearance kinetics of particles in different species should be gathered. Scaling factors should be developed based on measurements of total uptake of eases in different animal species. Overton and Miller; Schlesinger Overton and Miller; Schlesinger Schlesinger Ultman --I- - <~ High-risk groups Morphometric measurements are needed for sensitive groups such as the young, old, and diseased. New anatomic models should be developed. Airflow patterns and distribution could be better described in Schlesinger sensitive subgroups in laboratory animals and humans. Diesel Exhaust and Particle-Associated Organics Chronic studies should be undertaken at low concentrations of diesel exhaust, and long-term clearance, translocation, and retention of diesel particulates should be assessed. Coexposures to other pollutants should also be conducted. Healthy animals and models of sensitive populations should be evaluated. The effects of carrier particles on the ultimate disposition of adsorbed organics should be determined. Rates of desorption of adsorbed compounds from inhaled particles should be quantified. Gases Chemical reactions of specific pollutants with mucus, blood, and tissues should be quantified. Analysis of mass transport through individual diffusion barriers, Ultman particularly the mucous layer, the bronchial wall, and the alveolar capillary network is needed. Noninvasive techniques to evaluate the transport of soluble and reactant Ultman pollutants should be developed. These techniques coupled with appropriate mathematical models can be used to obtain information on regional inhomogeneities in dose and uptake. Overton and Miller; Schlesinger Schlesinger Schlesinger; Sun, Bond, and Dahl Sun, Bond, and Dahl Overton and Miller; Ultman Methods should be developed and experimental data should be obtained Bromberg; Overton and Miller for dosimetry model validation. The methodology to obtain useful ex- posure information on the regulated pol- lutants is now available. In contrast, en- vironmental levels of most unregulated pollutants have not been adequately char- acterized. Because government standards do not exist, there appears to be little incentive to develop monitoring equipment or programs. But we cannot be lulled into inaction by thinking that trace amounts of a particular substance will be of little conse quence. For example, in the atmosphere, the concentration of the hydroxyl radical is only 10-6 to 10-7 ppm; however, the hy- droxyl radical is one of the most reactive atmospheric chemical species known and participates in the majority of atmospheric scavenging reactions. Biologists will have to alert chemists and engineers to poten- tially toxic pollutants that should be mea- sured. Data on the concentrations of regulated

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Richard R. Bates and Ann Y. Watson 31 Table 5. Biological Responses Topic Author(s) Noncarcinogenic Pulmonary Effects Chronic diseases An epidemiologic cohort study of the effects of long-term exposure to oxidants on respiratory morbidity should be conducted. Role of injury: The pathophysiolozical significance of alterations in bronchoalveolar epithelial Last Bresnitz and Rest A ~ ~ _ _ permeability in animals and humans should be determined. Mediators derived from damaged epithelial cells and inflammatory cells should be Last; Wright identified and characterized by use of cell culture systems. The relationships among the various stages of injury and changes in populations of Last; Wright pulmonary macrophages and interstitial cells should be established. Regulation of repair: The reversibility of abnormal collagen structure or deposition should be determined. Last The relationship among digestive enzymes, connective tissue molecules, and abnor- Wright mat lung tissue should be examined. A better understanding of disease progression is needed. Lung structure and Last; Wright biochemistry should be evaluated during a postexposure recovery period. Asthma Panels of individuals with bronchial hyperreactivity should be studied to determine whether exposure to ambient oxidants affects respiratory symptoms or morbidity. Controlled clinical studies should be conducted with asthmatics exposed to chamber Bromberg atmospheres similar in composition to ambient atmospheres associated with increased symptomology. Bresnitz and Rest The effect ot the presence of allergens either during or after pollutant exposure Bromberg should be determined in extrinsic asthmatics. The role of airway C-fiber sensory systems in ozone effects in epithelial properties, Bromberg bronchial reactivity, and airways inflammation should be clarified. Respiratory infection Epidemiologic surveys should be performed in high-risk populations using serologic and cultural tests to confirm infection. In animal or human studies under controlled laboratory conditions, components of respiratory antiviral defense mechanisms should be evaluated. Carcinogenic Effects ~. . . . . Bresnitz and Rest; Pennington Pennington Critical data on the corrections used in extrapolations should be obtained for Kaufman .. . . . ... . . . ~ . . quantitative assessments. Diesel emissions Additional studies should be performed on the carcinogenicity of diesel exhaust. Methods should be developed for assessing the carcinogenicity of mixtures. PAHs and nitro-PAHs Structures of the major DNA adducts and protein adducts formed from representative PAHs and nitro-PAHs should be identified. Under conditions of chronic administration of PAHs or nitro-PAHs to experimental animals, the relationship between DNA or protein adduct formation and tumor development should be determined. In order to determine the feasibility of monitoring DNA and protein adducts in humans, pilot studies in individuals potentially exposed to PAHs or nitro-PAHs should be performed. Major pathways of metabolic activation and detoxification should be determined. Aldehydes A chronic inhalation toxicology study of acrolein should be undertaken in rats, with emphasis on carcinogenicity. A chronic inhalation toxicology study of mixtures of formaldehyde and acrolein should be undertaken in rats and hamsters, with emphasis on carcinogencity. Experiments should be undertaken in cells cultured from the upper respiratory tract to determine the mechanisms by which aldehydes exert pathological changes. Kaufman Hecht Marnett (Table continued next page.)

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32 A Strategy for Quantifying Risk Table 5. Continued Topic Author(s) Other Coronary heart disease Using ongoing cohort studies or other existing data bases, increased risk of heart disease should be evaluated in persons exposed to varying levels of automotive emissions. The effect of automotive emissions on various components of atherogenesis should be evaluated in animal studies that use cynomolgus monkeys. Neurobehavioral effects Tests to detect functional disorders and sensory impairments should be applied in a systematic manner to evaluate the magnitude and prevalence of behavioral alterations due to components of automotive emissions. Clarkson Wood as well as unregulated pollutants are inad- equate for indoor environments. Although residences and office buildings are the most logical indoor environments to investigate, the interiors of vehicles should also be considered. Some segments of the popula- tion (for example, commuters and truck drivers) spend considerable time, on a reg- ular basis, in vehicles where concentrations of pollutants could be high. In addition to improved charactenzat~on of human microenvironments, more infor- mation on the amount of time spent in various locations is needed. Documenta- tion of this sort is inadequate for different sectors of the population, but it is not technically difficult to obtain. Individual activity constitutes an essential component in the assessments of human exposure; the construction worker experiences a mark- edly different exposure than the business- person who walks down the same street on his or her way to lunch. To improve dose assessment, descriptive data bases about respiratory tract anatomy and ventilation must be expanded. Pollu- tant dose to the lung depends on airway geometry. Most particle deposition and gas transport dosimetry models use the sym- metrical lung model developed by Weibel in 1963 (Weibel 1963~; this model is based on measurements from one human speci- men. Recently, more elaborate models have been proposed that attempt to account for variations in lung geometry. Better anatomic models will improve the accuracy of dose estimates. The development and validation of more realistic models requires representative input data, which are largely unavailable. In addition, measurements of, and a greater emphasis on, the upper air- ways should be pursued. Large particles and their associated organics, as well as soluble gases, will contact respiratory tis- sues, and perhaps gain access to the circu- lation, in the upper airways. Without accu- rate physical and biochemical descriptions of the liquid lining, the fluid's role as a protective layer for underlying epithelial tissues cannot be determined. Finally, the distribution of inhaled particles and gases is also influenced, but poorly characterized, by ventilation. The effects of increased ven- tilation have a practical significance for physically active individuals. Measurements taken in a systematic manner on more specimens within and between species are needed. Experimental data from animals cannot be confidently extrapolated to humans until intra- and interspecies variability has been deter- mined. Data are needed on normal individ- uals as well as on high-risk subjects. Few descriptive data are available on the young, elderly, or special disease groups. The an- atomic and physiological status of these individuals may profoundly influence pol- lutant dose to their respiratory systems. Basic Disease Processes. The contribu- tion of any pollutant to the initiation or exacerbation of a disease cannot be accu- rately determined until we have more in- sight into the pathogenesis of that disease. By focusing our efforts on early events, we would like to identify the cellular and mo

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Richard R. Bates and Ann Y. Watson 33 lecular alterations that may link pollutant exposure to ill health. This information would also aid in the identification of sus- ceptible subpopulations. Thus, real prog- ress in defining human risks is not likely to occur until the cellular and biochemical mechanisms of various diseases are better characterized. Early events of many respiratory diseases involve damage to epithelial tissues; altered epithelial permeability is implicated in the etiology of an asthmatic attack; damaged epithelial cells release biochemical signals for inflammatory cells, which in turn ap- pear to regulate interstitial cell function; and proliferation of damaged cells is asso- ciated with cancers of the respiratory tract. Therefore, it is imperative to focus more attention on the mechanisms by which the epithelium translates insult to disease. Once the integrity of the pulmonary epithelium is compromised by injury, underlying tis- sues are more susceptible to harm from inhaled substances. In addition to their func- tion as a protective barrier, the extent to which epithelial cells actively contribute to pathological processes is unclear. The recent evidence that interactions between epithelial and interstitial tissue layers affect mutual structure and function suggests a more active role for epithelial cells. In addition to the identification of biochemical mediators in response to injury, it is also unknown how much of the specificity of outcome resides in the signals generated. Whether a pollutant induces the formation of free radicals or macromolecular adducts may influence tissue responses normal and abnormal. Another important area for investigation is improved characterization of the inflam- matory response. One cellular component, the macrophage, produces growth factors and mediators of activity for several other cell types. These macrophage-derived products probably play a role in the devel- opment of fibrosis, emphysema, small air- ways disease, and atherosclerosis. In addi- tion, evidence suggests that inflammation influences bronchial hyperreactivity. The balance between defense and dysfunction is more than likely regulated, in part, by biochemical signals generated during an inflammatory reaction. In addition to the characterization of these signals, the cir- cumstances that govern their production require clarification. For example, the tim- ing of insults during repeated exposure may be critical for normal repair. Ideally, we would like to elucidate the conditions that solicit physiological "backfire"-that is, when defense mechanisms no longer operate to protect the organism, but in- stead, promote disease. Inflammatory events after exposure to initiating agents should be examined in established model systems of specific disease states. Finally, research efforts should continue in the arena of genetic control mechanisms. The explosion of research in this area pro- vides toxicologists with a potentially im- portant methodology-the use of DNA adducts as dosimeters of carcinogenic inter- actions with target sites. However, we must still face the mystery and chal- lenge-of relating genome alterations to human disease. It is not enough to just identify adducts relevant to emissions or emission products. Genetic factors that affect individual susceptibility should be explored further. Tremendous variation exists among human individuals in the metabolic activation of substances to carci- nogenic compounds, the molecular basis of which has not been characterized. In addi- tion, factors that influence the capacity of pulmonary tissues to repair genome dam- age should be investigated. Comparisons of biochemical profiles between sensitive and resistant strains of laboratory animals may aid in the elucidation of these factors. In conjunction with animal studies, increased emphasis should be placed on applying current methodologies to or developing more appropriate analytical techniques for human samples. Finally, if we hope to assess the carcinogenic potential of com- plex mixtures of airborne pollutants, we need a better understanding of the molec- ular basis for the actions of promoters and . . q cocarc~nogen~c su Stances. Among these interconnected areas of re- search lie clues to many fundamental prob- lems in abnormal tissue structure and func- tion that constitute toxicity and disease. Opportunities for more quantitative toxi- cology should be pursued using the rapid . . ~

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34 A Strategy for Quantifying Risk advances in scientific methodology and the recent knowledge of molecular and cell biology. Summary Currently, our abilities to obtain data for risk determination directly from humans is limited. Epidemiologic studies that evalu- ate chronic diseases should be limited until, or unless, adequate estimates of exposure and early biological markers are available. Be- cause of the possibility of correlating expo- sure with outcome, the incidence of asth- matic attacks or respiratory infection holds the most promise for epidemiologic investi- gation, assuming that satisfactory methodol- ogy for the detection of infection can be applied. Controlled clinical trials are best applied to the analysis of neurobehavioral effects or bronchial hyperreactivity. Even in cases of asthma, data collection is restricted to a subpopulation of mildly affected subjects. We need more information on what deter- mines the severity of the disease. The example of asthma illustrates an- other important point; results in clinical studies have not supported epidemiological evidence of an effect of oxidants on airway sensitivity. Whether we have been unable to accurately duplicate ambient atmo- spheres\ or identify appropriate susceptible individuals for study is not known. Both factors require additional consideration when conducting further studies. For most health effects animal expen- ments must be used as a source of informa- tion from which human risks can be ap- proximated. But how can the data be linked more effectively to the human situ- ation? Since risk is related both to dose and to sensitivity, each should be considered a research area that might improve our abil- ity to quantify human risks from animal experiments. Fruitful directions that would improve dosage extrapolation are readily apparent. They lie partly in further devel- opment and application of mathematical models for comparing pulmonary deposi- tion in laboratory animals and humans. As the harmful components of automotive emissions are identified, biological markers of their presence in tissues can also be developed and used to compare target site levels. Definitive comparisons of sensitiv- ity of laboratory animals and humans to equivalent target site doses probably awaits better understanding of the molecular de- terminants in chronic disease development. Elucidation of missing links between acute effects and chronic disease would provide investigators with a powerful tool early indicators of subsequent injury. Knowing biological markers and factors that deter- mine individual sensitivity will not only provide better extrapolations from animals to humans, but will also improve the fea- sibility of using epidemiologic approaches. Ideally, a comprehensive research strat- egy would link molecular dosimetry to disease in laboratory animals and finally to exposure in humans. This strategy is best illustrated using PAHs carcinogenic com- ponents in vehicle emissions. First, it will be necessary to identify the appropriate DNA and protein adducts in PAH-exposed animals. Second, and probably most cru- cial, will be to determine the quantitative relationship between adduct levels and tu- mor formation. Finally, if a predictive cor- relation can be made between marker and disease, it will then be appropriate to apply these methods to PAH-exposed humans. Conclusion Each chapter in this book addresses some aspect of the problem of assessing exposure and risks to humans from automotive emissions and their transformation prod- ucts. Invariably, and inevitably, the authors found that the research needed to answer questions about automotive emissions IS also applicable to a much broader array of issues about human exposure and health. The development of new techniques and a better understanding of atmospheric chem- istry and physics, all of which would im- prove our knowledge of exposure to auto- motive emissions, are also applicable to other sources of air pollution. Similarly, the methods and the knowledge needed to assess health risks from motor vehicle emissions are also useful to evaluate the

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Richard R. Bates and Ann Y. Watson 35 effects of other substances in the environ- ment. Thus, rather than there being a sharp boundary of research questions around au . . . . , . tomot1ve emissions, a series ot concentric circles that overlap other topics of environ- mental exposure and health exists. Before proceeding too far toward the more peripheral circles, it is worth return- ing to the basic question: How important are automotive emissions as a risk to hu- man health? Referring to air pollution in general, a committee of the National Re- search Council recently concluded that "evidence from controlled human expo- sures, toxicology, and epidemiology is suf- ficient to warrant concern tliat current air pollution still produces substantial adverse health effects in some segments of the U. S. population." Furthermore, "The Commit- tee finds that current air pollution can cause acute and perhaps chronic health effects, particularly respiratory effects, in the pop- ulation of the United States. Respiratory disease is a major cause of work loss and disability. Even if only a small proportion of very prevalent disease is due to air pollution, the absolute amount of illness that could be prevented by reducing air pollution would be large" (National Re- search Council 1985~. These comments were balanced by another statement: "The impact of ambient air pollutants on the total respiratory disease burden in the United States must be small relative to the impact of cigarette smoking, and occupa- tional exposures might also have greater effects than pollution of ambient air" (Na- tional Research Council 1985~. Motor vehicle emissions are responsible for a substantial proportion of atmospheric exposure to carbon monoxide, nitrogen oxides, volatile organic compounds, and, in urban areas, total suspended particulate matter. Atmospheric organic compounds and nitrogen oxides derived from automo- tive emissions also contribute significantly to the formation of ozone. Thus, to the extent that these substances are a source of the health concerns of the National Re Correspondence should be addressed to Ann Y. Wat- son, Health Effects Institute, 215 First Street, Cam- bridge, MA 02142. search Council Committee' automotive emissions must also be of concern. Ques- tions about this issue have been raised, but not fully answered, as the chapters of this book indicate. Much less information is available on the hundreds, or perhaps thousands, of indi- vidual organic chemicals that contribute to the volatile organic and particulate fractions of atmospheric pollution. Neither the ex- posure levels, the atmospheric reactions, nor the health effects of many of these have been well characterized. Among these ma- terials are the PAHs, nitro-PAHs, and al- dehydes which are discussed in this book, as well as many other chemicals. It seems likely that many of the organic chemicals derived from motor vehicle operation are present at such low atmospheric levels that they do not threaten human health, even in sensitive individuals. On the other hand, highly toxic chemicals can harm health even at very low concentrations, especially when they are mixed with other substances and synergism occurs. Some balance needs to be struck between unnecessary Research on trivial problems and insufficient research on possibly important ones. Locating the balance point is not easy. It depends on a continuing dialogue between the experts on atmospheric exposure and the experts on biological effects of toxic substances. The former can contribute information about what is in the atmosphere, the latter on what may be important for health. Thus, each group can help guide the research priorities of the other. We hope that this book will contribute to the dialogue. References Klaassen, C. D., and Doull, J. 1980. Evaluation of safety: Toxicologic evaluation, In: Casarett and Doull~s Toxicology: The Basic Science of Poisons a Doull, C. D. Klaassen, and M. O. Amdur, eds.), 2nd ea., pp. 11-27, MacMillan, New York. National Research Council (Committee on the Insti- tutional Means for Assessment of Risks to Public Health). 1983. Risk Assessment in the Federal Govern- ment: Managing the Process, p. 191, National Acad- emy Press, Washington, D.C. National Research Council (Committee on the Epi- demiology of Air Pollutants). 1985. Epidemiology

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36 A Strategy for Quantifying Risk and Air Pollution, p. 224, National Academy Press, Washington, D.C. Paracelsus. 1958. Selected Writings U Jacobi, ea., and N. Guterman, trans.), Bollingen series XXVIII, p. 290, Pantheon Books, New York. U.S. Environmental Protection Agency. 1984. Na- tional Emissions Report, 1981, National Emissions Data System of the Aeromatic and Emissions Re porting System, Report EPA-450/4-83-022, Re- search Triangle Park, N.C. U.S. Environmental Protection Agency. 1986. Na- tional Air Quality and Emissions Trends Report, 1984, Report EPA-450/4-8~029, Research Triangle Park, N.C. Weibel, E. 1963. Morphometry of the Human Lung, Springer-Verlag, Berlin.