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Biological Disposition of Vehicular Airborne Emissions: Particle-Assoc~atec! Organic Constituents JAMES D. SUN JAMES A. BOND ALAN R. DAHL Lovelace Biomedical and Environmental Research Institute Significance of Carrier Particles / 300 Characteristics of Particle-Associated Air Pollutants / 301 Inhalation of Airborne Particles / 302 Disposition of Inhaled Particle-Associated Organic Compounds / 302 Bioavailability of Particle-Associated Organic Compounds / 304 Toxicity of Inhaled Organic Compounds / 306 Varieties of Toxic Responses / 306 Metabolism of Chemical Carcinogens / 306 Effects on the Immune System / 312 Summary / 315 Summary of Research Recommendations / 315 Air Pollution, the Automobile, and Public Health. 33 1988 by the Health Effects Institute. National Academy Press, Washington, D.C. 299

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300 Particle-Associated Organic Constituents Significance of Carrier Particles Public concern has been aroused in recent decades over damage to human health from inhaling man-made particles, and there is overwhelming evidence that this concern is not misplaced (Committee on Biological Effects of Atmospheric Pollutants 1972~. The concentration of man-made airborne particles is highest near industrialized areas and areas where the density of motor vehi- cle traffic is high. Among the major sources of man-made particles polluting the atmo- sphere are electrical power plants (Chrisp et al. 1978; Fisher et al. 1979~; industries that burn fossil fuels (Lofroth 1978~; and vehi- cles powered by internal combustion en- gines that burn either gasoline (Wang et al. 1978) or diesel fuel (Clark and Vigil 1980~. It has been suggested that the high inci- dence of human cancers in urban areas near industry and high-density traffic may be associated with inhaling organic pollutants, and other deleterious health effects have been attributed to organic pollutants as well (Committee on Biological Effects of Atmo- spheric Pollutants 1972~. Most studies of the toxicologic consequences of inhaled or- ganic pollutants reported in the literature have been performed using pure com- pounds. However, many organic pollut- ants are adsorbed on relatively inert and insoluble particles (Williams and Swarin 1979; Hanson et al. 1985~. Consequently, for a complete evaluation of the toxicity and human health risks of inhaled organic pollutants, studies with pure organic com- pounds must be complemented with stud- ies of organic compounds adsorbed onto particles. What organic pollutant is carried on a particle, how much, and how it later be- comes separated from the particle are af- fected by physical and chemical properties of both the organic pollutant and the "carrier" particle. Conditions for adsorp- tion of organic pollutants onto particles are particularly favorable with the components emitted in automotive exhaust. The distri- bution of organic pollutants in the body can be quite different from the distribution of inhaled organic pollutants not attached to particles and is determined by the chemical characteristics of the particle as well as the organic pollutant. These differences are particularly evident with respect to the rate and path of clearance of inhaled organic pollutants from the respiratory tract. A few inhalation studies have been per- formed with organic compounds adsorbed onto particles. These investigations have been limited to the potential carcinogenic effects of inhaled particle-associated poly- cyclic aromatic hydrocarbons (PAHs). However, other disease processes and chem- ical classes are also important. Many of the airborne particle-associated compounds of toxicologic concern are not directly toxic but produce adverse effects when. activated metabolically. Thus, the simple presence of such a potentially toxic compound within a tissue or organ does not necessarily cause a health problem; the tissue or organ in question must be capable of transforming the compound into toxic metabolites. In addition to tissues and organs, pulmo- nary alveolar macrophages may play an important role in the disposition and met- abolic fate of inhaled organic pollutants. Most organic compounds are relatively sol- uble in the lungs and can be cleared by direct absorption through the pulmonary epithelium into blood. In contrast, deep lung clearance of relatively insoluble parti- cles, such as those that carry adsorbed organic pollutants, depends primarily on the phagocytic activity of pulmonary mac- rophages and their eventual translocation to the lymphatic system. Adsorbed soluble organic pollutants may remain with these insoluble particles instead of dissolving im- mediately and may be cleared from the lungs by the same mechanisms that clear insoluble particles. Translocation of these potentially toxic organic compounds and their metabolites to the lymphatic system may have an effect on the immune system. This chapter first reviews certain relevant characteristics of polluting airborne parti- cles, emphasizing the importance of parti- cle-associated organic compounds. The bio- logical fate of inhaled particle-associated organic compounds is largely determined by two factors: their specific site of depo- sition among the different tissues that exist

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Sun, Bond, and Dahl 301 in the respiratory tract and their distribu- tion and metabolism by these and other tissues of the body. The disposition and clearance of particles per se is treated exten- sively by Schlesinger, and the disposition, absorption, and metabolism of vapors and gases are discussed by Overton and Miller and by Ultman (all in this volume). The concepts treated by those authors are essen- tial to an understanding of biological fate of organic compounds adsorbed on inhaled particles. This chapter proceeds with a discussion of the disposition of inhaled particle-asso- ciated organic compounds, including the effects of particle association on lung clear- ance and bioavailability of these organic compounds. This is followed by a discus- sion of the paths and mechanisms by which particle-associated inhaled organic com- pounds produce a biological effect. The bulk of relevant research in these areas up to now has dealt with the metabolism of chemical carcinogens and, to a lesser ex- tent, immunologic effects of inhaled parti- cles and particle-associated organic com- pounds. These sections are followed by a summary and an overview of the research needed to provide essential information for evaluating potential health risks from in- haled particle-associated organic com- pounds. Characteristics of Particle Associated Air Pollutants Hundreds of chemical compounds have been identified in spark-ignited and diesel automotive exhausts. Behymer and Hites (1984) provide a more extensive discussion on this subject.. At least four major classes of organic compounds are found associated with particles in automotive exhausts: 1. aliphatic hydrocarbons and their oxi- dation products (alcohols, aldehydes, car- boxylic acids); 2. aromatic compounds, including het- erocycles, and their oxidation products (phenols to quinones); 3. alkyl-substituted aromatic compounds and their oxidation products (alkylphenols, alkylquinones, aromatic carboxaldehydes, and carboxylic acids); and 4. nitroaromaticcompounds~nitro-poly- cyclic aromatic hydrocarbons or nitro- PAHs). Other chemical classes also exist but are of lesser importance in terms of their preva- lence and/or current knowledge of their toxicologic significance. Exhaust particles from diesel and spark- ignition engines carry the same types of organic compounds (Behymer and Hites 1984~. Some of the organic compounds carried by particles from other combustion processes such as conventional and fluid- ized-bed coal burning (Natusch 1978; Han- son et al. 1981) and cigarette smoke (Guerin 1980) are similar, but have important dif- ferences. Like automotive exhaust, ciga- rette smoke and effluents from burning coal contain PAHs, but they have far less of the nitro-PAHs that are the major toxic com- ponents of concern in automotive exhaust. On the other hand, cigarette smoke con- tains highly toxic alkaloids, nitrosamines, and aromatic amines that are present in negligible amounts in automotive exhaust. These dissimilarities arise from differences in the composition of the burning material as well as from differences in the mode of burning. For example, cigarette smoke has components arising from pyrolysis and va- porization of tobacco preceding the burn- ing cone as well as components resulting from the oxidation of tobacco and cigarette paper (Guerin 1980~. Quantitative data about individual com- pounds present in air samples collected from near highway tunnels, oil- and gas- fired electrical power plants, industrial boilers, coke ovens, oil refineries, and coal tar heaters, have been published in a recent report by Daisey et al. (1986~. Table 1 shows the reported concentrations of ben- zo~a~pyrene (BaP) in particulate matter. Toxic chemical compounds ranging in volatility from nitrogen dioxide (Hanson et al. 1985) to PAHs such as BaP (Williams and Swarin 1979) have been identified on airborne particles from many sources, in- cluding automotive emissions. Classed

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302 Particle-Associated Organic Constituents Table 1. Concentrations of Benzotaipyrene in Particulate Matter from Various Sources ppm BaP in Particulate Source Matter References Tunnel samples 66-500 Daisey et al. (1986) Coal burning Residential, anthracite 10-20 Sanborn et al. (1983) Residential, bituminous 240-600 Sanborn et al. (1983) Power plants 0.0007 Bennett et al. (1979) Oil-burning power plants 0.005 Bennett et al. (1979) Residential wood burning Fireplaces 3-141 Dasch (1982) Wood stoves 213-870,900 Truesdale and Cleland (1982) Knight et al. (1983) Coke plant 1,400-5,800 Bjorseth et al. (1978) Soil 0.1-2.3 Wang and Meresz (1982) Butler et al. (1984) SOURCE: Adapted with permission from Daisey et al. 1986, and from the Air Pollution Control Association. according to toxicity, particle-associated compounds include direct-acting mutagens such as pyrene-3,4-dicarboxylic acid anhy- dride (Rappaport et al. 1980), indirect car- cinogens and mutagens such as BaP (Wil- liams and Swarin 1979), and irritants such as acrolein and sulfur dioxide (Hanson et al. 1985), as well as others. Among the four major classes of organic compounds found in automotive exhausts, the ones that have been studied most are the nitro-PAHs, such as nitropyrene (NP) and dinitropyrene, and the unsubstituted PAHs such as BaP. These compounds and others of these classes command attention because so many of them are known to be muta- gens and/or carcinogens. But organic com- pounds carried on inhaled particles can produce other toxic effects that can also be as Important as cancer. Inhalation of Airborne Particles Disposition of Inhaled Particle Associated Organic Compounds Particles carrying adsorbed organic com- pounds are deposited in the respiratory tract by the same mechanisms and accord- ing to the same principles as particles with- out adsorbed compounds. Inhaled aerosols of BaP or NP alone, BaP or NP adsorbed onto gallium oxide (Ga2O3) or diesel ex haust particles, uncoated Ga2O3 particles alone, or diesel exhaust particles alone are all deposited along the respiratory tract in about the same pattern (Chan et al. 1981; Sun et al. 1982, 1983, 1984; Wolff et al. 1982~. Inhaled particles are cleared rapidly from the upper respiratory tract and tracheo- bronchial regions by the ciliated epithe- lium, which sweeps deposited particles upward for eventual removal by expecto- ration and then ingestion. In most measure- ments of this clearance mechanism, inor- ganic particles such as Ga2O3 have been used (Wolff et al. 1982), but there is no reason to believe that clearance occurs in a different manner for pure organic aerosols or particles with adsorbed organic com- pounds. Available evidence supports this inference (Schlesinger, this volume). Lipid and water soluble compounds and their metabolites can be absorbed also through the mucous membranes and into blood or lymph. Because mucociliary and absorption mechanisms clear material rap- idly, it is difficult to distinguish between the two experimentally. Studies have been performed in which rats were treated with radiolabeled organic particles or with the same organic materials adsorbed onto inor- ganic particles, either by intratracheal in- stillation (Sun and McClellan 1984) or by inhalation (Sun et al. 1982, 1983, 1984~. In these experiments, no radiolabeled particles

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Sun, Bond, and Dahl 303 were detected in the stomach at any time after exposure of the animals to pure or- ganic particles, but substantial amounts of organic constituents adsorbed onto inor- ganic particles were found in the stomach. One can infer that pure organic particles deposited in these regions clear primarily by absorption through the respiratory tract epithelium into the blood. These examples show that organic compounds associated with particles and the same compounds in pure form can clear by different routes and thus can expose different tissues of the body. Slowly dissolving inorganic particles do not clear from the pulmonary region as fast as from the upper respiratory tract. The main reason is that the lower respiratory tract lacks ciliated airways, and insoluble particles are cleared by the action of phago- cytic macrophages moving slowly to the lymphatic system. The long-term half- times of lung clearance of inhaled Ga2O3 or diesel engine soot particles in rats is about 65 days (Chan et al. 1981; Griffins et al. 1982; Wolff et al. 1982~. In contrast, lipid or water soluble com- pounds clear quickly from the pulmonary region, principally by dissolution and ab- sorption into the blood. Inhaled BaP (Mit- chell 1982; Sun et al. 1982), NP (Sun et al. 1983; Bond et al. 1986b), aminoanthracene (Mitchell et al. 1984), phenanthridone (Dutcher and Mitchell 1983), and diben- zotc~g~carbazole (Bond et al. 1986a) are almost completely cleared during the short- term phase of respiratory tract clearance (figure 1~. Attempts to measure lung clear- ance times of these chemicals yielded half- times that measured as short as hours rather than weeks or months. Particle-associated organic compounds clear from the upper respiratory tract (short-term phase) about as fast as pure organic particles (Sun et al. 1982, 1983~. However, the pulmonary clearance rates (long-term phase) of particle-associated or- ganic compounds are longer for many par- ticle-associated compounds than for in- haled pure organic compounds. The cause is presumed to be the tenacity with which the organic material is bound to the slowly cleared "carrier" particles. These binding moor z c] 10 m z E z IL o z 0.1 G UJ 1 0.01 ~ DBC or AA rNP r r BaP ~PNDO 0 4 8 12 16 _ , , I ~ DAYS AFTER EXPOSURE Figure 1. Lung clearance of benzota]pyrene (BaP), nitropyrene (NP), aminoanthracene (AA), phenan- thridone (PNDO), or dibenzotc,g]carbazole (DBC) in rats after acute exposures. strengths very likely vary with particle type and organic material, and probably govern long-term clearance rates of particle-associ- ated organic compounds. This increased long-term retention of particle-associated organic compounds in the pulmonary re- gions of the respiratory tract is believed to be of toxicologic importance. Recommendation 1. Additional re- search is needed on the actual toxic effects of increased lung retention of inhaled par- ticle-associated organic compounds. Sun and coworkers (1982, 1983) com- pared the clearance rates of inhaled BaP and NP aerosols from the lungs with those of the same PAHs adsorbed onto Ga203 (figure 2~. They reported that BaP ad- sorbed onto Ga2O3 cleared slower than BaP inhaled as a pure aerosol. However, NP on Ga2O3 and pure NP aerosols cleared at about the same rate. The data suggest that Ga203-associated organic material clears from lungs primarily by dissolution and direct absorption into the blood. In the pulmonary regions, the long-term reten- tion of BaP or NP adsorbed onto diesel engine exhaust particles is as much as 230

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304 Particle-Associated Organic Constituents 100 Q10 m z 3 ,~1 z o at UJ o.1 UJ BaP/Diesel NP/Diesel BaplGa2o3 0.01 _ 0 4 8 BaP 12 16 DAYS AFTER EXPOSURE Figure 2. Lung clearance of benzo~aipyrene (BaP) or nitropyrene (NP) adsorbed onto gallium oxide particles (Ga2O3) or diesel engine exhaust particles and of BaP and NP in pure form in rats after acute exposure. times greater than that of BaP or NP alone (Sun et al. 1984; Bond et al. 1986b) (figure 2~. Sun and McClellan (1984) further sup- port the finding that particle-associated or- ganics are cleared more slowly from the lungs than are pure organic aerosols. They operated a diesel engine on ~4C-radiola- beled fuel to create radiolabeled exhaust in which the majority of the i4C was with the organic compounds associated on the car- bonaceous core particles. Then, they intra- tracheally instilled this radiolabeled soot into rats and measured the clearance rate of i4C from lungs. For comparison, they ex- tracted the radiolabeled organic com- pounds from the soot and instilled it into the lungs of rats. These particle-free or- ganic compounds cleared much faster than the particle-associated organic compounds. Clearance of particle-associated organics from lungs appears to be governed by factors related to the binding properties of the particles on which the organic material is adsorbed. Chemical composition as well as physical properties of the particle surface appear to play a part, although the exact mechanisms are unknown. For example, when Henry and Kaufman (1973) measured clearance of intratracheally instilled BaP coated on carbon, aluminum oxide, and ferric oxide particles in hamsters, they found that the BaP cleared substantially slower when carried by carbon than when coated on metal oxide particles of similar size and shape. There was little difference between the clearance rates of BaP coated on aluminum oxide and BaP coated on ferric oxide. On the other hand, irregularly shaped particles or particles having a high degree of porosity have a greater surface area per unit mass than smooth spherical particles. An amount of material that would make a loosely bound layer several molecules thick on a smooth particle is carried in a more tightly bound monomo- lecular layer on a rough or porous particle (Gregg and Sing 1982~. After these organic compounds and their metabolites are cleared from the respiratory tract, they are widely distributed to many tissues in the body (Sun et al. 1982, 1983, 1984; Bond et al. 1986a,b). Bond and co- workers (1986b) used ~4C-NP associated with diesel exhaust particles to study what form this organic material has after reach- ing nonrespiratory tract tissues. Within 1 hr after exposure, a large proportion of the i4C had cleared from the lungs to other tissues and more than 90 percent of the ~4C in these tissues was associated with NP metabolites. Bioavailability of Particle-Associated Organic Compounds Vostal (1983) has postulated that particle- associated compounds must be eluted off the particle and made available for various cellular metabolic processes before a toxic response can result. Other researchers (Brooks et al. 1980; King et al. 1981) have reported that the mutagenic components associated with diesel engine exhaust parti- cles are removed by various physiological fluids, tissue homogenates, and serum. They found that, in the presence of such biological fluids, the mutagenic activity of these organic compounds was reduced, suggesting that organic constituents in the

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Sun, Bond, and Dahl 305 media are bound to proteins or metabo- lized. Similarly, King and coworkers (1983) found that when pulmonary alveolar macrophages were incubated with diesel engine exhaust particles, amounts of or- ganic compounds and mutagenic activity decreased measurably from the amount originally associated with these particles, suggesting that organics were removed from phagocytized particles. Collectively, these studies suggest that particle-associ- ated organics become "bioavailable" to res- piratory tract cells, allowing metabolic pro- cesses to occur. Increased toxicity to lung tissue caused by the long-term retention of particle-asso- ciated organics has been illustrated by Saf- fiotti et al. (1964), Creasia and Nettesheim (1974), and Henry et al. (1975~. Their stud- ies showed that BaP is retained in the lungs longer and results in a higher incidence of lung carcinomas when intratracheally in- stilled on iron oxide particles than when instilled alone. But how and why pro- longed retention of particle-associated or- ganics in lungs increases the toxic potential of those compounds has not been thor- oughly investigated. One way that particle association might make organic com- pounds more toxic is by facilitating their uptake into lipid bilayers and microsomes, primary sites for cellular metabolism of chemicals. Lakowitz and coworkers (1980) reported that BaP adsorbed on particles was transported into model membranes composed of phosphatidylcholine dipalmi- toyl faster than suspensions of BaP micro- crystals. The degree of enhanced uptake varied with particle type. Those researchers also found that four types of asbestos par- ticles facilitated transport into membranes to a greater degree than particulate hema- tite, silica, titanium dioxide, porous glass, or talc. However, transport was not en- hanced when BaP and particles were added to their assay system as a simple mixture. Bevan and coworkers (1981) reported that transport was enhanced for particle-associ- ated dibenzoanthracene, benzoperylene, and 3-methylcholanthrene, but not for di- benzocarbazole adsorbed onto particles. Automobile exhaust particles have not been used to characterize the transport of particle-associated organics. However, Be- van and Worell (1985) used BaP associated with carbon black particles, which have physical and chemical characteristics simi- lar to those of exhaust particles, and ob- served enhanced transport of this PAH into phospholipid vesicles. Bevan and Manger (1985) measured the rates of uptake into rat liver microsomes of BaP adsorbed onto asbestos and iron oxide particles and, using the Salmonella typhimu- rium microsome assay, they measured the microsomal metabolism of BaP and the mutagenicity of the metabolizes. They cor- related enhanced uptake of particle-associ- ated BaP into microsomes with higher rates of production of mutagenic metabolites. Formation of adducts to DNA is an important marker of effective dose to target tissues of organic compounds such as those found in vehicular exhaust. The interaction of reactive organic chemicals or their metabolites with DNA is important in the overall carcinogenic response of tissues to inhaled chemicals. Weinstein and co- workers (1984, 1985) have discussed some of the potential mechanisms involved in the carcinogenic response of the respiratory tract. For example, rats chronically ex- posed to high levels of diesel engine ex- haust have higher levels of DNA adducts in their lungs than rats exposed only to air (Won" et al. 1986~. Taken as a whole, these data suggest that inhaled diesel engine ex . . . . . naust may initiate a carcinogenic response. Indeed, Mauderly and coworkers (1987) observed an increased incidence of lung tumors in rats exposed to diesel exhaust. These results also suggest that measure- ment of DNA adduct formation may be an indicator for estimating exposure dose. We are in the early stages of understand- ing how particle association affects the tox- icity of inhaled organic compounds. A few inhalation studies suggest that the particle- associated organic compounds are more toxic than the same organic compounds in pure aerosol form, probably because they are retained in the lungs longer. However, in all of these studies the exposure was brief and at relatively high concentrations. Pro- longed exposures at lower concentrations would be more relevant. Under such con

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306 Particle-Associated Organic Constituents dictions, equilibrium concentrations of the inhaled organic compounds and their meta- bolites in various organs and tissues might be more important than their clearance rates from the lungs. To better evaluate the toxic potential of particle association of inhaled organic com- pounds, it will be necessary to understand how these insoluble particles influence the biological fate of these organics. The spe- cific site at which these inhaled organics are initially deposited along the respiratory tract is probably a crucial factor that de- termines their biological fate. Particle as- sociation may influence the deposition characteristics of these inhaled organic com- pounds to a high degree in terms of where the organics are carried alone the resuira- tory tract. Related to this is the rate at which particle-associated organic com- pounds are dissolved off these particles after deposition and become available for clear- ance, metabolism, and toxic action. It is likely that, if these organic compounds never desorb from their "carrier" particles, they will be biologically inert. ~ Recommendation 2. The effect of car- rier particles on the delivery of adsorbed compounds to specific regions of the respi- ratory tract needs to be determined. Recommendation 3. Desorption rates of adsorbed compounds from inhaled par- ticles should be quantified. Toxicity of Inhaled Organic Compounds Varieties of Toxic Responses A wide variety of toxic effects may result from the inhalation of chemicals. Carbon monoxide (CO), for example, avidly binds to hemoglobin, and its inhalation can lead to asphyxiation. The irritant gas sulfur dioxide (SO2) causes bronchoconstriction; and the oxidant gases nitrogen dioxide (NO2) and ozone (03), when inhaled at sufficiently high concentrations or for a prolonged period, can cause chronic lung disease. Inhalation of other substances, such as cocaine or the active ingredient of marijuana, tetrahydrocannabinol, on the other hand, can cause toxic effects that are more systemic in nature. This section fo- cuses on those toxic responses of great public concern that may result from inha- lation of organic compounds associated with automotive exhaust. People have coexisted with automotive exhaust for more than seven decades. Dur . . . . sing t nits time, most concerns over its acute toxicity have focused on the accidental or intentional deaths caused by inhaling high concentrations of CO that occur when a vehicle is operated in closed quarters. But as the number of automobiles on the road increases, especially in densely populated areas, the concern over the long-term ef- fects of chronic exposures to automotive exhaust has grown. A significant discovery about the organic compounds emitted in automotive exhaust is that many are mutagenic and/or carcino- genic; thus, carcinogenicity is one focus of this section; the other focus is immunotox- icologic effects. As discussed earlier in this chapter, many of the organic compounds in automotive exhaust are not released in their pure form, but are adsorbed onto the insol- uble, carbonaceous soot of automotive ex- haust. Clearance of insoluble particles from lungs depends on the phagocytic activity of pulmonary alveolar macrophages and their eventual translocation to the lymphatic sys- tem (Schlesinger, this volume), where they may have toxic effects on the immune system. The remainder of this chapter will therefore address the inhalation of particle- associated organic compounds as it pertains to chemical carcinogenesis and possible ef- fects on the immune system. Metabolism of Chemical Carcinogens Most carcinogens associated with automo- tive exhaust and other air pollutants are procarcinogens that must be transformed to reactive metabolites by metabolic activa- tion before they can produce a carcinogenic effect. Chemical metabolism may proceed through several stages to produce proxi

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Sun, Bond, and Dahl 307 mate carcinogens and finally ultimate car I. . . cmogens. n many instances, proximate and ultimate carcinogens are metabolized by enzymes to inactive metabolites. But the reactive metabolites interact with cells in many ways, most notably by binding co- valently with macromolecules such as RNA, DNA, and proteins. The balance between the rate of formation of reactive metabolites and the rate of formation of inactive metabolites plays a crucial role in determining the levels of reactive metabo- lites. Usually, ultimate carcinogens com- prise only a small fraction of the total metabolic products of a chemical. A num- ber of reviews have been published relating to the metabolism or metabolic activation of chemical carcinogens (Miller and Miller 1966, 1981; Dipple et al. 1985) and other toxic, but noncarcinogenic, chemicals that may be associated with particles (Magee 1974; Nelson et al. 1977; Boyd et al. 1980~. Enzymes responsible for most of the metabolic conversions of procarcinogens are part of the mixed-function oxyzenase system (Gelboin et al. 1970, 1972~. This enzyme complex responsible for biological activation of PAHs is found in most mam- malian tissues. It is NADPH-dependent and catalyzes the incorporation of molecu- lar oxygen into substrate molecules. The enzyme complex has an absolute require- ment for three components: a hemoprotein referred to as cytochrome P-450; a flavo- protein referred to as NADPH cytochrome c (or P-450) reductase; and a phospholipid, typically phosphatidylcholine. Lu (1976) has reviewed the components and proper- ties of this enzyme system; Guengerich and MacDonald (1984) have reviewed the mechanisms by which chemicals are me- tabolized by cytochrome P-450; and Hodg- son and coworkers (1980) and Testa and Jenner (1976) have summarized the dif- ferent enzyme systems responsible for bio- transformation of procarcinogens. Some classes of procarcinogens adsorbed on airborne particles include PAHs, nitro- PAHs, aromatic amines, nitrosamines, and N- or S-containing heterocycles. In cells, some PAHs are enzymatically converted to epoxide intermediates which can spontane ously rearrange to phenols, be converted enzymatically to trans-dihydrodiols via ep- oxide hydrolase, be reduced back to the parent compound via epoxide reductase, be conjugated enzymatically or nonenzymati- cally with glutathione via glutathione S- epoxide transferase, or react directly with cellular macromolecules. The trans-dihy- drodiols may be further oxidized to the diol epoxides which also react with cellular macromolecules (see figure 3 for some of the known pathways for metabolism of BaP, a frequently studied PAM). Nitro- PAHs are metabolized by "nitro-reduc- tases" to N-hydroxy intermediates that can be metabolized to N-sulfated acetamides (as in the case for N-hydroxy-acetyl amino fluorene) by the acetyl transferases and sulfo transferases (Miller and Miller 1981) (see figure 4 for some known pathways for metabolism of NP, a typical nitro-PAH). (For a detailed discussion of the metabolism of PAHs and nitro-PAHs see Hecht, this volume.) Aromatic amines are also metab- olized to N-hydroxy intermediates, possi- bly by the flavin-containing monooxyge- nases and the mixed-function monooxy- genases. Nitrosamines are metabolized by cytochrome P-450 monooxygenases to un- stable hydroxy (cr) carbon compounds that decompose to the highly electrophilic N- monoalkylnitrosamines (Farrelly and Stew- art 1982) (see figure 4 for some known pathways for aminopyrene metabolism, a typical aromatic amine). Biotransformation of carcinogens occurs in the nose (Dahl et al. 1985), lung, skin, intestine, placenta, kidney, testes, adrenals, and liver Jenner and Testa 1980~. The liver is believed to be responsible for the major quantitative contribution to the metabo- lism of xenobiotics (organic chemicals for- eign to the body), with a few exceptions noted below. However, relative levels of activating and detoxifying enzymes vary in different tissues, so that the amounts of ultimate carcinogenic metabolites formed in different tissues is not necessarily pro- portional to the amount of initial carcino- gen metabolized there. This may explain, in part the localization of certain chemi- cally induced tumors outside the liver.

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308 0 / ~ @~ 6, 1 2-qu~none tree ~ radical jMFO 0H HO ~ / 9-hvdroxv 1-hvdrox, 1~ radical ~ ~J _ MFO OH BENZOta]PYRENE 6-hydroxy tree |radical MFO - ~o 3,6-quinone 2,3-epoxide\ Particle-Associated Organic Constituents ., . 1 ~EHH~ MFO, Il0~) H2O HO~ 9,10-epoxide 9,10-diol 7,8-epoxicle-9,10-diol OH 7,8,E, 1 O-tetrol ~_ ~EH~oxi<~e 4,5-epoxide 4,5-diol ~H OH 4,5-diol-7,8-epox~de ~J EH (~OH 7,8-epo~lde 3-hydroxy ` OH 7 -hydroxy HO Flo 7,8-diol 7,8-diol-9, 1 0-epoxide HO~ OH 7,8,1., 1 0-tetrol Figure 3. Pathways of benzo[a]pyrene metabolism, where MFO = the mixed-function oxygenase enzyme system, and EH = epoxide hydrolase. Hydroxylated metabolites can undergo conjugation reactions that result in the formation of glucuronide, sulfate, or mercapturic acid derivatives of the metabolite. t~0, ~ ~H2 NITROPYRENE nitroso hydroxyamino AMINOPYRFNF MFO EH C ' O~ ~H ~ ~J acetoxyamino \ MFO H 3C-C~ ~OHC`N'H ~ @~ hydroxyacetamidoacetylamino | MFO E~ Ring Hydroxylation 1 Conjugation Reactions Figure 4. Pathways of nitropyrene and aminopyrene metabolism, where MFO = the mixed-function oxygenase enzyme system, and EH = epoxide hydrolase. Conjugation reactions result in the formation of glucuronide, sulfate, or mercapturic derivatives of the metabolite. MFO EH

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Sun, Bond, and Dahl 309 Respiratory Tract Metabolism of Particle- Associated Carcinogens. With few excep- tions, the quantitative formation of metab- olites by respiratory tract tissues is less than that by the liver. However, since the respi- ratory tract is directly exposed to particle- associated carcinogens, their activation by respiratory tract tissues may still have an important role in the pathogenesis of car- cinogen-induced lesions in these tissues. Carcinogen metabolism has been studied in different preparations of respiratory tract tissues (including nasal tissue), cultured tra- chea and bronchus, the perfused lung, iso- lated lung cells, and pulmonary alveolar macrophages. These studies focused on pure compounds, in particular PAHs, rather than particle-associated carcinogens. References to the liver, a major organ for metabolism of endogenous as well as exog- enous compounds, are introduced for com . . . . . parlson Wlt ~ various respiratory tract tlS- sues throughout the following review. Nasal Tissue. The metabolism of xeno- biotics in nasal tissue has been generally neglected, although some reports have been published (Dahl et al. 1982. 1987: Bond 1983a,b; Dahl and Hadley 1983; Had- ley and Dahl 1983; McNulty et al. 1983; Brittebo and Ahlman 1984; Casanova- Schmitz et al. 1984; Dahl 1986~. Nasal tissue metabolism is important because many environmental pollutants contain known carcinogens adsorbed onto particles of sizes that deposit in the nasopharyngeal region of the respiratory tract (Task Group on Lung Dynamics 1966; Natusch and Wallace 1974~. It's believed that nasal tissue contains the full complement of enzymes necessary for the metabolism of xenobiotics, but further work is needed to substantiate this belief. Xenobiotic-metabolizing enzymes known to be in the nasal cavity include cytochrome P-450 and flavin-containing monooxyge- nases, aldehyde dehydrogenases, epoxide hydrolases, glutathione transferases, UDP- glucuronyl transferases, and carboxyl ester- ases (for a review, see Dahl 1986, 1987~. In general, enzymes in the nasal tissue have turnover rates comparable to those in liver. The nasal tissue metabolism of only two PAHs BaP and NP-has been thoroughly investigated (Bond 1983a,b). Those in vitro studies using nasal tissue homogenates in- dicated that nasal tissue can metabolize these compounds to phenols, quinones, dihydrodiols, and tetrols. In viva studies in hamsters have also shown that BaP is metabolized by nasal tissue (Dahl et al. 1985~. The profile of BaP metabolites pro- duced in hamster noses is nearly identical to that measured using nasal tissue homoge- nates, suggesting that in vitro models for nasal tissue metabolism of PAHs may pre- dict the metabolic profile in the intact ani- mal. Further research on nasal tissue metabo- lism of chemicals is necessary to adequately characterize nasal tissue enzymes. It is im- portant to determine the capacity of the nose to activate and inactivate the various chemicals associated with pollutants. Ki- netic studies are also required to provide information on concentrations of pollutants that may "saturate" nasal tissue enzymes. These studies may provide clues about the mechanisms involved in nasal tissue carci- nogenes~s. in, . . . there are no reports in the literature of nasal tissue metabolism of particle-associ- ated organics. This deficiency must be ad- dressed in future studies if we are to under- stand the role of nasal tissue in the overall biological fate of particle-associated carcin- ogens. Other research is needed to deter- mine where the reactive metabolites and procarcinogens produced in nasal tissue are translocated and at what rates. Dahl and coworkers (1985) have shown that nasal tissue metabolites can be swallowed, ex- posing the alimentary tract to potentially reactive metabolites. Translocation of these reactive metabolites to other tissues re- quires further study. Trachea and Bronchi. A considerable amount of research has been done on bron- chial metabolism of PAHs (for a review, see Autrup 1982) and BaP in particular (Harris et al. 1974, 1976, 1977; Jeffrey et al. 1977; Yang et al. 1977; Daniel et al. 1983~. The data indicate that bronchial tissue is capable of metabolizing BaP to several compounds including phenols, dihydro- diols, and quinones. The profiles of organic soluble metabolites of BaP in the respira

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312 Particle-Associated Organic Constituents mav have been removed from the particle 30 ~ 26 WEEKS before metabolism occurred. Although macrophages can metabolize PAHs associated with particles, it remains to be determined whether site-specific me tabolism of PAHs is the major contributing factor in the overall carcinogenic response or whether the metabolites released from macrophages play any role in contributing ,,, lo to the total "dose" to tissue. Evidence from . . . . . . . in vitro anc in VlVO stuc .les 1nc .lcates that different portions of the respiratory tract can metabolize PAHs to compounds that bind to "critical" macromolecules. How ever, whether metabolites produced in macrophages and released in different por tions of the respiratory tract bind to critical macromolecules of other tissues is un known. Recommendation 6. The importance of macrophage metabolism in the activa tion of particle-associated organics and the contribution of metabolic products to tis sue dose need to be determined. Effects on the Immune System Organic compounds associated with in haled particles affect the immune system in at least two important ways: they affect the translocation of antigen from the lung to the lung-associated lymph nodes, and they directly affect lymphoid cells in these tis sues. Table 2. Decrease in Phagocytizing Pulmonary Alveolar Macrophages as a Result of In Vitro Exposures to Particle Extracts Particle Source ICso`' (~g/mL) Rural road City street City roof Auto tunnel Gasoline engine 471 270 24 43 a ICso is the concentration of extract needed to de- crease the number of phagocytizing pulmonary alveo- lar macrophages to 50 percent. SOURCE: Adapted with permission from Romert et al. 1985, and from Pergamon Journals, Ltd. 20 it J mu O O 30 of o J :: Macrophages EM Polymorphonuclear _ leukocytes ~ Lymphocytes ~ :-L 20- 10 o 48 WEEKS ah L 750 1 500 DIESEL EXPOSURE CONCENTRATION Figure 5. Cell populations in ravage fluid from rats exposed to different concentrations of diesel exhaust particles for 26 weeks or 48 weeks. The data are means + standard deviations (n = 6). (Adapted with permis- sion from Strom 1984.) Translocation Mechanisms. Particles and antigen deposited in the broncho-alveolar region of the lungs can be transported to the lung-associated lymph nodes where im- mune responses are produced. Macro- phages probably participate in this trans- port (Harmsen et al. 19851; therefore, any toxicant associated with the particle that kills macrophages or inhibits phagocytosis affects the capacity of the lung to clear antigen from the lung to lung-associated lymph nodes. Toxic effects on pulmonary alveolar macrophages have been observed from or- ganic chemicals associated with particles from a variety of sources including auto- motive emissions (Romert et al. 1983, 1985) (see table 2~. Undiluted automotive exhaust is highly toxic to pulmonary alve

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Sun, Bond, and Dahl olar macrophages in vitro. However, Strom (1984) found that, despite this tox- icity, the effect on overall phagocytosis in vivo may be small because the number of pulmonary alveolar macrophages in rats increased in response to exposure to diesel exhaust. After exposure of rats to high con- centrations of diesel exhaust, phagocytic neutrophils were recruited into the lung, thereby potentially further increasing the overall phagocytic capacity (figure 5~. This capacity to recruit polymorphonuclear (PMN) leukocytes (that is, neutrophils, eosinophils, and basophils) appears to be a common phenomenon after exposure to particles. It has been observed, for instance, after exposure to cigarette smoke particles, but not to the vapors (Kilburn and McKen- zie 1975~. The contribution of particle- associated organic compounds to the re- cruitment of these phagocytic cells, however, is not known. Also, if a portion of the organics originally adsorbed on the particles are transported with them to the lymph nodes, then toxic metabolites may be formed from them in the lymphatic system. Recommendation 7. Research should be pursued on the effects of particle-associ- ated materials on lung phagocyte recruit- ment and activity, clearance rates to the lymph nodes, and translocation of particle- associated organic compounds to the lym- phatic system. Lymphoid Cells. Cells responsible for immunity to antigens deposited in the lung are affected by some but not all of the compounds that often are associated with particles. For example, BaP instilled in hamster lungs suppressed the splenic sys- temic humoral immune response, whereas treatment with benzoteipyrene had no ef- fect on immune response (Zwilling 1977~. The effect of particle association of BaP, however, was not examined in that study. BaP instilled in the lungs can also alter the induction of immunity in the lung- associated lymph nodes in response to a particulate antigen (Schnizlein et al. 1982~. For example, the numbers of lung-associ- ated lymph node IgM as well as IgG anti 313 10,000~ L1J1'000 cn_ +1_ cn J lL Z100 _ 1 ,000 100 IgM i'* Control Mean ~SE -T-i: ~ T~; = ~15-- --~-~ r Control Mean ~ SE _ / 1V ' ~ 5 . . . . ~ -4 0 +4 8 12 14 DAY OF INTRATRACHEAL IMMUNIZATION RELATIVE TO BaP INSTILLATION Figure 6. The number of IgM and IgG antisheep red blood cell (SRBC) antibody-forming cells (AFC) per million lung-associated lymph node (LALN) cells seven days after intratracheal immunization of rats with 106 SRBC at various times relative to the instil- lation of 1 mg BaP into their lungs. (*) Denotes significance (p < 0.05) as determined by Student's t test. (Adapted with permission from Schnizlein et al. 1982.) sheep red blood cell antibody-forming cells increased in rat lungs instilled with BaP if the rats were immunized at the time of BaP instillation, but decreased if the rats were immunized four days after BaP exposure (figure 6~. This relationship raises interest- ing questions about BaP (or compounds with similar effects) adsorbed onto parti- cles. BaP adsorbed onto Ga~O3 (Sun et al. 1982) or diesel engine exhaust particles (Sun et al. 1984) cleared from the lung more slowly than pure BaP. A more pro- tracted dose of BaP to the lymph nodes might thus result from particle-associated BaP than from pure BaP. At present, no information is available that would predict whether the immune response to sheep red blood cells (SRBC) instilled four days af- ter instillation of particle-associated BaP

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314 Particle-Associated Organic Constituents 40 20 o E ._ _ ~ J 15 0 5 oL DE E 1 . RATS 18 24 18 6 12 MONTHS OF EXPOSURE Figure 7. Total number of lymphoid cells in the lung-associated lymph nodes from rats (top panel) or mice (bottom panel) exposed to different levels of diesel engine exhaust for 6, 12, 18, or 24 months. Data are presented as geometric means + 1 SE. (Adapted with permission from Bice et al. 1985.) would be like the response seen either when coadministered with pure compound or administered after a four-day delay. Automotive exhaust also affects the lung-associated lymph nodes. The particu- late fraction of the exhaust, along with associated organic compounds, may con- tribute to the effects. In rats and mice exposed to diesel exhaust at 0.35, 3.5, or 7.0 mg/m3 of soot particles for 7 hr/day, 5 days/~eek, the number of cells present in lung-associated lymph nodes increased significantly (figure 7) (Bice et al. 1985~. After immunization with SRBC, rats and mice exposed at the 7.0 mg/m3 level had elevated numbers of IgM antibody-forming cells. Combustion aerosols from nonautomo- tive sources that have been studied with regard to immune responses include coal fly ash and cigarette smoke. Fly ash had no effect on the response to antigenic challenge in mice immunized with live bacillus Cal- mette-Guerin organisms, or on the ability of pulmonary alveolar macrophages to function in T-lymphocyte mutagenesis as- says (Zarkower et al. 1982~. These negative findings might have resulted from the low concentrations of toxic organic compounds associated with coal fly ash (Hanson et al. 1981~. On the other hand, cigarette smoke, which has relatively high concentrations of particle-associated organic toxicants (Guer- in 1980) has significant effects on immune responses. For example, smokers had in- creased numbers of germinal centers in their carinal lymph nodes, suggesting ei- ther that increased translocation of antigen from the lungs occurred in smokers or that the lymphoid cells were directly stimulated by tobacco smoke (Souter 1977~. The response of the immune system to inhaled particles varies with the toxicity of the particles, their source, and other factors such as the timing between exposure and the measurement of effects. At present, there are not enough data to explain the observed effects rationally. Knowledge of the chemical composition of inhaled aero- sols, their rates of release from particles, and the metabolic fate of specific com- pounds are of key importance. Studies with lymph node tissue show that rat lymph nodes have low levels of the constitutive enzymes responsible for aryl hydrocarbon hydroxylase (AHH) activities (Ciaccio and De Vera 1975~. Intraperitoneal injection of BaP, however, increased the lymph node AHH activity by a factor of 11. The presence of AHH activities, and possibly or other enzyme activities, in lymph nodes shows that organic com- pounds on particles that clear to the lymph nodes may be metabolized in that tissue. As a result, electrophilic metabolites formed in the lymph nodes may produce toxic effects at that site. Recommendation 8. The transloca- tion of particle-associated organic com- pounds and their eventual metabolism to reactive metabolites in lymph nodes re . . . . qu~res ~nvest~gat~on.

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Sun, Bond, and Dahl 315 Summary All portions of the respiratory tract contain enzymes capable of metabolizing xenobi- otics (foreign organic chemicals) including PAHs. With few exceptions, metabolism of xenobiotics by these enzymes has been studied in vitro in tissues of various labo- ratory animals and humans. Significant progress has been made in our understand- ing of the comparative metabolism of the different anatomic portions of the respira- tory tract. Although people are exposed to many different chemicals associated with particles, most studies have involved only pure chemicals, often BaP. Inhaled particle-associated organic com- pounds are deposited in all areas of the respiratory tract. Association with particles can affect the deposition sites and retention times of such organic materials and creates opportunities for metabolic activation that would be different for the pure organic material. The few studies on the effects of particle association on clearance of organic compounds from lungs indicate that the rates of removal are much slower than those for the pure compounds and that the clearance mechanisms may be different. Thus, particle-associated organic com- pounds may pass through different paths, or at different rates or concentrations, or to different tissues, or be exposed to different metabolic environments, than pure com- pounds. Particle-associated organics are transported into microsomal membranes more readily than are pure compounds, and are susceptible to metabolic activation for a longer time. This increased activation may make the lungs a target organ for organics associated with particles that in pure form would be cleared rapidly and with less toxic effect. Inhaled particle-associated organic com- pounds have two kinds of effects on the immune system. First, they can impair phagocytosis by specific types of pha- gocytes, altering the clearance of inhaled antigens from the lung to lymphoid tissue. For example, extracts from particles gener- ated by a gasoline engine decreased the number of phagocytizing macrophages in an in viva assay (Romert et al. 1985~. Second, they can affect lymphoid cells in the lung-associated lymph nodes. Effects on the number of antibody-forming cells and the quantity of antibody produced in the lung-associated lymph nodes has been demonstrated, for example, in rats after inhalation of diesel exhaust at high (7 mg particles/m3) concentrations (Bice et al. 1985~. Compounds frequently associated with particles, such as BaP, have similar effects on lymph node cells. Enzymes that metabolize BaP and similar compounds to reactive (electrophilic) compounds are known to occur in lymph nodes and to be inducible by BaP. This is evidence that particle-associated compounds can have ef- fects on the immune system, but more research is required to establish the toxico- logic importance of such effects. Summary of Research Recommendations HIGH PRIORITY Because of the limited amount of information available concern- ing the toxicology of inhaled particle-associated organic com- pounds, further research is needed. Outlined below are the most critical areas of study that would provide the information needed for better estimations of the potential human health risks of inhaled atmospheric pollutants. Recommendation 2 Little information is available on the specific regions and/or cell types in the respiratory tract where inhaled organic compounds adsorbed onto particles become bioavailable. These particles may

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316 Particle-Associated Organic Constituents act as "carriers" of these compounds to sites or cell types that would be different from those to which inhaled pure forms of the same organic materials would be deposited. Such studies would determine if these carrier particles affect the delivery of adsorbed organic compounds to "critical" cell types. Recommendations Information is needed to determine the rate of Resorption of 3, 5 compounds from particles after deposition in the respiratory tract. Such information would provide insight into the rate of delivery of these organic constituents to respiratory tract tissues as well as to other tissues in the body. Studies in this area will determine if particle association of potentially toxic organic com pounds causes these inhaled chemicals to be delivered to "critical" cell types at an exposure rate that would ultimately result in a deleterious effect. MODERATE PRIORITY Studies using new methodologies that better determine the degree of toxicity and the mechanisms of action of inhaled particle associated organic compounds need to be developed and con ducted. Recommendation 1 Particle association of organic compounds appears to increase the long-term retention of those compounds in lungs. At present, it is usually accepted that the increased retention of inhaled toxic/carci nogenic compounds in lungs will increase the deleterious effects of those compounds. This may occur by maintaining the concentra tion of the organic compounds in lungs above some "critical" dose for extended periods. Alternatively, longer lung retention of particle-associated organic compounds may actually make those compounds less toxic/carcinogenic. In this latter case, the slow release of compounds from particles may result in keeping the concentration below the "critical" dose, which may be a level where metabolic detoxification or repair can effectively occur. The toxicologic effects of particle-associated organic compounds and ~ , o ~ r the mechanism of those effects need to be tested in long-term inhalation studies using organic compounds that are retained substantially longer in the lungs when adsorbed onto particles than when inhaled in pure form. Recommendation 4 Little is known about the capacity of respiratory tract tissues to metabolize organic compounds that are adsorbed on particles. This is particularly true for nasal tissue and the tracheobronchial regions of the respiratory tract. The "effective" dose of a carcinogen is thought to be determined by the amount of reactive metabolite bound to critical cellular macromolecules such as DNA. The key issue that remains to be addressed is whether particle-associated carcinogens can penetrate cells and be accessible to various metab olizing enzymes. Related to this is whether metabolism of particle associated carcinogens occurs in these regions of the respiratory tract, and, if so, whether reactive metabolites can then be translo cated to other tissues and at what rates. These are important areas

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Sun, Bond, and Dahl 317 of research that need to be addressed for the different anatomic regions and cell types of the respiratory tract. LOW PRIORITY Studies that investigate secondary or partial effects of particle- associated organic compounds that deposit in the respiratory tract are needed. Recommendation 6 In vitro data indicate that macrophages can metabolize pure as well as particle-associated organic compounds. However, it is not clear whether macrophages contribute to the overall "dose" to tissue in terms of formation of reactive chemical species that can interact with portions of the respiratory tract or other tissues. Since large numbers of macrophages are recruited following a "particle" insult, the importance of macrophage metabolism in the activation of particle-associated toxins/carcinogens needs to be determined. Recommendation 7 As part of the lung's normal defense mechanisms, phagocytizing cells are recruited to anatomic areas where inhaled particles have been deposited. An area needing further study is the effect that particle-associated organic compounds may have on this recruit ment process. Related to this is the need to further investigate the potential toxicity that these particle-associated organic compounds may have on phagocytizing cells and the role these cells may play in the overall clearance of these organic compounds from the different regions of the respiratory tract. Recommendation 8 Following phagocytosis, particles and associated organic com nounds are translocated to luna-associated lymphoid tissue. This translocation may allow for the metabolism of these organic compounds in the lymph nodes. The degree to which this may occur, the metabolic profile and characteristics of lymphoid tissue metabolism of particle-associated organic compounds, and the effect of these metabolites on the lung's normal immunologic . . . . response require investigation. Acknowledgments The authors give special thanks to Mary lo Waltman for providing technical assistance for this chapter. The authors also acknowl- edge Drs. D. E Bice, R. G. Cuddihy, R. L. Hanson, R. F. Henderson, T. R. Hender- son, C. H. Hobbs, I. L. Mauderly, R. O. McClellan, M. A. Medinsky, C. E. Mit Correspondence should be addressed toJames D. Sun, James A. Bond, or Alan R. Dahl, Inhalation Toxicol- ogy Research Institute, Lovelace Biomedical and En- vironmental Research Institute, P.O. Box 5890, Al- buquerque, NM 87185. chell, P. J. Sabourin, M. B. Snipes, and R. K. Wolff for their critical reviews. Portions of the research were supported by the Office of Health and Environmental Research under U.S. Department of En- ergy Contract No. DE-AC04-76EV01013. References Autrup, H. 1982. Carcinogen metabolism in human tissues and cells, Drug Metab. Rev. 13(4) :603-646. Autrup, H., Harris, C. C., Stoner, G. D., Selkirk, J. K., Schafer, P. W., and Trump, B. F. 1978.

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318 Metabolism of (3H) benzotaipyrene by cultured human bronchus and cultured human pulmonary alveolar macrophages, Lab. Invest. 38(3):217-224. Autrup, H., Harris, C. C., Schafer, P. W., Trump, B. F., Stoner, G. D., and Hsu, I. C. 1979. Uptake of benzotaipyrene-ferric oxide particulates by hu- man pulmonary macrophages and release of ben- zota~pyrene and its metabolites, Proc. Soc. Exp. Biol. Med. 161:2800-2804. Ball, L. M., Plummer, J. L., Smith, B. R., and Bend, J. R. 1979. Benzota~pyrene oxidation, conjugation and disposition in the isolated perfused rabbit lung: role of the glutathione S-transferases, Med. Biol. 57:298-305. Behymer, T. D., and Hites, R. A. 1984. Similarity of some organic compounds in spark-ignition and diesel engine particulate extracts, Environ. Sci. Tech- nol. 18:203-206. Bennett, R. L., Knapp, K. T., Jones, P. W., Wilker- son, J. E., and Strup, P. E. 1979. Measurement of polynuclear aromatic hydrocarbons and other haz- ardous organic compounds in stack gases, In: Poly- nuclear Aromatic Hydrocarbons (P. W. Jones and P. Leber, eds.), pp. 419028, Ann Arbor Science Pub- lishers, Inc., Ann Arbor, Mich. Bevan, D. R., and Manger, W. E. 1985. Effect of particulates on metabolism and mutagenicity of benzoiaipyrene, Chem.-Biol. Interact. 56:1~28. Bevan, D. R., and Worrell, W. J. 1985. Elution of benzotaipyrene from carbon blacks into biomem- branes in vitro, Toxicol. Environ. Health 15:697-710. Bevan, D. R., Riemer, S. C., and Lakowicz, J. R. 1981. Effects of particulate matter on rates of mem- brane uptake of polynuclear aromatic hydrocar- bons, Toxicol. Environ. Health 8:241-250. Bice, D. E., Mauderly, J. L., Jones, R. K., and McClellan, R. O. 1985. Effects of inhaled diesel exhaust on immune responses after lung immuni- zation, Fundam. Appl. Toxicol. 5:1075-1086. Bjorseth, A., Bjorseth, O., and Fjeldstad, P. E. 1978. PAHs in the work atmosphere. II. Determination in a coke plant, Scand. J. Work Environ. Health 4:224. Bond, J. A. 1983a. Some biotransformation enzymes responsible for PAH metabolism in rat nasal turbi- nates; effects on enzyme activities of in vitro mod- ifiers and intraperitoneal and inhalation exposure of rats to inducing agents, Cancer Res. 43:4804 1811. Bond, J. A. 1983b. Bioactivation and biotransforma- tion of 1-nitropyrene in liver, lung and nasal tissue of rats, Mutat. Res. 124:315-324. Bond, J. A., and Mauderly, J. L. 1984. Metabolism and macromolecular covalent binding of (~4C-1- nitropyrene in isolated perfused and ventilated rat lungs, Cancer Res. 44:392~3929. Bond, J. A., Butler, M. M., Medinsky, M. A., Muggenburg, B. A., and McClellan, R. O. 1984. Dog pulmonary macrophage metabolism of free and particle-associated ('4C)benzo~aipyrene, Toxi- col. Environ. Health 14:181-189. Bond, J. A., Mauderly, J. L., Henderson, R. F., and McClellan, R. O. 1985. Metabolism of 1-(~4C)ni- tropyrene in respiratory tract tissue of rats exposed to diesel exhaust, Toxicol. Appl. Pharmacol. 79:461- 470. Particle-Associated Organic Constituents Bond, J. A., Ayres, P. H., Medinsky, M. A., Cheng, Y.-S., Hirshfield, D., and McClellan, R. O. 1986a. Disposition and metabolism of ~4C-dibenzotc,gicar- bazole aerosols in rats after inhalation, Fundam. Appl. Toxicol. 7:7085. Bond, J. A., Sun, J. D., Medinsky, M. A., Jones, R. K., Yeh, H. C. 1986b. Deposition, metabolism and excretion of ~4C-1-nitropyrene and ~4C-1-ni- tropyrene coated on diesel exhaust particles as in- fluenced by exposure concentration, Toxicol. Appl. Pharmacol. 85:102-117. Boyd, M. R. 1980. Biochemical mechanisms in chem- ical-induced lung injury: roles of metabolic activa- tion, In: Critical Reviews in Toxicology (L. Goldberg, ed.), Vol. 7, pp. 103-176, CRC Press, Inc., Boca Raton, Fla. Boyd, M. R., Buckpitt, A. R., Jones, R. B., Statham, C. N., and Longo, N. S. 1980. Metabolic activation of toxins in extrahepatic target organs and target cells, In: The Scientific Basis of Toxicity Assessment (H.. R. Witschi, ed.), p. 141, Elsevier/North- Holland, New York. Brittebo, E. B., and Ahlman, M. 1984. Metabolism of a nasal carcinogen, phenacetin, in the mucosa of the upper respiratory tract, Chem.-Biol. Interact. 50:233- 245. Brooks, A. L., Wolff, R. K., Royer, R. E., Clark, C. R., Sanchez, A., and McClellan, R. O. 1981. Deposition and biological availability of diesel par- ticles and their associated mutagenic chemicals, Environ. Int. 5:26~267. Butler, J. D., Butterworth, V., Kellow, S. C., and Robinson, H. G. 1984. Some observations of the PAH content of surface soils in urban areas, Sci. Total Environ. 33:75. Cantrell, E. T., Warr, G. A., Busbee, D. L., and Martin, R. R. 1973. Induction of aryl hydrocarbon hydroxylase in human pulmonary alveolar macro- phages by cigarette smoking, J. Clin. Invest. 52(8): 1881-1884. Casanova-Schmitz, M., David, R. M., and Heck, H. D. 1984. Oxidation of formaldehyde and acetal- dehyde by NADH-dependent dehydrogenases in rat nasal mucosal homogenates, Biochem. Pharmacol. 33(7):1137-1142. Chan, T. L., Lee, P. S., and Hering, W. E. 1981. Deposition and clearance of inhaled diesel exhaust particles in the respiratory tract of Fischer rats,_r. Appl. Toxicol. 1:77-82. Chrisp, C. E., Fisher, G. L., and Lammert, J. E. 1978. Mutagenicity of filtrates from respirable coal fly ash, Science 199:7~75. Ciaccio, E. I., and De Vera, H. 1975. Effect of benzoia~pyrene and chlorpromazine on aryl hydro- carbon hydroxylase activity from rat tissues, Bio- chem. Pharmacol. 25:985-987. Clark, C. R., and Vigil, C. 1980. Influence of lung and liver homogenates on the mutagenicity of diesel exhaust particulate extracts, Toxicol. Appl. Pharma- col. 56:11~115. Cohen, G. M., and Moore, B. P. 1976. Metabolism of (3H)benzota~pyrene by different portions of the respiratory tract, Biochem. Pharmacol. 25:162~1629. Cohen, G. 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