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Potential Carcinogenic Effects of Polynuclear . Aromatic psycho car cons anc" N~troaromatics in Mobile Source Emissions STEPHEN S. HECHT American Health Foundation Historical Perspective and Directions for the Future / 556 Evaluation of Polyaromatic Hydrocarbon and Nitro-Polyaromatic Hydrocarbon Carcinogenicity / 556 Role of Polyaromatic Hydrocarbons as Human Carcinogens / 556 Tumorigenicity of Polyaromatic Hydrocarbons in Laboratory Animals / 558 Modifiers of Polyaromatic Hydrocarbon Carcinogenesis / 561 Carcinogenicity of Nitro-Polyaromatic Hydrocarbons / 562 Metabolic Activation and Detoxification of Polyaromatic Hydrocarbons and Nitro-Polyaromatic Hydrocarbons / 563 Absorption and Distribution upon Inhalation / 563 Benzotaipyrene / 564 Other Polyaromatic Hydrocarbons / 566 Nitro-Polyaromatic Hydrocarbons / 567 Research Problems Relating to the Potential Carcinogenic Effects of Polyaromatic Hydrocarbons and Nitro-Polyaromatic Hydrocarbons in Humans / 568 Individual Dosimetry / 568 Bioassays in Laboratory Animals / 570 Mechanisms of Polyaromatic Hydrocarbon and Nitro-Polyaromatic Hydrocarbon Carcinogenesis / 571 Summary / 572 Summary of Research Recommendations / 573 Air Pollution, the Automobile, and Public Health. (~3 1988 by the Health Effects Institute. National Academy Press, Washington, D.C. 555

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556 Effects of Polynuclear Aromatic Hydrocarbons and Nitroaromatics Historical Perspective and Directions for the Future Pott first observed an association between soot and cancer in 1775 (Pott 1775), and by the early twentieth century it was clear that soot, coal tar, and pitch could cause cancer in humans (International Agency for Re- search on Cancer 1985a). In the 1930s, pioneering studies by Kennaway and Hieger (1930) and Cook et al. (1933) established that polynuclear aromatic hy- drocarbons (PAHs) were carcinogenic com- ponents of pitch. Although the following 50 years have brought major advances in our understanding of the mechanisms by which PAHs can cause cancer, our ability to assess the health effects-and in particu- lar the potential carcinogenic effects of PAHs in humans, remains incomplete. The aspects of PAH carcinogenesis summarized in this chapter include epidemiologic stud- ies that may link PAHs to human cancer, . . . . . . carc1nogenlc1ty assays 1n .a ooratory an1- mals, key features of PAH metabolic acti- vation and detoxification, and the effects of modifiers on these processes. In contrast to the PAHs, known for half a century, nitro-substituted PAHs (nitro- PAHs) have only recently been recognized as environmental carcinogens, whose pres- ence in diesel exhaust is of particular con- cern (Schuetzle 1983~. Although less is known about their health effects than about those of PAHs, it is clear that some nitro- PAHs are potent mutagens and carcino- gens. Using these studies as a base, we identify significant gaps that detract from our abil- ity to assess PAH Carcinogenicity in hu- mans, summarize data on the carcinogenic effects and metabolism of nitro-PAHs in laboratory animals, and suggest directions for future research. Recent rapid progress in research on PAHs and nitro-PAHs is due to improved analytical and spectroscopic techniques as well as to major advances in molecular biology. Those new techniques, which may soon permit the measurement of an effective biological dose of a carcinogen for humans, combined with animal experi- ments, may make it possible to develop indicators of individual susceptibility to PAH or nitro-PAH carcinogenesis. These exciting developments represent an impor- tant frontier in chemical carcinogenesis re- search, and their application to assessing the health risks of PAHs and nitro-PAHs are a focus of this chapter. Evaluation of Polyaromatic Hydrocarbon and Nitro Polyaromatic Hydrocarbon Carcinogenicity Role of Polyaromatic Hydrocarbons as Human Carcinogens Since the PAHs to which humans are ex- posed always occur in a mixture of many compounds, some potentially carcinogen- ic, assessing PAHs as human carcinogens by epidemiologic studies is difficult. The International Agency for Research on Can- cer (IARC) has evaluated Carcinogenicity of such mixtures and published results in the IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. . . . . . . ~V1C .ence or carclnogen1c1ty rom stuc 1es in humans is categorized as follows: (1) "sufficient evidence" indicates a causal re- lation between the agent and human cancer; (2) "limited evidence" indicates a credible causal relation without excluding other ex- planations; (3) "inadequate evidence" indi- cates either that pertinent data are few or that the available data do not exclude a presumed chance association; and (4) "no evidence" indicates that adequate studies are available and these show no evidence of Carcinogenicity Other working groups have also considered the possible roles of PAH-containing mixtures in human cancer etiology. Studies of sources, other than automotive, implicate PAHs as human car- cinogens and are discussed below. Evidence for the role of mobile sources is discussed in Carcinogenicity of Nitro-PAHs. Tobacco Smoke. Sufficient evidence now indicates that tobacco smoke is carcino- genic to humans, that malignant tumors of the respiratory tract and upper digestive system are causally related to smoking to- bacco, and that malignant tumors of the bladder, pancreas, and renal pelvis specifi

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Stephen S. Hecht 557 cally are causally related to cigarette smok- ing (International Agency for Research on Cancer 1986~. The 1982 report by the Sur- geon General of the United States con- cluded that "cigarette smoking is the major single cause of cancer mortality in the United States. Tobacco's contribution to all cancer deaths is estimated to be 30 percent" (U.S. Department of Health and Human Services 1982a). Evidence increas- ingly suggests that passive exposure to tobacco smoke, as in polluted indoor envi- ronments, may increase the risk of lung cancer (International Agency for Research on Cancer 1986~. P`AHs are important carcinogenic con- stituents of the particulate phase of cigarette smoke in concentrations ranging from 1 to 60 ng/cigarette (U. S. Department of Health and Human Services 1982b), and their tumorigenic activities are enhanced by other agents in tobacco smoke. It is very likely that they are involved in the cancer- causing properties of tobacco smoke, but their role is difficult to assess because of the many other toxic and carcinogenic constit- uents of tobacco smoke, such as nitrosa- mines whose concentrations exceed those of PAHs (Hoffmann and Hecht 1985), vol- atile aldehydes, and aromatic amines. . Coal Tars, Shale Oils, and Soots. An IARC Working Group (1985a) concluded that occupational exposure to coal tars is causally associated with incidence of skin cancer in humans, and that coal tar pitches are carcinogenic in humans. They noted that a cohort study of U.S. roofers indi- cated a greater risk of lung cancer and other cancers. Among the 10,000 compounds that may be present in coal tars, PAHs occur in concentrations ranging from 0.1 to 10 percent in high-temperature coal tars, and certainly contribute largely to the ob- served carcinogenic properties of coal tars. Other IARC groups (1985b,c) have con- cluded that there is sufficient evidence that shale oils and soot are carcinogenic to hu- mans and contain relatively high levels of PAHs. Coal Gasification and Coke Production. The IARC (1984c) has concluded that cer- tain exposures in the retort houses of older coal gasification processes and in the coke production industry are carcinogenic in hu- mans. The relative risk of lung cancer is as high as 16-fold in topside coke oven work- ers with 15 years or more of exposure. Consideration of duration and location of employment in the plant has shown a dose/ response relationship for lung cancer. In an association between mortality from lung cancer and exposure to coal tar pitch vola- tiles, PAHs are again likely prominent causative agents (Redmond 1983~. Aluminum Reduction and Iron and Steel Founding. Although an IARC Working Group (1984b) found only limited evidence of increased incidence of cancer in alu- minum production and iron and steel foundry workers, some evidence links alu- minum production to bladder cancer. Lev- els of total PAHs in aluminum production range from <1 to 2,800 ,ug/m3, determined by personal sampling for 2~ hr at various sites. PAHs or their metabolites have also been detected in the urine of exposed work- ers (Becher and Bjorseth 1983; Interna- tional Agency for Research on Cancer 1984b). Mineral Oils. Mineral oils used in such occupations as mulespinning, metal ma- chining, and jute processing have been found to be carcinogenic to humans, and exposures have consistently been linked to cancer of the skin, and particularly of the scrotum. The levels of PAHs present in such oils vary, depending on source and processing (International Agency for Re- search on Cancer 1984a). Urban Pollution. In contrast to certain occupational exposures, epidemiological evidence indicates that after correction for smoking and occupation, exposure to gen- eral air pollution (defined as a body of contaminated air extending over a popula- tion area of appreciable size) has little, if any, effect on rate of death from lung cancer (Hammond and Garfinkel 1980~. Conclusion. Although none of the studies mentioned here has specifically incrimi- nated PAHs as causative agents of cancer, the overall data, together with the results

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558 Anthanthrene 2 904 8~2 7 6 6 S 4 Benzo[a]fluorene Benzolbifluorene ~ 2 3 2 1O 1 12 Q 11 - 6 7~3 lO - S 9 8 7 6 S 8 Effects of Polynuclear Aromatic Hydrocarbons and Nitroaromatics 7~2 10~?4 5 10 4 8 7 6 Anthracene Benzo[b]fluoranthene Benzo[ghi]Duoranthene Benzoij]fluoranthene 10~4 8 7 6 Benzo[k]fluoranthene Benzolghi]perylene 12 ~ ~2 7 6 Chrysene 2 12 ~ [~5 ^3 7 6 7 6 S fluoranthene Indenol1,2,3-cd]pyrene 10 ~10 1 8~3 8~3 6 6 5 Phenanthrene Pyrene tested most extensively on mouse skin, since such assays are convenient and inex pensive. Some compounds have been tested by other protocols, including subcu Benzla]anthracene taneous Injection in mice and rats, 1ntrapul 1 2 3 monary injection in rats, and intratracheal 10~4 instillation in hamsters. Tables 1 and 2 IS summarize an IARC Working Group eval senzOlc]f~uOrene nation of carcinogenicity of these PAHs in laboratory animals. 10 ~ 8~3 6 S 4 Cyclopentalcd]pyrene Perylene Figure 1. Structures of some PAHs commonly de- tected in exhaust emissions. of bioassays described below, strongly in- dicate that PAHs can cause cancer in hu- mans. Tu me rigenicity of Polyaro ma tic Hydrocarbons in Laboratory Animals Figure 1 illustrates the structures of the PAHs commonly detected in exhaust emis- sions (International Agency for Research on Cancer 1983~. Methylchrysenes as well as methyl- and dimethylphenanthrenes are also detectable. To evaluate carcinogenic potential, these compounds have been Mouse Skin Bioassays. Two protocols are used. The first, the initiation/promo tion protocol, consists of the application of a single large dose or series of smaller doses of the PAH to the skin, followed by re peated application of the tumor promoter 12-O-tetradecanoylphorbol-l~acetate (TPA). (A tumor promoter is a substance that Benzo~a~pyrene does not itself induce tumors, but when applied after a tumor initiator, for ex ample, a PAH, enhances its activity.) The second, or complete carcinogenicity pro tocol, consists of repeated applications of the PAH to the skin. Frequently, the results of both protocols agree (LaVoie et al. 1979~. Among the unsubstituted PAHs, signif icant activity is observed only in com pounds with four or five aromatic rings. Benzo~aipyrene (BaP) and benzo~b]fluo 2 3 ranthene are the most tumorigenic, fol ~ ~ r~4 lowed by benzo~fluoranthene. Weak ,O~s tumor~gen~c~ty has been observed for benz 8~6 [ajanthracene, benzo~k]fluoranthene, chrys Tripheny~ene ene, cyclopenta~cdipyrene, and indeno [1,2,3-cd~pyrene. Methyl substitution can significantly alter tumorigenicity. As shown in table 2, 5-methylchrysene is a potent tumorigen, with activity similar to that of BaP, and 1,4- and 4,10-dimethyl phenanthrene also are relatively strong tumor initiators. For a detailed review of structure/activity relationships among methylated PAHs, see Hecht et al. (1988~. Respiratory Tract Bioassays. These pro tocols are relevant to the problem of human respiratory exposure to PAHs, and include intratracheal instillation, lung implanta tion, and inhalation. Intratracheal instilla tion of PAHs has been used most exten sively with the Syrian golden hamster

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Stephen S. Hecht 559 Table 1. Representative Tumor-Initiating Activity of PAHs on Mouse Skill and IARC Evaluations of Carcinogenicity of Parent PAHs Commonly lDctectcd in Exhaust Emissions Representative Assays of Tumor-lnitiati~;, Activity on CD-I Mouse Skin Compound Dose (nmole) TEA (%) 7 14 23 10 9() 25 60 T/A Pcfcrcncc IA1lC Evaluation of Carcinogel1icity in Laboratory Animals'' Anthanthrene Anthracene Benz[a janthracene Benzota]fluorene Benzotb]fluorene Benzote]fluorene Benzotb]fluoranthene Benzotyhi]fluoranthene Benzot]fluoranthene Benzo~k]fluoranthene Benzotghi~perylene Benzo~a~pyrene Benzote~pyrene Chrysene Coronene Cyclopentatcdipyrene Fluoranthene Indenot1,2,3-edipyrene Perylene Phenanthrene Pyrene Triphenylene 91() 10,0()() 2,00() 4,63() 4,63() 4,63() 119 NT 119 119 910 119 6,()0() 4,390 1,670 2,5()0 4,950 900 3,970 5,620 4,950 NT ().1 HofEmallll and Wynder (1 t)66) ().1 Scribl,cr (1973) 0.3 Wood ct al. (1977) (). ~LaVoi: ct al. (1 t)X 1 a) ().4 LaVoic ct al. (19X1 a) 0.3 LaVoic ct al. (1981 a) 0.3 LaVoie ct al. (19X9b) 3() 85 14 55 30 37 3 17 5 () ().6 ().1 0.1 4.9 O.1 ().6 ().5 o ().3 ().1 () O.1 LaVoic ct al. (19X2b) LaVoic ct al. (19X9b) Hoffman and Wyndcr (1966) LaVoie et al. (19X9b) Bucning et al. (19X()) Hccht et al. (1974) Van Dunrcn ct al. (196X) Wood et al. (198()) HofEmanll ct al. (1 t)79) HofFmann and Wynder (1966) El-Bayoumy ct al. (19X9) LaVoic~ et al. (19X1 b) El-Bayoumy ct al. (19X')) Limited None Sufficient adequatc Illadequatc Inadcq~atc Sufficient Inadequate Suff~cicl~t Suff~cicnt ll~adeq~atc Suff~cicllt Inadeq~atc Limited Inadcq~ate Limited N Ol1C' Sufficient Inadcquatc Inadcq~atc North Inadequate ~ From International Agency for Research on Cancer (1983). b It was not active as a complete carcinogen On mouse skin (Wyndcr and Hoffman 1959). ' A study has shown that fluoranthenc is tumorigenic in newborn mice (Busby et al. 1~)84). NOTE: NT = not tested as a tumor initiator; T/A = tumors per animal; TEA = tumor-beari~,g animals. because it has no spontaneous lung tumors and is resistant to pulmonary infection and inflammation. Tumors are induced by in- stillation of the PAH and a carrier, for example, ferric oxide, (Fe2O3) or in a sus- pension in saline (Stinson and Saff~otti 1983~. Squamous cell carcinoma of the trachea and bronchi induced in a high per- centage of Syrian golden hamsters given intratracheal instillations of BaP closely re- semble human tumors. Although the carcinogenic effects of BaP in the hamster respiratory tract have been studied, investigations of other PAHs have been few. Sellakumar and Shubik (1974) found that when either benzotb]fluoran- thene, dibenz~a,hianthracene, benz~ajan- thracene, or pyrene was instilled with Fe2O3 in the hamster trachea, the incidence of respiratory tumors was insignificant. However, in this model system diben- zota,i~pyrene and dibenzo~c,gicarbazole were highly tumorigenic. In experiments with other species, Hirao and coworkers (1980) found that BaP in saline caused lung cancer in rabbits, and Yoshimoto and co- workers (1977) observed that BaP with a carrier induced tumors in mice and rats. Stanton and coworkers (1972) implanted PAHs dissolved in a mixture of beeswax and trioctanoin in rat lungs and observed the development of epidermoid lung carci- noma. Deutsch-Wenzel and coworkers (1983) tested a variety of PAHs using this protocol, and found that BaP was the most tumorigenic PAH of those commonly detected in exhaust emissions, while an- thanthrene, benzo~b]fluoranthene, and in- deno~l,2,3-cdipyrene were moderately tu- morigenic. However, the tumorigenicity

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560 Effects of Polynuclear Aromatic Hydrocarbons and Nitroaromatics Table 2. Representative Tumor-Initiating Activity on Mouse Skin and IARC Evaluations of Carcinogenicity of Methylated Chrysencs and Phc~anthrc~cs Rcpresentativc Assays of Tun~or-Initiating Activity on Mouse Skill Dose Parent System Isomer (nmole) Methyl TEA (%) T/A IAllC Evaluations of Carc~,ogen~c~ty ~, Laboratory Animals" Chryseneb Phenanthrene' 2 3 4 6 2 3 4 9 1,4 1,9 2,7 3,6 4,5 4,9 4,10 4, 1 3() 4,13() 4,13() 1, 94() 41() 4, 1 3() 4,13() 1, 94() 41() 1()() 33 4,130 5,910 5,91() 5,910 5,910 5,91() 4,85() 1 ,460 4'85() 4,85() 4,85() 4,850 4,85() 4,850 1,460 3() 49 7() 2() 15 35 ~5 10() 1 O() 9() 8() 35 () () i) () () 10() 8() () 5 () 5 1() 55 35 .3 ().7 1.3 ().4 ().5 4.S S.( 5.5 c ~ J. _ 3.9 ().6 () () () () () 5.3 3.9 () ().1 () ().1 ().1 1.5 1.6 Illadeqelatc Limitcd Limitcd Limitcd SufElcicl~t Linlited Inadcquatc NC NC NC NC NC NC NC NC NC NC NC NC NC ~ From International Agency for Research Ol1 Cancer (19~33). b Hecht et al. (1974). c LaVoie et al. (1981b, 1982a). NOTE: NC = not considered; T/A = tumors per animal; TBA = tumor-bearing animals. Of anthanthrene was higher than expected squamous cell carcinoma of the lung on the basis of mouse skin studies. (Laskin et al. 1970~. In another experiment, Kendrick and coworkers (1974) found A' ' ' '~' ' that instillation of PAHs into subcutaneous tracheal transplants in rats results in hyper plasia, dysplasia, squamous metaplasia, and squamous cell carcinoma. Benzotaipyrene, but not benzo~eipyrene (BeP), was carcino genic in that system. However, Topping and coworkers (1981) found that BeP was cocarcinogenic for the connective tissue, but not the tracheal epithelium. Because of their expense, inhalation ex- periments with PAHs have been limited. In one experiment, 2 of 21 rats housed in fresh air and 5 of 21 rats housed in an atmosphere containing sulfur dioxide (SO2) developed 1 hyssen and coworkers (~) observed exposure-related neoplasms in the nasal cavity, larynx, pharynx, esophagus, and forestomach of Syrian golden hamsters ex- posed to BaP. Dose/Response Relationships. Clear dose/ response relationships for BaP-induced tu- mor formation have been demonstrated by using the Syrian golden hamster intratra- cheal instillation model and the mouse skin initiation/promotion protocol. The yield of respiratory tract tumors, tumor latency, and tumor multiplicity related to dose in hamsters treated with BaP and Fe2O3 (Saf

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Stephen S. Hecht 561 fiotti et al. 1972a,b), or BaP in buffer and physiological saline (Ketkar et al. 1979), depended on the number of administra- tions, the dosage per administration, and the fractionation of doses. Similar effects have been observed on mouse skin (Saffiotti and Shubik 1956~. In the mouse skin initiation/promotion proto- col, a linear dose/response relationship for papilloma formation in Sencar mice ranged between 100 and 600 nmole/mouse; at higher doses the tumor response leveled off (Ashurst et al. 1983~. The effects of differing initiating doses of 7,12-dimethylbenz~a]- anthracene showed that linear extrapolation from high doses may lead to underesti- mation of low-dose tumor risks (Stenback et al. 1981~. Effects of Mouse Strain. Aryl hydrocar- bon (Ah)-responsive mice (for example, C57BL/6N) are more susceptible to tumor induction from subcutaneous injection of BaP, 3-methylcholanthrene, or dibenz- [a,hianthracene than are Ah-nonresponsive mice (for example, DBA/2N). These dif- ferences have been attributed to the dif- fering abilities of these mice to metabolize the PAHs to their ultimate carcinogenic forms. Inducibility of the cytochrome P-450 enzymes that metabolize PAHs ap- pears to be related to PAH tumorigenicity (Nebert 1981~. The Ah gene codes for a cytosolic receptor which can bind the in- ducer, such as 3-methylcholanthrene. The inducer/receptor complex is translocated into the nucleus and in some way initiates increased P-450 synthesis. Modifiers of Polyaromatic Hydrocarbon Carcinogenesis The influence of modifiers is perhaps one of the most important but least well under- stood areas of cancer induction by PAHs. Modifiers can be broadly classified as either promoters, cocarcinogens, or inhibitors of carcinogenesis. Promoters are generally noncarcinogenic substances which, when applied subsequently to PAHs, will cause tumors. In the case of the most widely studied promoter, TPA, tumors can be induced on mouse skin even if the TPA is applied one year after administration of 7,12-dimethylbenz~ajanthracene (Van Du- uren et al. 1975~. This observation supports the concept that initiation, even by a single dose of a PAH, is essentially irreversible, consistent with a change in DNA. Exposure to a single dose of a PAH can initiate cells but may not cause tumors, but exposure of initiated cells to multiple doses of a pro- moter can lead to tumor development. Thus, promotion may be important in de- termining whether or not environmental exposure to PAHs results in tumor devel- opment. TPA is an exceptionally effective tumor promoter for experimental studies, but it does not occur in significant quanti . ties in the environment. The most important known environ- mental tumor promoters are tobacco smoke and diet. The tumor-promoting ac- tivity of tobacco smoke and its condensate has been clearly demonstrated in studies using PAHs as initiators in either the mouse skin or the intratracheal instillation models (Hoffmann et al. 1978~. .. . .. . Epidemiologic stud~es ~nd~cate that cessation of cigarette smoking leads to a lower risk for lung cancer, consistent with reversibility of pro- motion (Wynder and Hoffmann 1979~. Ex- tensive studies with the 7,12-dimethylbenz- [ajanthracene-induced Sprague-Dawley rat breast tumor model have demonstrated that a high-fat diet can promote breast tumor development. This is also in agree- ment with some epidemiologic studies (National Research Council, Committee on Diet, Nutrition, and Cancer 1982~. Cocarcinogens are defined as substances that enhance tumorigenicity when admin- istered simultaneously with a carcinogen. Important environmental cocarcinogens in- clude tobacco smoke, polyphenols, and PAHs. The cocarcinogenicity of tobacco smoke is due to its neutral polar and weakly acidic fractions (Hoffmann et al. 1978~. Investigations of the compounds responsi- ble for this activity have led to the identi- fication of a number of cocarcinogens that are also environmental or dietary constitu- ents. Important among these is catechol, which is strongly cocarcinogenic with BaP on mouse skin (Van Duuren and Gold

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562 Effects of Polynuclear Aromatic Hydrocarbons and Nitroaromatics Schmidt 1976; Hecht et al. 1981~. Com- pounds related to catechol occur widely in the diet, and conjugates of catechol are excreted in normal human urine (Carmella et al. 1982~. The cocarcinogenic activities of PAHs are particularly important because PAHs always occur as mixtures in the environ- ment. Pyrene, benzo~eipyrene, and flue- ranthene are all essentially nontumorigenic, but they all enhance the tumorigenicity of BaP (Van Duuren and Goldschmidt 1976; Hoffmann et al. 1978~. Other cocarcino- gens include benzo~ghi~perylene, decane, undecane, 4,4'-dichlorostilbene, 1-methyl- indole, and 9-methylcarbazole (Van Duu- ren and Goldschmidt 1976; Hoffmann et al. 1978~. Such interactions have to be consid- ered when assessing human risk for cancer development upon exposure to PAHs. A broad spectrum of compounds, many of them dietary, are capable of inhibiting PAH tumorigenesis. These include a variety of phenols, phenolic antioxidants such as buty- lated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), naturally occurring dietary indoles and isothiocyanates, various flavones, selenium salts, protease inhibitors, retinoids, and carotenes (Slaga and DiGio- vanni 1984; Wattenberg 1985~. Inhibition has been observed in various model systems including mouse skin, mouse forestomach, mouse lung, and rat breast. A number of different protocols have been used, and the timing of admin- istration of inhibitor versus administration of PAH can be critical in determining whether inhibition of tumorigenesis is ob- served. The identification of naturally oc- curring and synthetic inhibitors of carcino- genesis offers promise for prevention of PAH carcinogenesis. However, the influ- ences of chemopreventive agents on PAH carcinogenesis are complex. For example, BHA is carcinogenic under certain condi- tions, and in some experimental protocols, BHA as well as BHT can act as tumor promoters (Ito et al. 1985~. Carcinogenicity of Nitro Polyaromatic Hydrocarbons Whereas the carcinogenic activities of PAHs have been evaluated extensively, re search on nitro-PAHs is relatively limited. The observation that nitro-PAHs appear to account for a major portion of the direct- acting mutagenicity of diesel exhaust par- ticulates has caused interest in their poten- tial carcinogenic effects. No epidemiologic studies are available on the potential carci- nop;enicity of the nitro-PAHs that have been identified in diesel exhaust; these in- clude 1-nitropyrene, dinitropyrenes, hy- droxynitropyrenes, methyl nitropyrenes, 3-nitrofluoranthene, 2-nitrofluorene, 9-ni- troanthracene, and 6-nitrobenzo~a~pyrene (Schuetzle 1983~. With respect to occupational exposure to diesel exhaust, "excess risk of cancer of the lung, or of any other site, has not been convincingly demonstrated" (National Re- search Council, Health Effects Panel of the Diesel Impacts Study Committee 1981~. However, the Committee found fault with the studies that have been performed and called for additional carefully controlled studies of populations occupationally ex- posed to diesel engine exhaust. Indeed, two recent studies of motor ex- haust-related occupations and bladder can- cer, based on the National Bladder Cancer Study, indicated that males usually em- ployed as truck drivers or deliverymen had a statistically significant 50 percent increase in risk of bladder cancer (Silverman et al. 1983, 1986~. The authors speculated that nitro-PAHs might be involved as causative agents. PAHs as well as nitro-PAHs are present in motor exhaust of various types. Experimental studies of nitro-PAH tu- morigenicity are summarized in table 3. 1-Nitropyrene, one of the predominant ni- tro-PAHs in diesel exhaust, induces tumors at the site of subcutaneous application as well as in the breast in newborn CD rats. It also is moderately tumorigenic in the A/J mouse lung adenoma assay. However, it appears to be inactive in adult CD rats and is weakly active or inactive in a number of other experimental models. In contrast to 1-nitropyrene, the dini- tropyrenes are highly tumorigenic. They have induced high incidences of subcutane- ous tumors in rats (Ohgaki et al. 1984, 1985) and in mice (Tokiwa et al. 1985), and 1,6-dinitropyrene has caused lung carcino- mas in 9~100 percent of Syrian golden

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Stephen S. Hecht Table 3. Nitro-PAH Tumorigenicity Assays Compound Test System 1-Nitropyrene 2-Nitropyrene ~Nitropyrene 3-Nitrofluoranthene 6-Nitroehrysene Newborn CD rat A/J mouse Mouse skin F344/I)u Crj rat Newborn mouse BALB/c mouse CD rat CD rat CD rat Newborn mouse A/J mouse Mouse skin Newborn mouse 6-Nitrobenzo[a~pyrene Mouse skin Newborns mouse Mouse skirt Newborns mouse F344/l)u Crj rat Newborn mouse F344/l)u Crj rat Syrian golden hamster 3-Nitroperylene 7-Nitrobenz [a] anthraeene 1, 3-Dinitropyrene 1, 6-Dinitropyrene 1, 8-Dinitropyrene 2-Nitrofluorene 5-Nitroaeenaphthene BALB/c mouse Newborn mouse F344/I)u Crj rat Holtzma~, rat Wistar rat Syrians golden hamster F344 rat B6C3F, mouse hamsters treated by intratracheal instilla- tion (Takayama et al. 1985~. In the new- born mouse, 6-nitrochrysene was excep- tionally tumorigenic (Busby et al. 1984; Wislocki et al. 1985) whereas a number of other nitro-PAHs were weakly tumori . . . gen1c or inactive. Taken together, these studies show that nitro-PAHs are carcinogenic in laboratory animals. Their activities depend greatly on structure and on the model system used. Further studies are necessary to define more clearly the structural requirements for tum- origenicity of nitro-PAHs as well as the most appropriate model systems for their bioassay. 563 Result Subcutaneous and mammary tumors Lung adenonlas . . ~ r i .llslgulrlcallt activity Ir 1lslgn~rlcallt activity Liver tumors r Inslglllrlcallt activity r 1lslgnlrlcallt activity lnsigllificallt activity Mammary tumors Liver and lung tumors Lung adeuomas Skin tumors Lung and liver tumors Insignificant activity Liver tumors (weak) Skill tumors Liver tumors (weak) Subcutallcous tumors . Llvcr tumors Subcutallcous fore Lung tumors alla Icukemia Subcutanco~ls torpors Liver tumors Subcutaneous tulllors Forcstonlach carcinoma Ear duct, mammary, small intcstillc tumors Cholallgiomas Ear duct, mammary, lung tumors Liver tumors Itcfcrcnce Hirose et al. (1~)~) El-13ayo~lmy et al. (1')~34a) El-Hayo~ln~y et al. (19~3~)) Nesl~ow et al. (I')X4) Ohgaki ct al. (1~385) Wislocki et al. (It)Xo) Tokiwa et al. (1984) Inlaida et al. ( I two) In~aida et al. (19X5) Imaida et al. (13X5) Wislocki et al. (I')X5) El-Bayoumy et al. unpublished observations El-Bayounly et al. (19~3~)) Busby ct al. (19~34) Wislocki et al. (19~35) El-Bayo~ln~y et al. (I'M) Wislocki et al. (1)X5) El-Bayoun~y et al. (Itchy) Wislocki et al. (I')X5) Ohgaki ct al. (19X5) Wislocki et al. (I'JX5) Ohgaki ct al. (1'JX5) Takayama et al. (13X5) Tokiwa et al. (1'3X4) Wislocki et al. (lC)X5) Ohgaki Ct al. (19X4) Miller Ct al. (1')55) TakClll~lra Ct al. (1'374) Takenlura et al. (1974) National Callcer Institute (1 t)78) Metabolic Activation and Detoxification of Polyaromatic Hydrocarbons and Nitro Polyaromatic Hydrocarbons Absorption and Distribution upon Inhalation Clearance of BaP from the respiratory tract is slower when it is associated with particles than when it is in a pure form (Stinson and Saff~otti 1983~. The major route of BaP excretion is in the feces (Heidelberger and Weiss 1951~. The results of a comparative inhalation study by Sun and coworkers

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564 Elects of Polynuclear Aromatic Hydrocarbons and Nitroaromatics (1982) suggests that most of a BaP aerosol was cleared by absorption into blood fol- lowed by biliary and fecal excretion, whereas in animals exposed to particle- associated BaP, a substantial amount of the lung clearance occurred by mucociliary clearance and ingestion. These studies dem- onstrate the importance of particles to the in vivo fate of inhaled BaP, and they are clearly relevant to evaluating health risks of environmental exposure to PAHs. Using a similar approach, Sun and co- workers (1983) studied the fate of 1-ni- tropyrene. In contrast to the results ob- tained with BaP, no apparent differences in lung retention were observed between pure and particle-associated material. However, the rats exposed to 1-nitropyrene coated on particles excreted the majority of the dose in the feces whereas those exposed to the 1-nitropyrene aerosol excreted most of the dose in the urine. The excretion in the feces is consistent with mucociliary clearance and subsequent ingestion, since 1-nitropyrene and its metabolites administered by gavage are excreted primarily in the feces (El- Bayoumy and Hecht 1984a). Benzota~pyrene It is now generally accepted that modifica- tion of DNA is a key step in the initiation of the carcinogenic process. PAHs, like many other carcinogens, do not themselves react covalently with DNA, but require metabolic activation to reactive species. Thus, they are considered procarcinogens. Metabolites that are on the pathway to reaction with DNA are called proximate carcinogens and those that react with DNA are termed ultimate carcinogens. The latter are electrophiles and are formed as interme- diates in the normal response of the orga- nism to foreign compounds, which is gen- erally to convert them to more polar forms that are readily excreted (see LaVoie and Hecht 1981~. Major metabolic transformations of BaP are summarized in figure 2. The metabo- lism of BaP has been extensively investi- gated in various systems, and reviews of its metabolic activation and detoxification are available (Gelboin 1980; LaVoie and Hecht 1981; Conney 1982; International Agency for Research on Cancer 1983~. The path- way BaP > BaP-7,8-epoxide ~ BaP-7,8- diol > BaP-7,8-diol-9,10-epoxide is gener- ally considered to be the major activation pathway in BaP-induced tumorigenesis. All other metabolic pathways illustrated in figure 2 are generally thought to be detox- Cation routes. These generalizations are useful for con- sidering the effects of BaP in various tissues and species, but it is becoming increasingly clear that they are oversimplifications. There are probably aspects of BaP metab- olism other than dial epoxide formation that contribute to its tumorigenic activity. DNA adducts are also formed from metab- olites other than the dial epoxides, such as the 4,5-epoxide of 9-hydroxy-BaP, and a number of unidentified BaP/DNA adducts are produced in cultured rat mammary cells in vitro and following direct application of BaP to rat mammary glands in vivo (Phil- lips et al. 1985~. In addition, major uniden- tified material that elutes rapidly from chromatographic columns and is indicative of unknown DNA adducts has been ob- served in virtually all studies of BaP/DNA adduct formation. Factors that Influence Metabolism. The metabolism of BaP is extraordinarily com- plex, and alterations in one of the many pathways could affect BaP-induced tumor . ~ . . . . . Genesis. l ile lnltla OX1C .atlon to arene oxides is controlled by the cytochrome P-450 system. The existence of cytochrome P-450 in multiple forms that differ in their capacity to catalyze oxidation of BaP at different positions is well established (Coon 1981; Conney 1982; Gelboin 1983~. The distribution of these forms is depen- dent on the tissue of interest, the strain and species, and to a great extent on the effects of numerous inducers. Inducibility can be controlled by genetic or environ- mental factors. Thus it is clear that the production of particular arene oxides and phenolic metabolites of BaP in a given system will depend on a great many con- tributing factors. The fate of the arene oxide intermediates is controlled to a large extent by the en

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Stephen S. Hecht OH HO' Oh 1 1'~ HO i" tetraolS "~( HO'''(: glutathione OH OH conjugates anti-7,8-diol- syn-7,8-diol 9,10-epoxide 9, 10-epoxide 1 Ah/ 565 e ( 8 ) _ ( 2 2 8 e ( ) 6 ( ) OH ) . ~O ~OH 1 ~ 1 1~ - glutathione conjugates )~: OH \* glucuronides I DNA dg NH H O,,: of OH 1 ,6-quinone 3,6-quinone 6, 1 2-quinone Figure 2. Metabolism of benzota]pyrene. (Adapted from LaVoie and Hecht 1981.) sulfates glucuronides zyme epoxide hydrolase. Its tissue concen- BHA, taken together with related studies, "rations depend on species, inducer pre treatment, and on the presence of inhibitors such as 1, 1,1-trichloropropene oxide (Oesch 1980~. Conjugation of phenolic and dihydrodiol metabolites catalyzed by gluc uronyl transferases, and detoxification of epoxides and dihydrodiol epoxides by mul tiple forms of glutathione-S-transferases are, like the cytochrome P-450 and epoxide hydrolase activities, dependent on multiple factors. The effects on metabolic activation and detoxification pathways of modifiers of BaP tumorigenesis are complex, but they do provide insights on potential mecha nisms of cocarcinogenesis or inhibition. Studies of the cocarcinogens catechol, fluo ranthene, pyrene, benzo~e~pyrene, and are for the most part consistent with the concept that formation of 7,8-diol-9,10- epoxides is an important activation path- way in BaP-induced tumorigenesis. Metabolism in Human Tissues. The me- tabolism of BaP has been extensively stud- ied in various subcellular, cellular, and or- gan culture systems from human tissues (International Agency for Research on Cancer 1983~. These studies have shown that the basic pattern of BaP metabolism is qualitatively similar in human tissues and in laboratory animal tissues, but major quan- titative differences can occur. The forma- tion of DNA adducts via the 7,8-diol-9,10- epoxide pathway is regularly observed in human tissues.

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568 Effects of Polynuclear Aromatic Hydrocarbons and Nitroaromatics vitro is 1,2-dihydro-1,2-dihydroxy-6-ni- trochrysene. Formation of the correspond- ing 7,8-dihydrodiol is not observed, indi- cating that the 6-nitro group inhibits oxidation at the adjacent position (El-Ba- youmy and Hecht 1984b). Inhibition of dihydrodiol formation has similarly been observed in studies of 6-nitrobenzo~aipy- rene, although an 8,9-dihydrodiol has been detected as a metabolite of 7-nitrobenz- [aJanthracene (Fu et al. 1982; Fu and Yang 1983~. Nitro-reduction alone does not gen- erally appear to be a major metabolic path- way for either 6-nitrochrysene or 6-nitro- benzota~pyrene. These results contrast to those observed with 1-nitropyrene (El-Ba- youmy and Hecht 1983, 1984b), and with the dinitropyrenes that appear to be acti- vated at least partially by nitro-reduction followed by O-acetylation (Beland et al. 1985~. Our present knowledge of the mecha- nisms of nitro-PAH metabolic activation is inadequate. The general aspects of activa- tion and detoxification are not clearly un- derstood, even for 1-nitropyrene which is the most extensively studied nitro-PAH. Further research is needed in this area. Given the advanced state of technology and experience with other carcinogens, these studies should proceed rapidly. Research Problems Relating to the Potential Carcinogenic Effects of Polyaromatic Hydrocarbons and Nitro- Polyaromatic Hydrocarbons in Humans Individual Dosimetry The wide interindividual variation in PAH metabolism observed in studies on human tissue samples or cells is a result of the extraordinary complexity of the metabolic pathways and the many factors, genetic as well as environmental, that control the levels of the various enzyme activities in- volved. DNA adduct formation and pro- tein adduct formation are significant end points of these processes because they re- flect the generation of electrophilic inter mediates in PAH metabolism, and the persistence of PAM/DNA adducts in repli- cating cells is probably one important de . . . . . - termlnant tor 1nltlatlon ot carclnogenesls. Although extensive studies of DNA adduct and protein adduct formation and persis- tence after single administrations of various doses of PAHs have been performed, little if any information is available concerning these end points under conditions of chronic PAH treatment (Stowers and An- derson 1985~. It will be essential to perform such stud- ies in animals treated with doses of PAHs known to result in differing tumor inci- dences and to determine the relationship, if any,. between DNA adduct and protein adduct levels and tumor development. These chronic administration experiments are important because they are more closely related to conditions of human exposure than are the acute administration protocols. The availability of sensitive assays for DNA adducts and protein adducts, without using labeled PAHs, will make these chronic studies feasible. The results of these investigations will be important in forming a baseline for interpretation of analogous data obtained from measurements of DNA adducts and protein adducts in humans. Recommendation 1. The structures of the major DNA adducts and protein ad- ducts formed from representative PAHs and nitro-PAHs should be determined in laboratory animals. For dosimetry studies to be undertaken, the structures of appropriate DNA adducts and protein adducts must be known. These studies should initially focus on repre- sentative PAHs and nitro-PAHs: BaP, benzo~blfluoranthene, fluoranthene, 1-ni- tropyrene, 1,6-dinitropyrene, and 6-nitro- chrysene are recommended based on current knowledge of their environmental occurrence and carcinogenicity in labora- tory animals. This list could change as further data become available. Among these six compounds, the structures of ma- jor DNA adducts formed in vivo are known only for BaP. Blood protein ad- ducts are formed via BaP-7,8-diol-9,10

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Stephen S. Hecht 569 epoxide (Santella et al. 1986; Shugart 1986~. Further studies are required to characterize the DNA adducts and blood protein ad- ducts of the other five compounds. ~ Recommendation 2. Methods should be developed for determining individual uptake and metabolic activation of repre- sentative PAHs and nitro-PAHs. Although our understanding of the proc- esses involved in tumor development is incomplete, there is no question that the metabolic generation of specific reactive PAH or nitro-PAH metabolites is one im- portant feature of the process. These metabolites bind to DNA and protein. The measurement of DNA adducts provides a biologically significant end point which bypasses the many variables involved in individual exposure to, uptake of, and me- tabolism of PAHs. A drawback of DNA adducts as dosimeters is that they are re- moved from various cells at different rates depending on repair mechanisms and on normal cellular turnover. In contrast, adducts with proteins such as hemoglobin have a more predictable and longer lifetime. The lifetime of hemoglobin in humans is four months and thus PAH/ hemoglobin adducts could provide a mea- sure of chronic exposure (Calleman et al. 1978; Garner 1985~. Although such adducts may not be biologically significant per se, they do provide a cumulative measure of individual exposure to PAHs and activation of PAHs to electrophiles. Thus, methods should be developed to measure DNA ad- ducts and protein adducts of the six com- pounds listed above. ~ ~ ~ 1 '1 1 1 ~ Several methods are available tor sens~- tive detection of PAM/DNA adducts. Im- munoassay techniques have been developed and applied to the analyses of BaP/DNA adducts in human tissue samples and in peripheral blood lymphocytes (Harris et al. 1985; Santella et al. 1985~. These studies have indicated the presence of these adducts in lung cancer patients, coke oven workers, roofers, and foundry workers, but not in noncancer patients. Other methods for measuring DNA ad- ducts include synchronous fluorescence spectrophotometry (Harris et al. 1985) and fluorescence-line-narrowed spectra (Heisig et al. 1984~. An alternative method that shows great promise for a variety of PAM/DNA adducts is the 32P-postlabeling technique (Randerath et al. 1985~. Al- though some of these techniques are still in the developmental stage and require refine- ment before being applied routinely to a variety of representative PAHs and nitro- PAHs, they are generally promising. Methods for assessing formation of PAH/protein adducts are being developed (Santella et al. 1986; Shugart 1986~. On the basis of results obtained with taminobi- phenyl (Green et al. 1984), the measure- ment of nitro-PAH/hemoglobin adducts is likely to be feasible. The further develop- ment of these methods should certainly be a focus of future research. In addition to the measurement of PAM/DNA adducts and PAH/protein ad- ducts, there are a number of other methods for assessing carcinogen activation which may be appropriate as an adjunct to the approaches described above. These include the measurement of urinary or fecal metab- olites (Becher and Bjorseth 1983), the use of monoclonal antibodies to type human tissues for individual cytochrome P-450s (Gelboin 1983), the detection of antibodies to PAM/DNA adducts (Harris et al. 1985), and the use of blood cells to metabolically activate BaP in vitro (Gelboin 1983~. Recommendation 3. Under condi- tions of chronic administration of PAHs or nitro-PAHs to laboratory animals, the re- lationship between DNA adduct or protein adduct formation and tumor development should be determined. In order to assess the relationship of PAH or nitro-PAH adducts with DNA or pro- tein to the risk for cancer development, it will be necessary to perform chronic stud- ies in laboratory animals. The most desir- able route of administration for such stud- ies would be inhalation, but practical considerations prohibit extensive use of this model. As a compromise, concurrent use of the Syrian golden hamster intratracheal in- stillation model is recommended. Groups of

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570 Effects of Polynuclear Aromatic Hydrocarbons and Nitroaromatics hamsters should be treated chronically with a range of doses of the six representative compounds listed above with Recommen- dation 1, as well as mixtures of these com- pounds. DNA adducts should be measured in respiratory tract tissue, in cheek pouch or other nonrespiratory tissues, and in periph- eral blood lymphocytes. Blood protein ad- ducts should also be quantified. Parallel inhalation studies with selected compounds should be carried out to validate the results obtained by intratracheal instillation. The results should be evaluated in light of the tumor incidence in the various groups. These data will provide the basis for inter- preting data that eventually will be ob- tained from human populations potentially exposed to PAHs and nitro-PAHs. These measurements in humans, taken together with the data from laboratory animals, should allow determination of in- dividual PAH dose and may provide mark- ers for assessing individual risk for cancer development. Such markers would be in- valuable in epidemiologic studies. The lack of data relating levels of DNA adducts and protein adducts to cancer risk in laboratory animals, under conditions of chronic PAH or nitro-PAH treatment, is probably the most significant gap in our present ability to assess risk in humans, given the fact that methods for making these measurements are becoming available. Recommendation 4. Pilot studies should be undertaken on individuals poten- tially exposed to PAHs or nitro-PAHs in order to determine the feasibility of moni- toring DNA adducts and protein adducts in humans. Application to humans is the goal of developing methods for measuring individ- ual dosimetry of PAHs and nitro-PAHs. Therefore, it is essential that the feasibility of these methods be assessed. As mentioned above, studies of this type are already ongo- ing for some PAM/DNA adducts and aro- matic amine/protein adducts. When assays have been shown in animal studies to have the requisite sensitivity, they should be ap- plied to groups of 2~50 individuals who are supposed to have been exposed to PAHs or nitro-PAHs, and to corresponding numbers of controls. The results should be carefully cross-checked with other methods, to ensure their validity. For example, PAM/DNA ad- ducts could be measured by immunoassay and by 32P-postlabeling. If both methods are valid, the results should agree. Multilabora- tory collaborative studies should be under- taken for cross checking of results. Parallel assays should also be made to aid in identifi- cation of the exposure source, for example, . . . . . . urinary or sa Vary nicotine or cot~mne as monitors for tobacco exposure. Bioassays in Laboratory Animals Although extensive evaluations of PAH tumorigenicity have been performed using the mouse skin bioassay system, and struc- ture/activity relationships are fairly well understood, limited data are available on induction of respiratory tumors by PAHs. Assays by intratracheal instillation have been performed with only a few PAHs that are found in mobile source emissions (Sel- lakumar and Shubik 1974~. Several other PAHs have been tested by lung implanta- tion with results not entirely in agreement with expectations based on mouse skin studies Stanton et al. 1972; Deutsch- Wenzel et al. 1983~. Inhalation experiments are practically nonexistent. It is possible that the extensive reliance on mouse skin assays could give a distorted perspective of the potential importance of particular PAHs in respiratory carcinogenesis. Recommendation 5. Inhalation bioas- says and intratracheal instillation bioassays of selected PAHs should be performed. Although inhalation experiments on eAiis are necessary, practical consider- ations demand that they be somewhat lim- ited. Of the PAHs present in mobile source emissions, BaP and benzo~b]fluoranthene are the most tumorigenic on mouse skin. They are also tumorigenic in the rat lung implantation system. It would be impor- tant to determine the comparative carcino- genicity of these two hydrocarbons by in- halation studies in rats or Syrian golden

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Stephen S. Hecht 571 hamsters. Fluoranthene and pyrene are the two most prevalent cocarcinogenic hydro- carbons in mobile exhaust emissions, ac- cording to mouse skin assays. Their cocar- cinogenicity with BaP in inhalation assays should be tested. Intratracheal instillation bioassays have been performed on only a limited num- ber of PAHs present in mobile source emissions. These studies should be ex- tended at least to some of the more preva- lent or carcinogenic components such as anthanthrene, benzo~ghi]fluoranthene, benzo ~ ~ fluoranthene, benzo [ah i] perylene, 5-methylchrysene, cyclopentatcd~pyrene, fluoranthene, indeno[1,2,3-cdipyrene, and pyrene. The intratracheal instillation model would probably also be the most suitable for testing mixtures of PAHs as they occur . .. . . In mo ~1. .e source emissions. Bioassays of nitro-PAHs have been lim- ited, and structure/activity relationships are not yet predictable. Extensive systematic studies on nitro-PAH carcinogenicity in several model systems are required. In ad- dition, it is possible that carcinogenic activ- ities of PAH mixtures could differ signifi- cantly from expectations based solely on activities of the components of the mix- tures. Many examples of cocarcinogenic or inhibitory activities of one PAH upon an- other are known. It would be important to assess the respiratory carcinogenicity of PAH/nitro-PAH mixtures, using relative concentrations similar to those observed in mobile source emissions. Recommendation 6. The tumorige- nicity of environmental nitro-PAHs should be evaluated. percents to complement those already in progress with 1-nitropyrene. Limited data are available on the effects of modifiers of PAH carcinogenesis in res- piratory tract carcinogenesis models. It would be important to determine the ef- fects of such cocarcinogens as catechol, or of dietary inhibitors, on PAH carcinogen- esis in the respiratory tract. In addition, only limited data are available on the po- tential cocarcinogenicity and tumor-pro- moting activities of compounds to which humans are extensively exposed. ~ Recommendation 7. Bioassays should be performed to discover environmental modifiers of PAH and nitro-PAH carcino . . genlclty. To study environmental modifiers of PAH and nitro-PAH carcinogenicity, rela- tively inexpensive assay systems such as mouse skin, mouse forestomach, A/} mouse lung, or the newborn mouse should be used, with BaP, benzo~b]fluoranthene, fluoranthene, 1-nitropyrene, 1, 6-dinitro- pyrene, and 6-nitrochrysene as repre- sentative carcinogens. This work should focus on exploring structural analogues of known cocarcinogens, such as catechol, or analogues of known chemopreventive agents such as p-methoxyphenol, indole-3- carbinol, benzyl isothiocyanate, or sodium selenite and related organoselenium com- pounds. Emphasis should be on those com- pounds to which humans are exposed in relatively high concentrations. The most appropriate system for bioas- says of nitro-PAHs is probably intratra- cheal instillation, at least for screening the activities of the numerous nitro-PAHs that are present in diesel exhaust. Studies with 1,6-dinitropyrene have shown that it does induce lung tumors when applied by intra- tracheal instillation in hamsters (Takayama et al. 1985~. The nitro-PAH showing the ~reatest activity in other model systems, such as 1,6-dinitropyrene and 6-nitrochry- sene, should be chosen for inhalation ex Mechanisms of Polyaromatic Hydrocarbon and Nitro-Polyaromatic Hydrocarbon Ca rcin ogen es is Although a great deal is known about the metabolic activation of BaP as a repre- sentative PAH, there are many unanswered questions about the process by which ex- posure to BaP results in tumor induction. It is well established that BaP must undergo enzymatic oxidation to an electrophile that can react with DNA, and that DNA is the key macromolecular target for initiating the tumorigenic process. It is also known that a BaP-7,8-diol-9,10-epoxide is one of

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572 Effects of Polynuclear Aromatic Hydrocarbons and Nitroaromatics the major DNA binding metabolites. How- ever, multiple DNA adducts are formed from BaP and it is not known which of these, or which combination of adducts, is most important in tumor initiation. Other aspects of cellular damage by BaP that may enhance the effects of DNA damage, such as free-radical generation, and their rela- tionship to tumor initiation, remain largely unexplored at present. The steps by which modified DNA can cause transformation of cells resulting even- tually in frank appearance of tumors remain poorly understood, although it is known that BaP-7,8-diol-9,10-epoxide can activate the c-Ha-ras-1 oncogene (Marshall et al. 1984~. The role of oncogenes in carcinogenesis is an exciting area of investigation which may provide major leads in understanding the process of tumor development. The effects of BaP metabolites, or of endogenous factors, as cocarcinogens or tumor promoters in BaP carcinogenesis need to be explored. Whatever gaps exist in our knowledge about BaP carcinogenesis are even greater for most other PAHs. With the possible exception of 7,12-dimethylbenz~ajanthra- cene (DMBA), no PAH has been so exten- sively investigated as BaP. Important dif- ferences are found in the mechanisms of activation of BaP and DMBA (ripple et al. 1984~. Therefore, further research is needed on the mechanisms of tumor induction by other major carcinogenic PAHs found in mobile source emissions, in particular the benzofluoranthenes. Recommendation 8. The mechanisms by which carcinogenic PAHs and nitro- PAHs undergo metabolic activation and detoxification should be determined. Rational evaluation of the potential car- cinogenic effects of PAHs and nitro-PAHs in humans requires a basic understanding of the major pathways of metabolic activation and detoxification of these compounds in laboratory animals. The most important tumorigenic compounds that require fur- ther study for elucidation of these basic pathways include the six listed with Rec- ommendation 1 as well as benzot]fluoran- thene, indenot1,2,3-cdipyrene, 1,3-dinitro- pyrene, and 1,8-dinitropyrene. These studies should be performed in the species and tissues in which these com- pounds induce tumors. In general, in vitro experiments are useful for identification of metabolites and evaluation of their role in metabolic activation. However, in vivo studies are essential for relating metabolic pathways to carcinogenesis. In particular, . . . . extensive furt ner investigations are neces- sary on the disposition, metabolism, and DNA binding of PAHs and nitro-PAHs under conditions of inhalation exposure. Although modifiers of carcinogenesis are important in determining whether or not a PAH or nitro-PAH will induce cancer, research on the mechanisms by which they affect the carcinogenic process is still fairly limited. The studies carried out so far indi- cate a complex network of effects. It will be important to select one or two environ- mentally prevalent modifiers of PAH car- cinogenesis and to carry out in-depth inves- tigations of their mechanisms of action. ~ Recommendation 9. The mechanisms by which environmental compounds mod- ify PAH and nitro-PAH carcinogenicity should be investigated. Further in vitro and in vivo studies should probe the mechanistic basis for the cocarcinogenic effects of such compounds as fluoranthene, pyrene, and catechol and for the inhibitory effects of certain phenols, isothiocyanates, and indoles. Since these effects can be extraordinarily complex, it is recommended that the studies focus on one or two cocarcinogens, such as fluoranthene and catechol, and one or two appropriate inhibitors such as p-methoxyphenol and indole-3-acetonitrile. These studies should be performed initially with BaP in mice because of the extensive data base that . . . ex~sts on th~s system. Summary Epidemiologic studies have been per- formed on cohorts exposed to numerous mixtures containing PAHs, including to- bacco smoke, coal tars, and soots. Many of these studies have shown that exposure to

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Stephen S. Hecht 573 such mixtures causes cancer at various tis sue sites, but individual PAHs have not been specifically incriminated as the caus ative agents because they occur together with other carcinogens. Nevertheless, these data, taken together with the extensive an imal bioassays of PAHs, strongly indicate that PAHs can cause cancer in humans. The role of nitro-PAHs in human cancer is unclear at present. Studies of PAH metabolism in animal and human tissues have elucidated many of the important pathways of activation present. and detoxification and have demonstrated that their metabolism is extremely com- plex. The balance of activation versus detoxification can be influenced by a mul- titude of genetic and environmental fac- tors. However, it is clear that formation of specific PAH metabolite/DNA adducts is the key step in the initiation of the carcinogenic process. Similar conclusions can be drawn about nitro-PAHs, but their metabolic activation and detoxification pathways are not very well characterized at Summary of Research Recommendations HIGH PRIORITY Recommendation 1 The structures of the major DNA adducts and protein adducts formed from representative PAHs and nitro-PAHs should be determined in laboratory animals. Recommendation 2 Methods should be developed for determining individual uptake and metabolic activation of representative PAHs and nitro-PAHs. Recommendation 3 Under conditions of chronic administration of PAHs or nitro PAHs to laboratory animals, the relationship between DNA adduct or protein adduct formation and tumor development should be determined. Recommendation4 Pilot studies should be undertaken on individuals potentially exposed to PAHs or nitro-PAHs in order to determine the feasi bility of monitoring DNA adducts and protein adducts in humans. Recommendation 8 The mechanisms by which carcinogenic PAHs and nitro-PAHs undergo metabolic activation and detoxification should be deter mined. MEDIUM PRIORITY Recommendations Inhalation bioassays and intratracheal instillation bioassays of selected PAHs should be performed. Recommendations The tumorigenicity of environmental nitro-PAHs should be evaluated. LOW PRIORITY Recommendation 7 Bioassays should be performed to discover environmental mod ifiers of PAH and nitro-PAH carcinogenicity. Recommendation 9 The mechanisms by which environmental compounds modify PAH and nitro-PAH carcinogenicity should be investigated.

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574 Effects of Polynuclear Aromatic Hydrocarbons and Nitroaromatics Acknowledgments I thank Ms. Gail Thiede for typing and editing the manuscript. Our studies on PAHs and nitro-PAHs are supported by NCI Grants CA-44377 and CA-35519. References Ashurst, S. W., Cohen, G. M., Nesnow, S., DiGio- vanni, J., and Slaga, T. J. 1983. Formation of benzotaipyrene/DNA adducts and their relation- ship to tumor initiation in mouse epidermis, Cancer Res. 43:10201029. Autrup, H., Jeffrey, A. M., and Harris, C. C. 1980. Metabolism of benzota]pyrene in cultured human bronchus, trachea, colon, and esophagus, In: Poly- nuclear Aromatic Hydrocarbons: Chemistry and Biolog- ical Effects (A. Bjrseth and A. J. Dennis, eds.), pp. 8~105, Battelle Press, Columbus, Ohio. Becher, G., and Bjrseth, A. 1983. Determination of exposure to polycyclic aromatic hydrocarbons by analysis of human urine, Cancer Lett. 17:301-311. Beland, F. A., Heflich, R. H., Howard, P. C., and Fu, P. P. 1985. 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