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"= ~ 1~ ~ CLl~`C. deficiencies are known to increase the toxicity of pesticides--including carbonate carbaryl, parathion, and captanl70--and heavy metal~.37~98 Nutritional status can influence microsomal enzymes and thus affect the toxicity of PAHs. Protein deficiencies can lower AHH activity,ll and the type of dietary protein can affect AHH acti- vity.36 Nutrient deficiencies are observed in both childrenl25 and adults;189 deficiencies in iron, vitamin A, and vitamin C are the most prevalent. Whether these deficiencies play a role in PAH-related effects in humans is not known. Deficiencies or alterations in vitamins (vitamins A and C) can influence the incidence of PAH-induced cancers in animal-model systems.8~19,l76 Dietary vitamin A (i.e., retinoids) may also influence the expression of cancer in humane. 138 The effects of vitamins seem to be centered on the later stages of carcinogenesis, especially tumor progression. Chemoprevention shows promise for alter- ing or controlling inherent sensitivity (or resistance) to carcino- genesis, but it should be borne in mind that some vitamins, such as retinoids, sometimes increase cancer expression and sometimes suppress it.164 Diets high in fat and meat and low in fiber have been associated with increased risk of cancer, especially cancer of the ^^~ 51.199.200 The effect of dietary fat may be related to ~ - - ~ ~bile acids, which Jo 1`JLl ~ - alterations in the concentration of colonic secondary act as colon-tumor promoters.l50,l5l PAHs can act as cocarctnogens, comutagens, or promoters, but whether they play these roles in humans and whether the nutritional status of the host alters these roles are not known. 7-11 ~. ....

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TABLE 7-1 Studies Suggesting Correlation between Carcinogen Metabolic Capacity and Cancer Susceptibility in Humans Disease Tissue Assayed Reference Comments Lung cancer Lymphocytes 72 Assay only for "inducibiIity" Lung cancer Lymphocytes 49 Radiometric assay; 11 cancer patients monitored Laryngeal Lymphocytes 185 No controls cancer Lung cancer Bronchi 53 BaP binding to DNA higher in bronchi from lung-cancer patients; large individual differences Renal and Lymphocytes 186 No controls ureteral cancer Lung cancer Lymphocytes, 106 Dichotomy of AHH in ly~pho PAMs cytes and PAMs in lung-cancer patients Lung cancer Lymphocytes 32 - Lung cancer Antipyrine 1 - -(half-life) Lung cancer Lymphocytes, 107 Correlation of~AHH depended on PAMs, patient--lung cancer vs. normal lung tissue ~ Lung cancer Lymphocytes 39 Absolute AHH activity dominantly inherited; values given relative to "standard" panel; no AHH values presented Lung cancer Lymphocytes 4 Lung cancer Antipyrine 71 Leukemia Lymphocytes 11 7-12 Inducibility determined by non- induced AHH activity Antipyrine half-life related to cancer and smoking Susceptibility related to low ARH ~..

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TABLE 7-2 Studies Suggesting Lack of Correlation between Carcinogen Metabolic Capacity and Cancer Susceptibility in Humans Disease Lung cancer COPD, chronic bronchitis Lung cancer Laryngeal and lung cancer Lung cancer Lung cancer Lung cancer Lung cancer Tissue Assayed Reference Lymphocytes 127 Lymphocytes 110 Lymphocytes 67 Lymphocytes 194 Lymphocytes (BaP binding) Lung (organ) cultures Antipyrine (metabolism) Lymphocytes 66 188 91 7-13 Comments Progeny vs. spouse; cancer patients showed low AHH and were not tested Smoking, not cancer, associated with high BaP metabolism; high AHH correlated with lymphocyte stimulation. Measured AHH in disease-free subjects; 40t on medication; lymphocytes from all groups grew well. BaP-macromolecule binding measured. HPLC analysis of BaP metabolites . In six cancer patients. Nine hospitalized patients used. -.. .. .. . .

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Cancer threshold 100 90 60 In u, 80 70 50 40 30 a 20 so to / 10 Genetic n . / resistance Gradually increasing polygenic risk requiring sub stantlal environmental exposure for tumor induction ~ I t . 0 10 20 3040 SO 60 ~ 100 Percent of Population FIGURE 7-1. Interplay between genetically controlled variations and environmental exposure leading to cancer susceptibility. The population of humans is viewed as a sigmoidal curve where the extremes are either genetically resistant or genetically predisposed to cancer. The shape of the curves would be expected to change for given subpopulations that contain higher per- centages of genetically resistant or genetically predisposed persons. Reprinted with permission from Lynch; 5 copyright Academic Press. 7-16 _ . Cancer pre- disposi single- gene defects

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1 1L c ~ ~ ~ ~ In In ~ c a Id ED z ~ = 1 lo ~- ~IHHY 7-18 . _~ it_ _ . _~, I _8 1= \1 _ _ i_ ~ ~. _ - _s NEW 1 ~ Or, ! ~ it:. $: :~.:~ _ - :e ~ e a: 0 Z 0 a ~ . - - 0 . - TIC rl 0 ~ em a: o ~1 e to - - - o 00 - 0 - - Cal ~ ^ 0 CJ' JO ~ :^ C) O- :- ~S to C) O - ~ ~ ' ~ O 0 ~ - C) 00 ~0 :^ 1 ~ 1_ ~ - ' A' 1 ~ c- - 3 O Cal ~'. .

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l ~ EXPOSURE TO AGENT | INCOMPLETE OR NO | EXCISION REPAIR _ ~ r _ ~ DNA REPLICATION AND CELL DIVISION [:: FURTHER DAMAGE IN NEW DNA . . i.,, e_ Deed | INCOMPLETE OR NO | POSTREPLICATION REPAIR | | ~=REPLICATION REPAIR | DAMAGE TO CELLULAR DNA 1'_ _ META80LIC ACTIVATION EXCISION REPAIR I . , 1 NORMAL, NEW AND OLD DNA DNA REPLICATION AND CELL DIVISION l ~ CYTOXIC, MUTAGENIC, CHROMOSOMAL EFFECT , SOME NORMAL PROGENY FIGURE 7-4. Scheme depicting nuclear changes and their toxic effects. Cytotoxic, mutagenic, or carcinogenic effects are thought to result from nonrepair or misrepair of particular DNA damage. Reprinted with permission from Roberts;157 copyright Academic Press. 7-19 | NORMAL l L PROGENY l

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REFERENCES 1. Ambre, J., D. Graeff, F. Bures, D. Haupt, and K. Deason. Antipyrine metabolism and bronchogenic carcinoma. J. Med. 8:57-70, 1977. 2. Andrews, A. D., S. F. Barrett, and J. H. Robbins. Relation of D.N.A. repair processes to pathological aging of the nervous system in xero- derma pigmentosum. Lancet 1:1318-1320, 1976. 3. Arlett, C. F., and A. R. Lehmann. Human disorders showing increased sensitivity to the induction of genetic damage. Ann. Rev. Genet. 12:95-115, 1978. Arnott, M. S., T. Yamauchi, and D. Johnston. Aryl hydrocarbon hydroxylase in normal and cancer populations, pp. 145-156. In A. C. Griffin and C. R. Shaw, Eds. Carcinogens: Identification and Mechanisms of Actioon. New York: Raven Press, 1979. Atlas, S. A., E. S. Vesell, and D. W. Nebert. Genetic control of interindividual variations in the inducibility of aryl hydrocarbon hydroxylase in cultured human lymphocytes. Cancer Res. 36:4619-4630, 1976. 6. Autrup, H., C. C. Harris, B. F. Trump, and A. M. Jeffrey. Metabolism of benzo~a~pyrene and identification of the major benzo~a~pyrene-DNA adducts in cultured human colon. Cancer Res. 38:3689-3696, 1978. 7. Benda, C. E. Down's Syndrome: Mongolism and Its Management. Rev. ed. New York: Grune and Stratton, 1969. 279 pp. 8. Benedict, W. F. 9 W. L. Wheatley, and P. A. Jones. Inhibition of chemically induced morphological transformation and reversion of the transformed phenotype by ascorbic acid in C3H/lOTl/2 cells. Cancer Res. 40:2796-2801, 1980. 9. gingham, E., and W. Barkley. Bioassay of complex mixtures derived from fossil fuels. Environ. Health Perspec. 30:157-163, 1979. 10. Blot, W. J., L. A. Brinton, J. F. Fraumeni, Jr., and B. J. Stone. Cancer mortality in U.S. counties with petroleum industries. Science 198:52-53, 1977. 11. Blumer, J. L., R. Dunn, M. D. Esterhay, T. S. Yamashita, and S. Gross. Lymphocyte aromatic hydrocarbon responsiveness in acute leukemia of childhood. Blood 58:1081-1088, 1981. 12. Borresen, A. L., K. Berg, and P. Magnus. A twin study of aryl hydro- carbon hydroxylase (AHH) inducibility in cultured lymphocytes. Clin. Genet. 19:281-289, 1981. 13. Boutwell, R. K. Biochemical mechanism of tumor promotion, pp. 49-58. In T. J. Slaga, A. Sivak, and R. K. Boutwell, Eds. Carcinogenesis--A Comprehensive Survey. Vol. 2. Mechanisms of Tumor Promotion and Carcinogenesis. New York: Raven Press, 1978. 14. Brewen, J. G. Cytogenetic studies and risk assessment for chemicals and ionizing radiation, pp. 97-115. In V. K. McElheny and S. Abrahamson, Eds. Assessing Chemical Mutagens: The Risk to Humans. Banbury Report 1. Lloyd Harbor, N.Y.: Cold Spring Harbor Laboratory, 1979. 15. Carlstedt-Duke, J. M. B. Tissue distribution of the receptor for 2,3, 7,8-tetrachlorodibenzo-p-dioxin in the rat. Cancer Res. 39: 3171-3176, 1979. 7-20

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16. Carter, D. M., A. Gaynor, and J. McGuire. Sister chromatic exchanges in dyskeratosis congenita after exposure to trimethyl psoralen and UV light. J. Supramol. Struct., Supplement 2:84 (abstr. no. 207), 1978. 17. Casciato, D. A., and J. L. Scott. Acute leukemia following prolonged cytotoxic agent therapy. Medicine 58:32-471, 1979. 18. Chaganti, R. S. K., S. Schonberg, and J. German. A manifold increase in sister chromatic exchanges in Bloom's syndrome lymphocytes. Proc. Natl. Acad. Sci. USA 71:4508-4512, 1974. 19. Chan, W. C., and Y. Y. Fong. Ascorbic acid prevents liver tumor pro- duction by aminopyrene and nitrite in the rat. Int. J. Cancer 20:268-270, 1977. 20. Cleaver, J. E. Defective repair replication of DNA in xeroderma pigmentosum. Nature 218:652-656, 1968. 21. Cleaver, J. E. Xeroderma pigmentosum: Variants with normal DNA repair and normal sensitivity to ultraviolet light. J. Invest. Dermatol. 58:124-128, 1972. 22. Cleaver, J. E., and D. Bootsma. Xeroderma pigmentosum: Biochemical and genetic characteristics. Ann. Rev. Genet. 9:19-38, 1975. 23. Cockayne, E. A. Dwarfism with retinal atrophy and deafness. Arch. Dis. Child. 21:52-54, 1946. 24. Cohen, G. M., R. Mehta, and M. Meredith-Brown. Large interindividual variations in metabolism of benzo~a~pyrene by peripheral lung tissue from lung cancer patients. Int. J. Cancer 24:129-133, 1979. 25. Creasia, D. A., J. K. Poggenburg, Jr., and P. Nettersheim. Elution of benzota~pyrene from carbon particles in the respiratatory tract of mice. J. Toxicol. Environ. Health 1:967-975, 1976. 26. Diamond, L., T. G. O'Brien, and G. Rovera. Inhibition of adipose conversion of 3T3 fibroblasts by tumor promoters. Nature 269: 247-249, 1977. 27. DiGiovanni, J., J. R. Romson, D. Linville, and M. R. Juchau. Covalent binding of polycyclic aromatic hydrocarbons to adenine correlates with tumorigenesis in mouse skin. Cancer Lett. 7:39-43, 1979. 28. DiGiovanni, J., T. J. Slaga, and R. K. Boutwell. Comparison of the tumor-initiating activity of 7,12-dimethylbenz~ajanthracene and benzota~pyrene in female SENCAR and CD-1 mice. Carcinogenesis 1: 381-389, 1980. Duran-Reynals, M. L., F. Lilly, A. Bosch, and K. J. Blank. The genetic basis of susceptibility to leukemia induction in mice by 3 methylcholanthrene applied percutaneously. J. Exp. Med. 147: 459-469, 1978. 30. Eastman, A., and E. Bresnick. Persistent binding of 3-methyl- cholanthrene to mouse lung DNA and its correlation with suscepti- bility to pulmonary neoplasia. Cancer Res. 39:2400-2405, 1979. 31. Ekelman, K. B., and G. E. Milo. Cellular uptake, transports and macromolecular binding of benzo~a~pyrene and 7,12-dimethyl- benz~ajanthracene by human cells in vitro. Cancer Res. 38: 3026-3032, 1978. 32. Emery, A. E. H., N. Danford, R. Anand, W. Duncan, and L. Paton. Aryl-hydrocarbon-hydroxylase inducibility in patients with cancer. Lancet 3:470-471, 1978. 7-21

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8 SUMMARY The present report attempts to make current the information relative to the sources (both mobile and stationary) , formation, atmospheric transformations, biologic effects, and pharmacokinetics of a select group of polycyclic aromatic hydrocarbons (PAHs) and mixtures thereof, to identify populations hypersensitive to them and to determine the human risks associated with exposure to them. The specific PAHs considered were chosen on the basis of relative concentrations in various kinds of emission or combustion products or because of some unique pharmacologic property. SOURCES, ATMOSPHERIC PERSISTENCE, AND TRANSFORMATIONS OF PAHs The emphasis of this report is on PAHs emitted from mobile sources, but these substances are ubiquitous--they are found in terrestrial and aquatic plants, in soils and bottom sediments, and in fresh and marine waters, as a result of emission from both mobile and stationary sources. The total annual release of benzo~a~pyrene (BaP), as a surrogate PAH, in the United States from all sources is estimated at 300-1,300 metric tons; approximately 40 tons are produced from mobile sources. It is estimated that bv the Year 2000 the atmospheric BaP concentration in highly , , urbanized areas- will be approximately O.6 ng/m'. The concentration of a particular PAH depends on its source (among other things), but the phenanthrenes (including methyLated derivatives), the fluorenes (including methylated derivatives), fluoranthene, pyrene, BaP, benzotghi~perylene, chrysene, perylene, dibenz~ac~anthracene, and benz~aJanthracene have many common sources. Emission from the combustion of wood contains more alkylated PAHs than combustion products from other sources. Wood stoves and fireplaces, nonregulated sources of PAHs, are important contributors to environmental pollution, particularly in rural areas with restricted airflow. Wood smoke contains considerable amounts of particles and adsorbed PAHs, and it is anticipated that this source will become even more significant wi th the increased use of wood as a primary fuel. Of the total motor-vehicle mileage accumulated in this country, the light-duty passenger car with spark-ignition engine is the major contributor, although the number of diesel engines is increasing. By the mid-1990s, approximately 257 of the passenger fleet will probably be powered by diesel engines. Rates of emission of particles from diesel engines are about 2 orders of magnitude greater than those from catalyst-equipped spark-ignition engines. The total PAH emission from mobile sources in 1979 was approximately 6,500 metric tons; phenanthrene, pyrene, fluoranthene, methylphenanthrene, cyclopentapyrene, anthracene, benzofluorene, chrysene, benzofluoranthene, the benzopyrenes, and 8-1 At. . . . .

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benzoperylene were major contributors. Nitropyrene and other nitro-PAHs have also been found as emission products, but whether these very reactive substances are artifacts of the sampling process or are present in the initial emission has not been established. It has been estimated that the total emission of PAHs in 2000 will be considerably lower because of advances in collection devices on mobile sources. There are large uncertainties concerning the persistence of the PAHs, their chemical transformations, and their atmospheric transport and fate, although some general principles can be derived. There is evidence of long-range transport from the analysis of cores from sediments; the PAHs can be transported over long distances in the atmosphere without important degradation. The principal processes by which the PAHs are chemically removed are photooxidation, reaction with ozone, and reaction with nitrogen dioxide. The latter reaction may be responsible for the generation of nitro-PAHs, some of which are potent mutagens. Of the PAHs that have been selected for study, only BaP and pyrene have been investigated in detail with respect to chemical transformations. Considerably more study is needed. BIOLOGIC EFFECTS OF SMOKE, EMISSION, AND SOME OF THEIR PAR COMPONENTS . It has been estimated that as much as 13% of all human cancer deaths may be attributed to environmental factors, one of which is pollution resulting from emission from mobile and stationary sources. Then tested, however, particles from diesel and spark-ignition engines and organic-solvent extracts of these particles have not been very toxic to animals. Only minimal effects on pulmonary function, reproductive capacity, and glandular or hepatic function have been observed. The chronic exposure of newborn rats to diesel-engine exhaust appears to result in some abnormal development of the central nervous system, as demonstrated by the slower acquisition of spontaneous locomotor activity and bar-pressing ability; and small abnormalities have been noted in visual evoked and somatosensory evoked potentials in exposed neonatal rats. Whether these changes resulted from exposure to the PAR components of diesel-engine exhaust has not been ascertained. Although no immunologic changes have been observed after exposure - rats to diesel-engine exhaust, it is known that some PAHs are immunosuppressive. In particular, high doses of 3-methylcholanthrene, dibenz~ahianthracene, 7,12-dimethylbenzanthracene, and BaP reportedly depress the response of mice and rats to various immunologic challenges This immunosuppressive effect, exhibited by some PAHs but not by exhaust or emission, can be divorced from the carcinogenicity of these agents. Extracts of particles from spark-ignition and diesel exhaust are mutagenic to Salmonella typhimurium in forward- and backward mutation assays and in several animal-cell model systems. The extracts were directly active in the bacterial assay, whereas emission from coke ovens, roofing tar, cigarette-smoke condensate, wood combustion products, and Pap 8-2 lo. ...

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were positive only after metabolic activation--indirect mutagenesis. After fractionation of the various extracts, the fraction that contained the PAHs demonstrated the greatest mutagenicity in the bacterial assay. A major PAH in soot, automobile exhaust, cigarette smoke, and coal fly ash is cyclopentatcd~pyrene; it proved to be highly mutagenic in the indirect assay. Indeed, the total mutagenic activity of kerosene-soot extract could almost be reproduced by cyclopentatcd~pyrene alone. The direct mutagenicity appeared in part to be caused by nitro-PAHs. These substances have been found in automobile-exhaust particles and in cigarette smoke, but not in wood combustion products. The nitro-PAHs were much more mutagenic than the parent compounds, with 1,8-dinitropyrene being the most mutagenic of all compounds that have been subjected to the Salmonella/microsome assay. The mutagenicity of these nitro derivatives has not been tested consistently in animal-cell models. The mouse skin tumorigenesis model has been used to assay the carcinogenicity of extracts of various particles. The condensates from spark-ignition engine exhaust proved carcinogenic in this model; those from diesel exhaust were less active. The exhaust preparations had both initiation and promotion activities with this model. There are conflicting reports as to whether the tumorigenicity of the extracts reflected the additive activity of the major PAHs in the condensates. When tested for tumorigenicity by inhalation and intratracheal instillation, the condensates proved not very active. The literature is contradictory on whether the incidence of neoplasia in animals receiving automobile-exhaust condensate intratracheally reflected the BaP content of the condensate. Of a series of compounds that were tested for carcino- genicity in a mouse-adenoma model, 3-methylcholanthrene, dibenz~ah~anthra- cene, and BaP proved most active. The effect of alkyLation, particularly methylation, on the carcino- genicity of various PAHs has been determined with biologic models. The fluorenes, phenanthrenes, and anthracenes are major components of smoke and emission, so there has been considerable interest in determining the effects of methylation of these agents on tumorigenicity. The insertion of a methyl group at particular positions of the benz~aJanthracene ring increased tumorigenicity considerably. 9-Methylfluorene was much more- mutagenic than the parent compound in the bacterial assay system. In the phenanthrene series, the l- and 9-methyl analogues were more mutagenic than the parent compound. The methylchrysenes are known environmental pollutants; although the parent compound is generally inactive as a carcinogen, the 5-methyl derivative was as carcinogenic as BaP and was the most potent of all the methylated derivatives when tested as an initiator. Methylated BaPs have been tested for tumor initiation, and some (the 1-, 3-, and 11-methyl) analogues have been found to be more active in this regard than the parent compound. It is apparent that the methylated PAHs, which are present in exhaust and smoke, can contribute to . . . carctnogen~c~ty. 8-3 ~;

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EFFECTIVE BIOLOGIC DOSE After administration to laboratory animals, PAHs are absorbed readily and distributed to various tissues. Nonmetabolized material accumulates and persists in body fat. This phenomenon may be useful for monitoring the chronic exposure of various populations to emission and smoke that are rich in PAHs. Particle-bound PAH is retained in the lung to various degrees that depend on the size and composition of the particles. Once in the lung, the particle-bound material can be desorbed and distributed to other tissues. The clearance of a PAH from an animal-model system appears to depend on the concentration of nonmetabolized compounds in the fat, the metabolism of the PAH, and biliary, fecal, and urinary excretion. The excreted metabolizes of PAH are largely glucuronides, sulfates, and hydroxylated and phenolic derivatives. Virtually all tissues can metabolize PAHs, although liver exhibits the greatest activity in this regard. The initial metabolism is conducted by membrane-bound cytochrome P-450-dependent monooxygenases that yield epoxide derivatives. The Latter may spontaneously rearrange to phenols that serve as building blocks for Later conjugation. The epoxides may give rise to bans dial derivatives in reactions catalyzed by the membrane-bound enzyme epoxide hydratase; these dial derivatives may be excreted unchanged or conjugated as glucuronides. Secondary metabolism by the cytochrome P-450-dependent monooxygenases yields very reactive diol- epoxides that can spontaneously rearrange to electrophiles that can interact with macromolecular nucleophiles, such~as DNA. The activity of the monooxygenases and epoxide hydratase is genetically determined and is inducible by exposure of an organism to PAHs; the extent of induction is also genetically determined. PAHs may also be activated through an arachidonic acid-dependent co-oxygenation step involving the prostaglandin synthetase complex. Through this mechanism, the bans dial of BaP, for example, is transformed to the diol-epoxide at the expense of prostaglandin G2. The reactive metabolites of PAHs, such as diol-epoxides, interact covalently with ONA to form addicts. The adducts of BaP diol-epoxide with DNA have been examined in lung, liver, forestomach, colon, kidney, brain, and muscle after oral administration of BaP to mice. Human tissues also are able to catalyze adduct formation. The DNA-adduct profiles appear specific for a particular tissue. The amount of BaP-DNA adduct formed in a particular tissue is not correlated with the susceptibility of that tissue to PAH-induced carcinogenesis. This is evident from consideration of liver, a tissue that is not ordinarily a target organ for PAH-induced carcinogenesis, but one in which adducts readily form. The PAM-DNA adducts have varied turnover rates in different tissues. The turnover rate is related in part to the normal rate of replication of the cell and in part to an enzymatic DNA-repair system. Different addicts are removed from DNA at different rates.

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With regard to BaP, a linear dose-response relationship has been observed with formation of DNA adducts as the end point. There appears to be no threshold dose below which adduct formation will not occur. The administration of a number of inducers of monooxygenases and of the conjugating enzyme systems reduces the in viva formation of adducts; administrat ion of antioxidants has a similar effect. It has been proposed that the concentration of PAM-DNA adducts in a particular tissue can be used as a measure of the "effective biologic dose" of a specific PAR. It should be s imple to determine this dose with currently available sensitive radioimmunoassay methods. Such methods could be applied to readily accessible lymphocytes of human populations. HUMAN EXPOSURE TO AND METABOLISM OF PAHs . Humans are exposed to PAHs almost exclusively through the gastrointestinal and respiratory tracts. Possibly 99t of exposure to these substances is through the diet. The daily human exposure to PAHs from air, water, and food has been estimated. Of approximately 1.8-16 fig of total PAHs ingested or inhaled, 0.2 and 0.02 fig would be derived from inhalation or ingestion in water, respectively, and the rest from food. Of the total, approximately 10% would be BaP. Although the PAHs are ubiquitous in foodstuffs, their content can be surprisingly high in some foods as a result of pollution from soils, irrigation waters, atmospheric fallout, and food-processing. The number of PAHs ingested may be as high as 100, or even higher. Boil ing or barbecuing substantially affects the composition and quantity of PAHs in foods . Occupational exposure to PAHs can lead to inhalation of great quantities. It has been estimated that a normal adult breathing 20 ma of air per day can inhale approximately 700 fig of PAHs per day in a work setting that is rich in PAHs, e.g., coal and pitch-coking plants, gasworks, and roof-tarring operations. It has also been estimated that people who remain in tunnels with heavy motor traffic all day can inhale BaP that would be equivalent to that found in a pack of "old-style" cigarettes. In accordance with the occupational exposure, cancer mortality among men employed in coal-tar industries reflects excess cancer in one or more s ;tes, particularly those involving the lungs. The manner by which PAHs gain access to the systemic circulation is not known. Serum lipoproteins may constitute a substantial circulatory pool of the PAHs, which can be transferred into cells by a non-receptor mediated process. The pharmacokinetics of PAHs other than BaP in humans are not well understood. Normal and malignant human tissues have the metabolic capacity to biotransEorm PAHs, especially BaP. The individual variation in this capacity is very large in the human and appears to be genetically determined. Although it has been proposed that aryl hydrocarbon hydroxylase activity in lymphocytes and monocytes of lung-cancer patients 8-5 Hi;

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is highly inducible, compared with that in "normal" patients, this relationship has not been definitively established and deserves further study. There is little information to implicate diet-derived PAHs in any form of clinical pathology, despite the relatively large amounts of these compounds ingested. The gastrointestinal system, including the liver, may be relatively "resistant" to the PAHs; the nature of such resistance should be explored. POPULATIONS OF HYPERSENSITIVE PERSONS The exposure of cells or animals to pollutants, including PAHs, can lead to toxicoses, mutagenesis, carcinogenesis, and teratogenesis. Susceptibility to PAH-induced effects may be controlled at the level of uptake into specific cells, metabolic activation or inactivation, DNA repair, expression of DNA damage and its progression to the phenotype of a mutant cell, and immunocompetence of the person. Several of these steps (perhaps all) are subject to genetic regulation, although information in this regard is sketchy. Natural variations in capacity for human DNA repair lead to increased susceptibility to cancer in some instances, but the role of the PAHs in this development is not established. Genetically controlled variations in immunocompetence are observed in people with high susceptibility to carcinogenesis; no definitve role of the PAHs has been suggested. The physical state of a PAR and the nutritional or developmental state of the host contribute substantially to the observed biologic effect. 8-6

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9 RECOMMENDATIONS MOBILE SOURCES Several of the polycyclic aromatic hydrocarbons (PAHs) found in emission from heavy-duty diesel vehicles and other vehicles are potentially hazardous to human health. On the basis of what is currently known, research should be conducted to discover practical and economical adjustments in engine design for reducing particulate and gaseous PAH emission. In vitro mutagenesis tests could be used to determine the types of adjustments that influence the concentrations of PAH chemicals active in these short-term tests. On preliminary testing, the nitro-PAHs have been mutagenic; thus, they are an important subgroup of the PAHs purportedly found in mobile-source emission. However, it is not clear whether these compounds are formed in exhaust or are artifacts of sampling; more information is needed to clarify this issue. ATMOSPHERE _ Data from core sampling of bottom sediments in rivers and bays show long-range transport of presumably unreacted PAHs. PAH chemistry of urban and industrial emission plumes should be systematically studied both regionally and on a continental scale. It is recommended that monitoring of wet and dry PAH deposition be included in existing ambient-air quality monitoring networks. The heterogeneous photooxidation and reactions of PAH with ozone and oxides of nitrogen should be examined under experimental conditions with emphasis on the nature and size distribution of carrier particles on both PAH and reaction products; the findings should be correlated with findings on what actually occurs in the ambient air. A system for monitoring in large residential localities should be encouraged, to determine the concentrations of PAHs emitted from residential fireplaces, wood-burning stoves, and coal-fired heating systems and the contributions from these sources relative to those from industrial and commercial boilers and rural municipal waste-burning units. Concurrently with the monitoring studies, research should be conducted on design of equipment, technologies, or methods for controlling PAH emission from residential fireplaces and wood- and coal-burning stoves. Extracts of the condensates of smoke and other gaseous emission from wood, coal, diesel and spark-ignition engines , and tobacco must continue to be tested in in vitro mutagenicity systems, so that activity profiles can be established and specific active PAHs identified. There is a need to develop double checks on the findings of research on extracts of condensates, to eliminate the uncertainty regarding artifacts that occur in the sampling or extraction processes. The mutagenicity and it. a .

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carcinogenicity of each active PAR (especially nitro-PAHs and sulfur- containing PAHs) should be determined in several animal-model systems to guide the assessment of their contribution to human disease. EXPERIMENTAL-ANIMAL STUDIES . Some data on cocarcinogenic activity of PAHs with other chemicals are available, but this data base needs to be strengthened, and PAHs other than benzotaipyrene (BaP) need to be studied further. Specifically, data are needed to establish whether various PAHs exhibit cocarcinogenic activity with other components of exhaust from mobile sources or emission from other combustion sources, especially wood smoke. The potential promoting activity of PAHs (including BaP) needs to be established. A model for promotion other than the mouse skin tumorigenesis system is needed. Of special interest would be a promotion system using human cells. Extrapolation of findings from animal studies to humans is tentative without additional biochemical and pharmacokinetic data. Sorting out the toxic chemicals in any complex mixture (such as automobile exhaust, wood smoke, or cigarette smoke) is always difficult. Animal models and compound-specific testing systems are needed to ascertain the toxic effects (if any) of long-term (chronic) exposure of animals to diesel exhaust and other complex kinds of emission. In this regard, it is important to stress that the animal model systems include introduction of the PAHs (alone, in mixtures, and bound to particles) into the diets of animals in lifetime studies of carcinogenesis. Such dietary exposure is based on the data that indicate that ingestion contributes heavily to the body burden of the PAHs. As results from these studies begin to distinguish the toxic components, biochemical and pharmacokinetic data on experimental primates (e.g., squirrel monkeys) will be particularly useful in confirming the findings in animal species and extrapolating to humans. With improving characterization of the toxic components, studies should be conducted on lung deposition, uptake, and clearance of PAHs. Studies on the relationships of carrier-particle size, surface properties in the submicrometer range, and absorption and adsorption of individual PAHs should be continued and expanded with an eye to learning the source of the greatest exposure to the toxic chemicals. Preliminary studies in animal models should be conducted as soon as possible to determine the relationship of PAH exposure to birth defects and other genetic anomalies. Specifically, it would be important to know whether chronic exposure of newborns to various types of exhaust and smoke and to mixtures of PAHs and individual PAHs (present in high concentra- tions in exhaust) affects development of the central nervous system. DNA ADOUCTS, ENZYME INnucERs AND REPAIR What is the relationship of the enzymes and their activity to the metabolism of PAHs 5 other than BaP, and to the formation of PAM-DNA adducts and their repair? A broader question is: What are the consequences of the various DNA adducts known to be formed? 9-2

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To answer these questions, developed for detecting PAH me antibod ies . Such as says would metabolite-DNA adduct formatio ~ , r ~ 0 -~~ ~ ~ such as the lung, after in vivo experimental exposure to PAHs, especially low-dose, long-term exposure. With appropriately designed cell-model systems that use various cell types, the relationship of in vivo repair of PAH metabolite-DNA adducts should be examined and an activity profile developed for the individual known active PAHs. Animals other than mice and rats should be used to examine PAH metabolite-DNA adduct formation and the mechanisms by which phenolic antioxidants and inducers of aryl hydrocarbon hydroxylase (AHH) inhibit the formation of adducts. more sensitive and specific assays must be tabolite-DNA adducts, e.g., with monoclonal be used to determine rates of PAH n in individual cell tvoes and in organs Can the PAH metabolite-DNA systems be quantified and further developed for use in monitoring exposure to specific PAHs? The feasibility of using adducts as a measure of effective biologic dose should be studied for low-dose extrapolation of bioassay findings to dose-response curves that show the rate of adduct formation and its relationship to PAH-induced neoplasia in animal-model systems. The importance of the findings will depend on a careful analysis of the background concentrations of PAM-DNA adducts in tissues--i.e., "noise." HUMAN STUD IE S Obviously, all health-related research findings are useful in improving the protection of human health. Although research that uses human beings directly poses difficult problems,.there are various kinds of human studies that avoid those problems. For instance, human tissues can be used to study the relationship of specific biotransformations of PAHs to findings of carcinogenicity in animals. To determine the PAH dose absorbed from human lung tissue, there is a need to know-the chemical form and binding of PAHs on particles, particle size, composition, clearance rates, and ultimate fate of inhaled particle-adsorbed PAHs. These findings would be essential in studying the relationship of formation of PAR metabolite-DNA adducts and the incidences of adverse health effects found in animal studies. Progress in understanding research findings could be greatly improved if an "inventory" of PAHs identified and measured in normal and diseased human tissues could be developed. Perhaps samples of appropriate tissues could be analyzed specifically for this purpose, and biologic and historical information on the donors could be accumulated. The tissue profiles of PAH metabolite-DNA adducts or other indicators could be compared with those derived from environmental sampling or air monitoring. The findings ;n this report show that a high fraction of human exposure to PAHs is attributable to dietary intake. The possible relationship of ingested PAHs to increased incidences of gastrointestinal (or other) malignancies should be included in epidemiologic analyses.

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Such analyses should attempt to Isolate the portion of the prevailing gastrointestinal malignancy rate in selected populations that is due to food-derived exposure to PAHs. It is apparent that there is resistance in the gastrointestinal system to the carcinogenic potential of the PAHs. The mechanisms responsible for this resistance might involve a great variety of body systems; no specific body function can be pinpointed. However, some effort should be directed toward finding these mechanisms. There can be few clinical parallels to this combination of (1) sustained impingement of carcinogenic compounds on a system of tissues and (2) so little evidence of realization of the potential deleterious effects of such chemicals as the PAHs. The following studies are suggested for the further development and evaluation of models for assessing the carcinogenicity relationships in humans or cell cultures derived from humans. ~ Consider the use of radiolabeled tracers or immunologic methods to study the metabolism of select PAHs, such as benzotaipyrene, in humans. The absolute amounts of compound required for single-dose exposure would be insignificant, compared with the heavy daily exposure commonly found in foods, but the medical and scientific value of the data obtained would be very large indeed. _ Examine the metabolism, pl~armacokinetics, and DNA binding of nitro-PAHs . o Conduct systematic studies of the patterns of tissue enzymatic activities relevant to PAH metabolism as a function of age, sex, hormone activities, nutritional state, or state of health (disease). O Correlate enzymatic activities, especially those involved in PAH activation to ultimate carcinogens, in one tissue type with the same biochemical properties of other tissues in the same person. These data would have the great advantage of eliminating the factor of genetic diversity in assessing the pathophysiologic significance of such enzymatic characteristics. Determine which genetically controlled deficiencies in immuno- competence are related to specific immune dysfunctions. ~ Develop better methods for determining the numbers of heterozygotes at any given Locus and use these methods specifically in populations exposed to high concentrations of PAHs. On the basis of such data, monitor the development of DNA adducts in humans with the hope of extrapolating to cancer risk. Reassess the role of genetically mediated differences in AHH -- responsiveness in determining cancer susceptibility by using multiple human tissues and multiple enzyme end points (assay for PAH receptors in human tissue; assay for total and specific cytochrome P-450s by mono- cLononal antibodies; assay for AHH expression of these genes; use of lymphoid, epidermal, and fibrobLastic cells as sources of tissues for enzymatic assays; and use of multiple functional assays for AHH, e.g., fluorimetry, high-performance liquid chromatography, and UNA binding and repair). ~ Determine whether the promotion-associated steps that occur in mouse skin also occur in human skin. Attempt to develop assays to measure for "promotability" among humans; i.e., are there genetic variants among humans for "promotability"? 9-4 I. ....