Polycyclic Aromatic Hydrocarbons Evaluation of Sources and Effects (1983) / Chapter Skim
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6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES
6 POLYCYCLIC AROMATIC HYDROCARBONS IN FOOD AND WATER AND THEIR METABOLISM BY HUMAN TISSUES
Pages 273-348
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From page 273... ...
The kinetics of BaP transfer between human plasma lipoproteins have been examined by Smith and Doodyl63 with high-density lipoproteins (HOL) , low-density lipoproteins (LDL)
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, , ,57,1 2 The specific process of BaP uptake from human LDLs into cultured human cells was examined by Remsen and Shireman.149 The cell lines used were WI-38, a human embryonic lung-fibroblast line, and GM 1915, a skin-fibroblast line derived from a patient with homozygous familial hypercholesterolemia; the former cells are LDL-receptor-positive, and the latter LDL-receptor-negative. Thus, in these studies, it was possible to explore the role of LDL receptors in the cellular uptake of PAHs that enter the bloodstream transported by chylomicrons and plasma lipoproteins.
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The large intrasubject variation in AHH inducibility of monocytes also indicated that, in addition to the clear genetic influences on this process, unknown environmental or technical factors expressed themselves in the test procedure. An abundant literature exists related to the monooxygenase activity of lymphocytes; the inducibility of this activity by mitogens, which have the property of stimulating lymphocyte transformation, during which a number of metabolic activities are concurrently greatly increased; and the use of mitogen-stimulated lymphocytes to study the genetic control of AHH in man and its relation to the occurrence of Some human cancers -- notably those of the l~lg,2 Kouri and colleagues have1 revi2ewed key aspects of this subject; ' McLemore et al.
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Most importantly, this group, 7 while affirming a significant heritable determinant of AHH inducibility in human lymphocytes, failed to confirm the monogenic model and trimodal distribution of AHH indu86bility in the general population, proposed by Kellermann _ al.; rather, the population distributions for AHH inducibility (and for plasma antipyrine half-life) were consistent with polygenic control of both traits in man.
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The authors concluded that, although the ratios of some metabolites may differ and although lymphocytes form several more derivatives than does liver, many identical metabolizes are produced in these two human cell types. Schonwald et al.l58 studied the effect of BaP on sister chromatic exchange in mitogen-stimulated lymphocytes of 11 normal subjects and 18 patients with lung cancer.
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From page 278... ...
There was considerable individual variation in PAH metabolism among the subjects studied, but the formation of water-soluble metabolites by the tissue samples accounted, in each instance, for a major portion of the total of each PAH metabolized. The extent of binding of each PAH to cellular DNA and proteins also varied considerably.
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From page 279... ...
In summary, it was clear that normal human endometrium could enzymatically convert BaP to a wide variety of oxygenated derivatives that cochromatographed with dihydrodiols, quinones, and monohydroxy products of the PAH; sulfation was also identified. HPLC analysis of metabolites revealed marked individual variation in metabolite formation among the subjects studied; smoking did not account for this difference, but some evidence of hormonal influences on the patterns of PAH metabolism was adduced.
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Namkung and Juchaul28 studied the oxidative biotransformation of BaP in preparations of human placental microsomes with HPLC. The investigations revealed that the use of substrate concentrations high enough to ensure zero-order reaction kinetics markedly inhibited the formation of dihydrodiols in the reaction mixtures.
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From page 281... ...
The ability of human bronchial epithelial cells to bind and presumably to activate such PAHs as 7,12-DMBA, 3-MC, BaP, and dibenz~ahianthracene was described by Harris and colleagues in 1974.7 Four tissue samples were studied (one control and three lung cancer) in explant cultures, and radiolabeled PAHs were used; radioactivity from all four compounds tested was found in both cytoplasm and nuclei and in all tissue samples studied (see Table 6-8~.
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This important investigation pointed the way toward study of the metabolic activation of chemical carcinogens into promutagens and mutagens directly in differentiated epithelial cells derived from human tissues; and the human tissue-mediated mutagen assay opened the possibility of testing the hypothesis that people differ in mutagenic and oncogenic susceptibility to environmental chemicals, depending on individual capacity to activate and deactivate chemical procarcinogens. Autrup et al.12 compared the metabolism of BaP by cultured tracheobronchial tissues from humans and four other species (mice, hamsters, rats, and cows)
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Cohen et al.34 showed, with cultured human bronchial epithelium, that BaP was converted promptly to metabolites that cochromatographed with 9,10-dihydro-9,10-dihydroxy-BaP and 7,8-dihydro-7,8-dihydroxyBaP. Similar results were obtained with human lung cultures, except that a major metabolite, benzota~pyrene-3-yi hydrogen sulfate, was identified.
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In a study of-the effect of tobacco-smoke compounds on the plasma membrane of cultured human lung fibroblasts, Thelestam et al.175 examined 464 compounds, of which nearly one-fourth gave rise to severe membrane damage. PAHs proved inactive in this test system; the PAHs tested included anthracene, benz~aJanthracene, chrysene, pyrene, BaP, perylene, fluoranthene, and coronene.
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. aspects of mortality from lung cancer is spoking." The equally emphatic conclusion of Pike and Henderson1 1 that "the epidemiologic evidence implicating cigarette smoking as the major cause of lung cancer is overwhelming" puts the clinical studies reviewed here related to the potential pulmonary hazards of atmospheric PAHs in proper perspective.
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From page 286... ...
A more detailed analysisl08 showed the following: The excess of respiratory cancer previously reported for coke-plant workers was limited to men employed at the coke ovens, the relative mortality for this disease being 2.5 times that predicted. The greatest part of the excess was accounted for by an almost fivefold risk of lung cancer in men working on the tops of the coke ovens.
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The data in this study also confirmed the long latency in cancer formation, even under the conditions of high exposure to carcinogens characterizing coke-oven workers; the time between first exposure to coal-tar pitch volatiles and death from lung cancer varied from 10 to 40 yr, with an average of 25 yr. Toxicologic experience with workers in the developing shale-oil industry is incomplete, although historical evidence indicates that potential health hazards related to malignancy may exist in the processes involved in oil extraction.187 Some data on the content of BaP and pyrene analogues from shale materials, as reported by Weaver and Gibson, 187 are useful to record here (Tables 6-13 and 6-14~.
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Several major reviews of the importance of water and food as vehicles of human exposure to PAHs have been published in the last 5 yr. These include a special issue of the Journal of Environmental Pathology and Toxicologyl54 devoted to the health aspects of PAHs and several monographs focusing on PAHs in drinking-water sources and on PAHs in the marine environment.l9,l29' PAHs in Water It can be stated at the outset that human exposure to PAHs through the ingestion of water is quantitatively insignificant, compared with exposure through food -- the contribution of drinking water is estimated to be only about 0.1% of the total PAH derive]
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Total PAH entry into the marine environment from petroleum spills is estimated at 17 x 104 tons/yr, of which BaP would constitute 20-30 tons/yr.129 Conservative figures for the total world contribution of industrial and domestic wastewaters to marine pollution with PAH have been estimated to be BaP at about 29 tons/yr and total PAH at 4.4 x 103 tons/yr. For terrestrial runoff, the figures are about 118 tons/yr and about 2.9 x 103 tons/yr, respectively, and for atmospheric fallout, 500 tons/yr and 50,000 tons/yr.
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From page 290... ...
In the local marine areas of high PAH pollution -- principally river basins and estuarine and coastal waters -- the degree of PAH contamination and the PAH composition in water, sediments, and nonmigratory marine life are determined by the nature of the point sources of contamination. In the organisms found in these areas, the PAH composition depends on metabolic processes related to the selective bioconcentration, biotransformation, and accumulation of the PAHs or metabolites or their discharge into the aquatic environment.
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From page 291... ...
Seasonal changes in P-450-dependent oxidation have been reported in fish,49 and alterations in this enzymatic activity have been related to ambient temperature, food status, and exposure to inducing chemicals in their natural habitat.48349 Apart from carrying out biotransformation, the capacity of marine species to accumulate and discharge PAHs from the surrounding waters is important in relation to the pattern of distribution of these compounds in the marine environment and to the use of marine species as food, in view of their contribution to the exposure of humans to PAHs via the gastrointestinal tract.
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From page 292... ...
, and half-lives can range from hours to many days. The substantial concentration gradients of PAHs that may occur between an organism and its aqueous environment can have importance for man in r44ali2nl93 marine species that are eaten by man or by edible species.
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From page 293... ...
Edible marine species may contain variable amounts of PAHs derived principally from polluted terrestrial runoff waters, from marine sediments, and from petroleum-contaminated aquatic environments. As noted above, such environments are largely in-shore (e.g., estuaries and river basins)
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From page 294... ...
PAH contamination of foods associated with smoke-curing results in part from the resinous condensates of liquid smoke flavors and from food combustion products.64,lo6,l~o~l77~9l The type of smoke generation and other characteristics of the smoking process can influence the amounts and types of PAHs produced -- e."., the temperature of combustion, the air supply, the length of smoke ducts, and the density and temperature of the smoke-cure. 177 Domestic smoking clearly produces more PAH than the commercial process, 14 probably 6-32
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From page 295... ...
, nor for dietary constituents that are known to have a high PAH content, such as yeast oils some leafy vegetables and fruits, roasted coffee, and teas.24364~653261 PAHs formed by pyrolysis can be derived (at least with pure substrates) from carbohydrates, fatty acids, and amino acids, and the extent of their production depends on temperature.206 The data of Masuda et al.115 (Table 6-24)
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From page 296... ...
also stimulates the oxidative metabolism of these drug substrates; however, neither high-unsaturated-fat nor highsaturated-fat diets produce alterations in drug oxidation distinct from those produced by high-carbobydrate diets alone. Thus, with respect to influences on microsomal mixed-function oxidases, carbohydrate and fat in the diet appear to be interchangeable.
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From page 297... ...
. These systematic and pronounced effects of specific dietary manipulations on the metabolism of model drug substrates by the cytochrome P-450-dependent mixed-function oxidase system provide a valuable means for defining the metabolic responses of both normal and subjects to the ingestion of various foodstuffs or foods prepared ways.
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TABLE 6- 1 PAHs in Human Livera Concentration (wet basis)
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TABLE 6-5 Binding of [3H] Benzotaipyrene to DNA in Human Endometrial Tissue Taken Throughout Mens trual Cycle and Before and After Menopausea Hormonal S tatus Early and midproliferative Late proliferative and early secretory Midsecretory and late Premenopausal Postmenopausal cre tory aReprinted with permission from Dorman et al 52 6-40 [3H]
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From page 303... ...
TABLE 6-6 Effect of PAHs in Cigarette Smoke on Benzopyrene Hydroxylase Activity in Rat Placentaa PAH Control 1,2-Benzanthracene L, 2,5, 6-Dibenzanthracene 3,4-Benzopyrene Chrysene 3,4-Benzofluorene Anthracene Pyrene Fluoranthene Perylene Phenanthrene 8-Hydroxybenzopyrene formed ng/~-h 218 + 81 4 ~ 034 + 5 19 3 ~ 577 + 494 3 $ 543 + 114 33267 + 117 1, 939 + 98 1, 377 + 3 16 1, 232 + 306 1, 123 + 129 805 + 159 721 + 155 aReprinted with permission from Welch et al.l90 bRats pregnant for 18 d were given PAH orally at 40 mg/kg. Placenta was assayed for benzopyrene hydroxylase activity 21 after the dose.
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5,267 15,181 16,524 17,100 aReprinted with permission from Conney et al.42 All subjects in this study were Caucasian, and all smoked 15-20 cigarettes daily during pregnancy. Variability in benzopyrene hydroxylase activity was not related to medication taken during or before delivery.
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From page 305... ...
PAH 7, 12-Dimethylbenzanthracene Benzo ~ a i pyrene 3-Methy 1 cho lanthrene Dibenz ~ ah janthrac~ne TABLE 6-8 Specific Activities of Binding of Tritium-Labeled PAHs t o Human Branch ia 1 DNAa No . Cases 3 4 2 3 Specific Activity .
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From page 311... ...
TABLE 6-14 PAHs in Shale Retort Oils,a ppb ComponentParentMethyl-Substituted Pyrene17,50050,500 Fluoranthene5,6508,050 Benz[a] anthracene1,20012,000 Chrysene2,85023,500 Triphenylene5405,700 Benzota~pyrene4,2508,350 Benzoteipyrene1,9502,650 Perylene3251,015 Anthanthrene275455 Benzotghi~perylene1,9008,650 Coronene aReprinted with permission from Weaver and Gibson-187 6-49 it.
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TABLE 6- 15 PAHs in Drinking Watera Concentration, ng/L Source Mixed tap water at Mainz, Germany Water at :b __ Carc inogenic Total BaP PAH PAH 7.0 Syracuse, NeYo 0 ~ 3 0 ~ 31. 1 Buffalo, N.Y.
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PAN TABLE 6-16 PAHs in Tapwatera Naphthalene 2-Methylnaphthalene 1-Methyloaphthalene -Biphenyl Acenaphthene Dibenzofuran Fluorene Dibenzothiophene Phenanthrene Anthracene 2-Methylanthracene 4,5-Methylenephenanthrene l-Methylphenanthrene Fluoranthene Pyrene Benzota~fluorene Benzotbifluorene 4-Methylpyrene Methylpyrene 1-Methylpyrene Benz~aJanthracene Benzo~b~fluoranthene Benzo~jk~fluoranthenes Benzoteipyrene Benzo~a~pyrene aData from Olufsen~l32 Concentration, ppt 2.9 1.4 1.1 0.32 0.82 0.
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From page 314... ...
TABLE 6-17 PAHs in Extracts from Shucked Oystersa Compound Benz 0 [ah i ~ pe rylene Benzo [ a ] pyrene Benz [ a ~ anthracene Benzo [k]
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TABLE 6- 18 PAHs in Foodstuffsa Concentration, b ~g/kg (wet wt.) Foodstuffs Benzo[a]
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From page 317... ...
TABLE 6-20 PAHs in Foodsa 1 Anthracene 2 Benz an thracene* 3 Methylbenzanthracene 4 Dibenz~aj~anthracene*
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TABLE 6-21 PAHs in Foodstuffsa Concentration, Foodstuff Compound /kg Broiled sausage Benz[ajanthracene 0.2-1.1 Smoked sausage 0.4-9.9 Heavily smoked ham 12 Spinach 16 Crude coconut oil 98 Refined vegetable oil 1 Broiled sausage Benzota~pyrene 0.17-0.63 Charcoal-broiled meat 2.6-11.2 Smoked fish 2.1 Spinach 7.4 Tomatoes 0.2 Crude coconut oil 43.7 Roasted coffee 0.1-4 Tea 3.9-21.3 Cereals 0.2-4.1 Smoked ham Benzoteipyrene 5.2 Smoked fish 1.9 Spinach 6.9 Tomatoes 0.2 Crude coconut oil 32.7 Roasted coffee 0.3-7.2 Roasted peanuts 0.4 Broiled sausage Chrysene 0.5-2.6 Heavily smoked ham 21.2 Spinach 28 Tomatoes 0.5 Cereals 0.8-14.5 Roasted coffee 0.6-19.1 Black tea 4.6-6.3 Spinach Tomatoes Cereals aReprinted with permission from Zedeck. 201 6-56 Dibenz [ah]
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From page 319... ...
TABLE 6-22 Benzota~pyrene in Soilsa Benzota~pyrene Origin and Type of Soil Oak forest, West Falmouth, Mass. Pine forest, West Falmouth, Mass.
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From page 320... ...
TABLE 6-23 PAHs in Charcoal-Brotled Steaksa PI Alkylbenzanthracene Anthanthrene Anthracene Benz[a] anthracene BenzoEb]
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From page 322... ...
TABLE 6-25 Estimated Daily Human Exposure to PAN from Air, Water, and Fooda Source Benzotaipyrene, fig Total PA, Air . 0.0095-0.0435 0.207 Water 0.0011 0.027 Food 0.16-1.6 1.6-16 aReprinted with permission from Santodonato et al.154 6-60 it ...
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From page 323... ...
Human endometrial tissue was incubated for 18 hr in organ culture in medium containing 1 Mt3H)
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From page 324... ...
Incidence and significance of polycyclic aromatic hydrocarbons in the water environment.
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From page 325... ...
Ts'o, Eds. Polycyclic Aromatic Hydrocarbons and Cancer.
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From page 326... ...
Determination of polycyclic aromatic hydrocarbons in oysters collected in polluted water.
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From page 327... ...
Toxicity of aromatic hydrocarbons on normal buman epidermal cells ~n vitro. Cancer Res.
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From page 328... ...
Hildebrandt. Concentration and estimatation of 14 polycyclic aromatic hydrocarbons at low levels in highprotein foods, oils and fats.
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Bioactivation of polycyclic aromatic hydrocarbons in the aorta: Evidence for a role in the genesis of atherosclerotic lesions, pp.
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From page 330... ...
Positive correlation between high aryl hydrocarbon hydroxylase activity and primary lung cancer as analyzed in cryopreserved lymphocytes. Cancer Res.
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From page 331... ...
Joe, Jr. Survey of polycyclic aromatic hydrocarbons in smoked foods.
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From page 332... ...
Di-sassociation between aryl hydrocarbon hydroxylase activity in cultured pulmonary macrophages and blood lymphocytes from lung cancer patients. Cancer Res.
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From page 333... ...
M Polycyclic Aromatic Hydrocarbons in the Aquatic Environment: Sources, Fates and Biological Effects.
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From page 334... ...
Aryl hydrocarbon hydroxylase induction in mouse peritoneal macrophages and blood-derived human macrophages.
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Basu. Health and Ecological Assessment of Polynuclear Aromatic Hydrocarbons.
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Lech. Effect of polycyclic aromatic hydrocarbons on hepatic microsomal enzymes and disposition of methylnaphthalene in rainbow trout _ vivo.
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From page 337... ...
Determination of polycyclic aromatic hydrocarbons in liquid smoke flavors.
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From page 338... ...
S Polycyclic aromatic hydrocarbons : A review.
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From page 339... ...
, X-linked recessive disorders, and chromosomal abnormalities account for only about 5% of the human disease burden, the impact of heterozygous recessively inherited abnormalities similar to the monogenic disorders is very ill-identified, but could outweigh all other contributions.115 The heterozygous recessively inherited disorders may be the major reason why cancer incidences are not uniformly distributed.95397 In fact, of the millions of people exposed to such environmental chemicals as diethylstilbestrol, estrogen oral contraceptives, vinyl chloride, and cigarette smoke, only a very small proportion develop or express the cancer thought to be associated with these exposures. It is likely that genetic variability within the human population accounts in part for the distribution pattern.
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From page 340... ...
Concentrations of a variety of PAHs (e.g., pyrene, anthracene, and BaP) in human tissues average about 1,100 parts per trillion (ppt)
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From page 341... ...
In rodents, the induction of the microsomal monooxygenase system by some PAHs depends on the presence of particular cytosol receptor proteins.56314231 3 These receptor proteins are not evenly distributed in all tissues, but are highest in thymus and lung, lower in liver and kidney, lower yet in testes, brain, and skeletal muscle, and not detectable in pancreas, adrenal, or prostate.l5 Most importantly, receptor proteins are found in high concentrations in strains of animals or cultured cells in which PAHs induce the enzyme aryl hydrocarbon hydroxylase (AHH) and are nondetectable in those in which AHH is nonrespons ive .
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From page 342... ...
' 3 Blood monocytes and pulmonary alveolar macrophages are examples of other human cell types whose AHH activity is Correlated with that in lymphocytes or cultured human tissue, but there are problems of accessibility with each of these cell types. If the cell samples are cultured and assayed on the same days, the v5r~2t~30 seems to be ac3eptable.5°379 Culturing lymphocytes ~ ~ or monocytesl2 from fraternal or identical twins at the same time has shown that AHH activity is under a degree of genetic control, and the numbers of genes in question are probably small.
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From page 343... ...
. O The 14 highest AHH activities were found in patients with lung cancer, with the mean in the 21 lung-cancer patients (0.89 unit AHH/unit Cyt _)
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From page 344... ...
found, including interactions with the N4 deoxyadenosine,177 the backbone phospt~tl,70f ONA, 1 and the exocyclic amino group of deoxyadenosine. ~ The latter may be important, because its formation from various PAH-like chemicals closely parallels their carcinogenic potencies on mouse skin.27 No apprec~,b{~ syggificity of binding with respect to base sequence is apparent, ~ 8, but binding may be influenced by chromatic structure, with a greater extent of binding associated wi th internuc leosomal regions.6 ,76 ' A potentially important anomaly is that, although in vitro metabolism of BaP to forms that bind to DNA parallels the AHH activity of the microsomal preparations and the Genetic background of mice used to generate these microsomal samples,13 the in viva results from strains of mice that differ widely in ASH activity so that there is very little strain variation in BaP-DNA binding.
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From page 345... ...
Those who are heterozygous for ataxia telangiectasia and are less than 45 yr old have a fivefold increase in the risk of cancer,180 and those heterozygous for Fanconi's anemia may account for 5% of all leukemia deaths (approximately a fivefold increase in susceptibility) .179 Because these people are deficient in the ability to repair radiationinduced DNA damage and chemical-induced DNA damage, 169 it has been suggested that alteration in DNA-re~air capacity may put them at greater risk of chemically induced cancers.
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From page 346... ...
For example, persons with ataxia telangiectasia and Bloom's syndrome have severely impaired DNA-repair capacities,169~195 and those with severe combined immunodeficiency also have adenosine deaminase deficiency.73 Therefore, it is difficult to determine the reasons for the increased cancer susceptibility of these persons. Epidemiologic evidence fails to support the idea that immunosurveillance mechanisms are generally involved in carcinogenesis 5 but does provide clues to immunologic processes that may predispose to particular neoplasms.38 In animal-model systems, PAHs can cause tumors of the lymphoreticular system, and association with the Ah locus has been suggested.29~113 In humans, exposure to some hydrocarbons, such as benzene, has been repeatedly associated with leukemia.
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From page 347... ...
137 Maternal cigarette-smoking is associated with decreased birthweight, increased perinatal morbidity and mortality, and other harmful effects on the newborn.l41 The PAHs in cigarette smoke may account for some of its biologic activity, inasmuch as a relationship has been shown between cigarette-smoking, induction of AHH activity in human placental tissue,ll4'l98 and a decrease in placental size;135 PAHs are the major class of AHH inducers found in cigarette smoke, 83 and thus it is important to note that BaP, which is in cigarette smoke, can cross the placental barrier.92 Because PAHs must be metabolized before they produce a biologic effect, the impact of PAHs on maternal and fetal tissues can be quite complex. Some examples of these complexities are differences in developmental patterns of specific enzymes, the relative importance of maternal and fetal metabolism, the role of metabolism in placental tissue, the relative importance of hepatic and extrahepatic metabolism, and sex differences in developmental patterns.
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From page 348... ...
, PAHs can be taken up and distributed through the placenta intact or in the form of metabolites, that the metabolites themselves can cause fetal toxicity or the delayed effects of immune suppression or cancer, and that intact PAHs can cause fetal enzyme induction, metabolism, and the sequelae mentioned earlier. MODIFYING FACTORS A variety of environmental factors can mitigate or exacerbate the inherent sensitivity of mammalian tissues to PAHs.
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