Polycyclic Aromatic Hydrocarbons Evaluation of Sources and Effects (1983) / Chapter Skim
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4 BIOLOGICAL EFFECTS OF SMOKE, EMISSION, AND SOME OF THEIR PAH COMPONENTS
4 BIOLOGICAL EFFECTS OF SMOKE, EMISSION, AND SOME OF THEIR PAH COMPONENTS
Pages 145-206
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From page 145... ...
Emission from spark-ignition combustion and diesel engines has been tested for mutagenic activity in the Salmonella system.27~79~83~10l It is known that particulate emission from light-duty diesel engines is considerably greater than that from light-duty catalyst-equi~ped spark-ignition engines -- i.e., 0.2-1.0 vs. 0.006-0.02 g/mi.l4 Table 4-8 presents data of Claxton 8 relative to comparative mutagenic activity of emission of diesel and spark-ignition engines, of cigarette-smoke condensate, of coke-oven emission, of roofing-tar emission, and of BaP (positive control)
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From page 146... ...
pyrene proved the most mutagenic; it was also present in the highest concentration (see Table 4-11~. C~cloyentatcd~pyrene is a known component of all soots, 53' 74' 75 of cigarette smoke,l59 of automobile exhaust,57 and of coal fly ash.25 The sum of the mutagenicities of the identified individual PAHs was slightly greater than that of the kerosene-soot extract itself.
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From page 147... ...
that the concentration of nitropyrene alone in diesel particulate extracts could account for 13-24: of the total direct mutagenic activity with-TA 98. Tokiwa et al.170 have assayed the mutagenicity of the nitrophenanthrenes, 1-nitropyrene, 3-nitrofluoranthene, and 6-nitrochrysene.
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From page 148... ...
A similar situation occurred with the trinitropyrenes and tetranitropyrene. The mutagenic activity of 1,8-dinitropyrene is the highest ever recorded in the 1 iterature, 112 The presence of the 1, 6- and 1,8-dinitropyrenes as predominant mutagenic components in dieselparticle extract has been confirmed by Pederson and Siak,124 who estimated that 15-20: of the total mutagenic activity of the extract may be contributed by these dinitropyrenes (in addition to as much as 24t contributed by 1-nitropyrene)
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From page 149... ...
What is needed is additional experimentation on the mechanism of action of the nitrated PAHs in both bacterial and mammalian-cell systems. Sister chromatic exchange has been used to assess genotoxic activity of various kinds of emission.
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From page 150... ...
These investigators determined SCE induced by BaP with human lymphocytes obtained from normal persons and lung-cancer patients; no difference was observed. Guerrero et al.58a intratracheally exposed Syrian hamsters to 200 ng of BaP over a 10-wk period, examined in vitro cultures of lung tissue for sister chromatic exchange (SCE)
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From page 151... ...
Schmahl and colleagues extended these studies by determining whether groups of nonactive PAHs would interact with the carcinogens in a synergistic or inhibitory manner.149 The proportions of the various compounds were chosen on the basis of their relative concentrations in automobile exhaust. The groups of carcinogens and noncarcinogens are shown in Table 4-21, and the percent tumor formation after lifetime application is shown in Table 4-22.
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From page 152... ...
The subcutaneous injection of AEC and fractions thereof into mice produced sarcomatous lesions;135 administration of 20-60 mg yielded tumors in up to at of mice, and administration of 10 or 90 fig of BaP yielded tumors in 17t or 75t of the animals, respectively. Simultaneous administration of 20 mg of AEC with 90 fig of BaP yielded lower tumorigenesis.
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From page 153... ...
Neal and Rigdonl2l, 40 have examined the effects of oral administration of BaP on tumor formation in mice. No gastric tumors developed in any of the 289 mice that were fed a control ration; the incidence of tumors in the BaP-fed mice depended on concentration in the food and on the number of days of feeding.l2l These investigatorsl40 also established that the incidences of pulmonary adenomas, gastric tumors, and leukemia in BaP-fed mice were genetically determined.
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From page 154... ...
Tumor-initiating activity of several of these alkylated PAHs was determined with the mouse-skin two-stage carcinogenesis model.l°° In a series of fluorene, 9-methylfluorene, 1,9-dimethylfluorene, benzota~fluorene, benzo~b~fluorene, benzotcifluorene, 11-methylbenzo~a~fluorene, 11-methylbenzotbifluorene, and 7-methylbenzotcifluorene, only 11-methylbenzotb~fluorene resulted in a marked increase in tumorigenicity. All other compounds exhibited rather weak initiator activity.
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From page 155... ...
Approximately half of tobacco smoke consists of particulate constituents in which over 2,000 compounds are represented. The carcinogenicity of cigarette smoke was demonstrated ~hrough skin application to the backs of mice and the ears of rabbits7 and has been confirmed repeatedly in a number of laboratories.
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From page 156... ...
However, the combination of tar and PAHs resulted in tumor formation in 55% of the mice at 13 wk. whereas tar alone yielded tumors in only 18% of the mice.
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From page 157... ...
TABLE 4-l Categories of Short-Tenm Testsa Category Tests in bacteria and phage Tests in eukaryotic microorganisms Mammalian-cell mutagenesis tests In vitro transformation tests No. Methods Identified 13 19 21 18 Tests of DNA repair and other effects 14 In viva tests in mammals Tests in insects Mammalian cytogenetics tests 14 4 13 aData from Hollstein et al.74 Many assays detect the same genetic event, but are considered separate systems because of other differences, such as in target organism or cell line.
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From page 158... ...
. Mammalian mutagenesis tests: Mouse lymphoma TK +/ CHO/HGPRT Chinese hamster V79 BALB 3T3 OuaR Insect test: Drosophila sex-linked recessive-lethal test In viva tests in mammals: Sperm-abnormality test Dominant-lethal test Mouse specific-locus spot test 4-24 Sister chromatic exchange · ~ In VlVO Sister chromatic exchange in vitro Chromosomal aberrations in viva Chromosomal aberrations in vitro Micronucleus test Tests of DNA effects and other effects: Unscheduled DNA synthes is (UDS)
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From page 159... ...
Mammalian somatic cells in culture, with and without metabolic activation Mouse specific-locus test For detecting chromosomal aberrations, three of the following In vivo cytogenetics tests in mammals Insect tests for heritable chromosomal effects Dominant lethal effects in rodents Heritable-translocation tests in rodents For detecting primary UNA damage, two of the following: DNA repair in bacteria, with and without activation Unscheduled DNA synthesis (repair test) in mammalian cells, with and without act iva Lion Mitotic recombination and/or gene conversion in yeast cells, with and without act ivation Sister chromatic exchange (SCE)
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From page 160... ...
enzyme activity Mammalian-cell point-mutation assay with and without exogenous metabolic activity For detection of chromosomal damage: In viva cytogenetics assay in rodents In vitro cytogenetics assays with and without exogenous metabolic activity: Sister chromatic exchange Chromosomal aberrations 4-26
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From page 161... ...
- TABLE 4-5 Genetic Markers Developed in Cultured Mammalian Cells Resistance to cytotoxic chemicals -- e."., 8-azaguanine (8-AGR) , 6-thioguanine (6-TGR)
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From page 162... ...
TABLE 4-6 Markers for Evaluating Mutagenesis in Cultured Mammalian Gel Is Merits ~ _ Purine-analogue rests Lance Specificity: Low spontaneous background No lethal mutants, because non essent ial pathway involved Detects both base-pair and frameshift alterations, with latter more efficient Dominance: X-linked 5-Bromodeoxyuridinea resistance Specificity No lethal mutants, because nonessential pathway involved Detects both base-pair and frameshift alterations, with latter more efficient May detect chromosomal alterations Expression time: short Ouabain resistance Specificity: low spontaneous background Dominance: independence of ploidy and genotype Artifacts: minimal aTrifluorothymidine also used. Limitations .
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From page 163... ...
Period of usefulness in tenms-of sensitivity to focal transformation by chemical carcinogens is unknown 2. Aneuploid 3 .
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From page 164... ...
Some Aye t ems require genetical ly aberrant 2. Diploid chromosome target cells compl emen t ~ s ome sys tems ~ 3.
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From page 165... ...
TABLE 4-8 Mutagenic Activity of Various Particulate Emissions and of Cigarette-Smoke Condensates, Compared with Benzo~a~pyrenea Source of Emission Mutagenic Activity, revertants/ 100 fig of organic material Without S-9 With S-9 Spark-ignition engine138 342 Diesel engineb66 Unaltered 1,225 Unaltered Cigarette-smoke condensates0 - 98 Coke ovens164 252 Roofing tarO 99 Benzotaipyrene0 15,202 aData from Claxton,28 who used TA98 strains of with and without the S-9 activating systems. lmonella tyRhimurium bDifferent values were obtained for various diesel engines; the lowest and highest are given here.
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From page 166... ...
TABLE 4-9 Influence of Alcohol on Direct Mutagenicity of Particulate Extracts of Spark-Ignition-Engine Exhausta Particulate TA 100 Revertants/ Emission, Revertants/ Vehicle and Fuel g of Extract mg/mi mile Ford Escort: Gasoline 10 1.5 15,000 Ethanol blendb 9 1.1 9,900 Gasohol 4 1.2 4,800 01 dsmob lie Cutlass: Gasoline 10 1.7 17, 000 Ethanol blendb 5 0.6 3,000 Gasohol 13 0.6 7,800 Chevrolet Citation: Gasoline 17 1.9 32,300 Ethanol blendb 14 0.9 12,600 Gasohol 10 1.0 10,000 Mercury Monarch: Gasoline 16 7.1 114,000 Ethanol blendb 12 2.8 34,000 Gasohol 20 1.1 44,000 aData from Naman and Clark.l19 Ego% gasoline-10% ethanol .
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From page 167... ...
DO x us a 0 1_ U' ~ U]
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From page 168... ...
determined the amounts of the individual PAHs in the kerosene soot and, knowing the mutant fractions that these amounts would induce from a dose-response curve, were able to estimate mutagenic contributions that compounds would elicit. The induced mutant fraction = [(no.
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From page 169... ...
TABLE 4-12 Mutagenic Efficacy of PAHs in Relation to Benzo[a] pyrenea Concentration, Relative Mutagenic Compound~g/ml Potencyb 2-M~thylanthracene15.4 0.15 9-~ethyLanthracene14.4 0.08 1-Methylphenanthrene15.4 0.50 2-~ethylphenanthrene7.7 0.30 Pyrene28.3 0.07 1-Methylpyrene17.3 0.05 Cyclopen-ta[cdipyrene13.9 1.51 Benz~aianthracene14.8 0.14 Chrysene10.3 0.20 1,2-Benzodibenzothdithiophene117.0 -o Fluoranthene1.0 1.00 Benzota~pyrene1.3 1.00 Benzoteipyrene22.7 0.11 Perylene2.8 6.00 Anthanthrene12.1 0.08 Dibenz~ac~anthracene3.6 0.77 Dibenz~ahianthracene20.9 0.08 Coronene51.0 0 or Anthracene40.0 0 or Phenanthrene or Dibenzotbdithiophene v, aData from Kadin _ al.°~ 53.4 55.2 o bRelat~ve to benzo~a~pyrene, set at 1.00; rate-limiting factor is concentration that produced too much cell death.
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From page 170... ...
TABLE 4-13 Mutagenicity of Nitrated Pyrenes in Salmonella typhimur~um TA 98 and TA 98 NRa CompoundTA 98b TA 98 NRb TA 98/TA 98 NR 1-Nitropyrene484 35 14 1,3-Dinitropyrene28,600 4,900 5.8 1,6-Dinitropyrene36,350 37,850 1.0 1,8-Dinitropyrene75,500 75,500 1.0 1, 3,6-Trinitropyrene31,400 28,220 1.1 1,3,6,8-Tetranitropyrene7,700 5,200 aData from Mermelstein _ al.112 1.5 bStrains TA 98 and TA 98 NR are nitroreductase-positive and -negative respectively.
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From page 171... ...
b Occurrence Control Benzo~a~pyrene 36 0.5 78 2.0 277 Dibenzo~bd~thiophene 20.0 27 Tobacco smoke Phenanthrot4,5-bod] - O.S 73 Coal tar; thiophene 1.0 85 carbon black Benzotbinaphtho- 10.0 44 [2,1-dithiophene Renzo[2,3Jphenanthro- 0.5 122 Coke-plant t4,5-bedlthiophene effluent Triphenylenet4,5-bed]
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From page 172... ...
Mutant cells were selected for resistance to 6-thioguanine. bConcentration of test agent yielding mutation frequency of 5 x 105 CExtracts obtained from two different engines.
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From page 173... ...
Diesel exhausts from one heavy-duty and two light-duty engines are included; former yielded lower value.
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From page 174... ...
TABLE 4-17 Induction of Ouabain- and 8-Azaguanine-Resistant Mutants by PAHsa Mutants/106 Survivors_ Cloning Treatmentb Efficiency, ~Resistant Resistant Solvent 92 1 6 Pyrene 94 1 5 Phenanthrene 79 1 8 Chrysene 85 2 9 Benz~ajanthracene 92 2 9 Dibenz~ac~anthracene 95 3 22 Dibenz~ah~anthracene 79 4 17 7-Methylbenz~a] - 61 24 75 anthracene Benzo~a~pyr~ne 27 45 - 128 (0.3 ~g/ml)
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From page 175... ...
TABLE 4-18 Weight Proportion of Various PAHs in a Simulated "AEC" Mixturea Component Benzo[~] phenanthrene Cyclopentenopyrene Benz~aJanthracene Chrysene Benzotbifluoranthene Benzo~k~fluoranthene Benzo~j~fluoranthene Benzota~pyrene 1,12-Methylenebenzoteipyrene 10,11-Methylenebenzotaipyrene Dihenzo~aj~anthracene Indenot1,2~3-cd~pyrene Dibenz~ah~anthracene aData from Misfeld.ll4 I; 4-41 Weight, fig 0.08 1.85 O .09 0.21 0.17 0.06 0.09 0.30 0.14 0.05 0.10 0.21 0.02 ^.
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From page 176... ...
TABLE 4- 19 Carcinogenic Activity of AEC, DEC, and PAHs on Mouse Skina Treatment, ~ g ~ Tumors Latency Period, wk Solvent `:ontrol o Benz ota] pyrene: 3.85 32.8 7 .69 60.9 74 61 15 .4 89 .1 44 AEC :b 290 10.3 72 880 44 .3 2, fi30 83 .3 72 52 DEC: b 4, 300 00 8, 600 2 .6102 l7, 150 12.7 Mixture of PAHs: I: aData from Misfeld.
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From page 177... ...
46 0.2 0.3 o 0.1 0.3 Mustang gasoline-engine exhaust 0.1 Cigarette-smoke condensate aData from Slaga et al.158 o bMaterial was applied to mice once as initiator. TPA (2 Egg, twice a week, was used as promoter.
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From page 178... ...
Carcinogens Benzo[a] pyrene Dibenz~ahianthracene Benz[~]
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From page 179... ...
TABLE 4-2 2 Carcinogenicity of PAHs in Combinationa Treatment, pg Solvent . O Benzo ~ a ~ pyrene: 1 .0 14 1.7 ~28 3.0 56 Carcinogens: 4.0 36 6.8 68 12.0 71 Noncarc inogens: 6 5 1 195 585 1, 755 Papillomas + Carcinomas o 1 17 Carc inogens + noncarc inogens: 69 5 0 117.3 60 207 .0 70 aData from Schmahl et al.149 .^ 4-45 it.
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From page 180... ...
TABLE 4-23 Tumor-In i t fat ing Act iv i ty of C igaret te-Smoke Ingredient sa Relative Tumorigenic: Concentration, Compound Activityb ng/cigarette B~nzo~a~pyrene +++ 10-50 5-Me thylchrys ene +++ 0 . 6 Dibenz ~ ah ~ anthra`:ene ++ 40 Benzo~b]
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From page 181... ...
o o o 0/+ o o o + o o 0/+ o ++ 'O ++ o o o + 0/+ + ++ ++ ++ 4-47 Relative In Vitro Mutagenic Act ivi tyb Animal O O o O O + + Ba`:teria ++ + o + + ++ ++ +++ +++ ++++ +++ ++ ++ ++ +c ++d +d o + + + + + , ....
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From page 182... ...
2-, 3-, or 6-Methyl-DBA 7-Methyl-DBA Coronene Benz[aJacridine Dibenzo[bd~thiophene Dibenz~ac~anthracene Carcinogenic Activitya ++ ~+ ~ or 12 ++ + o ++ 0/+ o ++ + + + ++ o/+ + + In Vitro Mutagenic Activit b _ Y Animal Bacteria ++ ++ + + O ++ ++ ++ + ~ O O o + + 80, no tumors; +, tumors in up to 33% of animals; ++, tumors in over 337 of the animals. bBenzo~aipyrene mutagenicity set at ++ ~7-Methyl-BA.
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From page 183... ...
In vivo induction of sister chromatic exchanges by three polyaromatic hydrocarbons, pp.
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From page 184... ...
Rutter. Nitrated polycyclic aromatic hydrocarbons: Potent bacterial mutagens and stimulators of DNA repair synthesis in cultured human cells.
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From page 185... ...
Sister chromatic exchange in marine alveolar macrophages, bone marrow, and regenerating liver cells induced by styrene inhalation. Toxicol.
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From page 186... ...
A] on the skin tumor initiating activity of polycyclic aromatic hydrocarbons, pp.
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From page 187... ...
Leber, Eds. Polynuclear Aromatic Hydrocarbons: 3rd International Symposium on Chemistry and Biology -- Carcinogenesis and Mutagenesis.
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From page 188... ...
Viral antigen induction and mutability of di'fferent genetic loci by metabolically activated carcinogenic polycyclic aromatic hydrocarbons in cultured mammalian cells, pp.
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From page 189... ...
Mutagenicity of soot and associated polycyclic aromatic hydrocarbons to Salmonella typhimurium. Cancer Res.
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From page 190... ...
Linblad. Sister chromatic exchanges in lymphocyte cultures of patients receiving chemotherapy for malignant disorders.
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From page 191... ...
Wolff. Increase of sister chromatic exchanges and perturbations of cell division kinetics in human lymphocytes by benzene metabolites.
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From page 192... ...
E Chemical mutagens and sister chromatic exchanges, pp.
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From page 193... ...
Atmospheric reactions of polycyclic aromatic hydrocarbons: Facile formation of mutagenic nitro derivatives. Science 202:515-519, 1978.
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From page 194... ...
W.- Rudiger. Benzpyreneinduced sister chromatic exchanges in lymphocytes of patients with lung cancer.
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From page 195... ...
The identification of high molecular weight polynuclear aromatic hydrocarbons in a biologically active fraction of cigarette smoke condensate. Beitr.
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From page 196... ...
Sister chromatic exchange.
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From page 197... ...
Finally, there is a discussion of the possibility of using PAH metabolite-DNA adduct content as a measure of effective biologic dose for in vitro mutagenesis, initiation of carcinogenesis, and inhibition of replication and transcription. PHARMACOKINETICS Many phanmacokinetic and enzymatic processes are involved before a PAH reaches a target cell and is metabolized to reactive metabolites that interact with DNA and other cellular macromolecules free Figure 5-1~.
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From page 198... ...
Moreover, PAR metabolite-DNA adduct content in various tissues is not linearly related to exposure dose (as discussed later)
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From page 199... ...
5 However, some recent studies have suggested that particulate adsorption of PAHs does not alter retention time in the lung or their distribution to other tissues. Adsorption on ferric oxide did not increase the retention time of BaP in hamster lung after intratracheal instillation.57 Pylev et al.l55 examined the clearance of intratracheally instilled BaP from the hamster lung; the disposition and clearance from liver, kidney, and blood; and excretion into feces and urine.
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From page 200... ...
The in vivo formation of PAH metabolite-DNA adducts is discussed later in this chapter. These biochemical changes to biologically active intermediates depend on the balance between enzyme systems: those enzymes generating and those detoxifying the intermediates.
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From page 201... ...
* The bay region is a molecular region between adjacent fused aromatic rings (see reference 115~.
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From page 202... ...
It contains two bay regions and, by theoretical calculations, should approximate BaP in carcinogenic activity. Metabolic studies have determined that the probable reason for its lack of carcinogenicity is that its major metabolism is distal to the bay region, so that the molecule does not favor formation of diol-epoxide intermediates.
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From page 203... ...
anthracene is a marginally carcinogenic PAN that has both bay-region and K-region areas. The original metabolic studies with benz~a~anthracene were done with thin-layer chromatography .21 ,26-28 ,75, 169, 171 (See reference 115 for explana~ Lion of the K-region.
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From page 204... ...
OH 3-tlydroxy 1 OHM; S-Bydroxy HO H on 8, 9-Dlhytso-8, 9~dltydroxy Benz 1e ] anthracene .; S
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From page 205... ...
sulfate and glucuronic conjugates at the 3, 4, 8, and 9 positions, presumably as products of phenols; and 10,11-dihydro-10,11-dihydroxybenz~ajanthracene were also reported. The 3,4-dihydro-3,4-dihydroxy derivative of benz~aJanthracene was later confirmed with high-pressure liquid Chromatography as a metabolite formed by rat-liver microsomes.1 7 This 3,4-dihydrodiol adjacent to a bay region leads to the idea of benz~aJanthracene bay-region activation, including the possibility of an isolated double bond in the 1,2 position after formation of a diol-epoxide.
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From page 206... ...
Several of these metabolites have been identified with the use of synthetic standards.122 Three dihydrodiols have been characterized: the 1,2-, 3,4-, and 5,6-dihydrodiols. This metabolic profile has been concerned with the use of rat or mouse skin-organ culture.l23 The dihydrodiol metabolites are presumably formed through reactive epoxide intermediates by the P-450 mixed-function oxidases.
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