Specificity of DNA damage in chemical carcinogenesis.
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Suramin, a polyanionic and polycyclic compound, was initially used for the treatment of trypanosomiasis and onchocerciasis. In the last decade, it has been used in therapy of cancer and acquired immune deficiency syndrome (AIDS). The influence of suramin on the expression of various markers by human mononuclear phagocytes is not known and was, therefore, presently investigated. Suramin inhibited the proliferation of U937 cells and mitogen-induced T-cell proliferation in a dose-dependent manner. The constitutive and cytokine-driven expression of Fc receptors for IgG (Fc gamma RI and Fc gamma RII), IgE (Fc epsilon RII) and IgA (Fc alpha R) on blood monocytes and U937 cells was suppressed by suramin. The basal level, as well as cytokine-induced major histocompatibility complex (MHC) class II antigens, was markedly diminished on suramin-treated monocytes. Furthermore, suramin dramatically reduced expression of CD14 and partially reduced complement receptor type 3 (CR3) and CR4 expression on monocytes. In contrast, suramin slightly induced MHC class I antigens on monocytes and CD71 on U937 cells. The capacity of monocytes to phagocytose IgG-sensitized ox erythrocytes, opsonized Escherichia coli, or fluorescein isothiocyanate (FITC)-conjugated latex beads was significantly inhibited. Northern blot analysis showed that the amount of Fc epsilon RII-specific mRNA was only partially reduced, suggesting that other mechanisms may be involved in the regulation of Fc epsilon RII expression. Our data demonstrate that suramin suppresses the expression of various cell-surface structures on human mononuclear phagocytes and impairs their phagocytic capacity.
The balance between catecholamine (CA) release and reuptake is closely regulated and determines the effective level of transmitter at the synaptic cleft. Drugs that block CA uptake have potential utility as antidepressant medications. One such drug is racemic (+/-)-(1' R*,3R*)-3-phenyl-1-[1',2',3',4'-tetrahydro-5',6'- methylenedioxy-1'-naphthalenyl-methyl]-pyrrolidine methanesulfonate (A-7500), a novel polycyclic compound developed at Abbott Laboratories. This compound is known to bind to CA transporters in the central nervous system, however, its effects on an intact neurosecretory system have not been studied. In this regard, norepinephrine (NE) release from bovine adrenal chromaffin cells (BACC) is a classic model system for CA release and is an excellent system in which to examine the effects of drugs which modulate neurotransmitter release. We compared the effects of A-75200 and its two constituent enantiomers, A-74111 and A-74112, to the effects of three well-characterized uptake inhibitors, desipramine (DMI), nomifensine and cocaine. We found that the Abbott compounds inhibit [3H]norepinephrine ([3H]NE) uptake with an EC50 comparable to cocaine. In addition, unlike nomifensine and cocaine, these compounds inhibited nicotine- and K(+)-stimulated NE release, whereas histamine-stimulated release was preserved. Thus, the Abbott compounds block the effects on secretion of two agonists (nicotine and K+) which depend on a depolarization-dependent influx of extracellular calcium. We conclude that in addition to blocking NE uptake by inhibiting the NE transporter, the Abbott compounds may modulate peripheral NE release by inhibiting calcium flux through voltage-gated channels. This study demonstrates the utility of bovine adrenal chromaffin cells for preclinical trials of drugs that affect catecholaminergic neurotransmission.
As part of the remediation process at a former creosote-handling facility in Washington, target groundwater concentrations were developed as goals for the planned cleanup efforts. Considering state regulatory requirements and site-specific conditions, these concentrations were established to protect surface water in the lake adjacent to the site. These risk-based values were calculated assuming that chemicals will (1) be transported in groundwater, (2) discharge into the lake, and (3) be taken up by aquatic organisms that may be consumed by humans. Among the primary chemicals driving remediation decisions at this site are carcinogenic polycyclic aromatic hydrocarbon (cPAH) compounds, which have limited environmental mobility and are metabolized by many types of potentially edible aquatic organisms. This work included assessing the validity for cPAH compounds of the required default regulatory assumptions and deriving alternative risk-based concentrations. These analyses focused on factors that would modify the generic assumption regarding bioconcentration of cPAH compounds in aquatic biota and influence bioavailability of cPAH compounds to humans consuming the biota. Modifications based on these factors and the use of toxicity equivalency factors resulted in alternative risk-based concentrations for individual cPAH compounds that ranged from approximately 7 to 700 times greater than the default value of 0.03 microg/l.
A seven-year study was conducted to assess the effectiveness of hybrid poplar trees to remediate polycyclic aromatic hydrocarbon (PAH) compounds in soil and groundwater at a creosote-contaminated site. A reduction in the areal extent of the PAH plume was observed in the upper half of the 2-m-thick saturated zone, and PAH concentration levels in the groundwater declined throughout the plume. PAH concentrations began to decline during the period between the third and fourth growing seasons, which coincided with the propagation of the tree roots to the water table region. Remediation was limited to naphthalene and several three-ring PAHs (acenaphthylene and acenaphthene). PAH concentrations in soil and aquifer sediment samples also declined over time; however, levels of four-ring PAHs persisted at the lower depths during the study period. The naphthalene to total PAH concentration ratio in the most contaminated groundwater decreased from >0.90 at the beginning of the second growing season to approximately 0.70 at the end the study. Remediation in the lower region of the saturated zone was limited bythe presence of a 0.3-m-thick layer of creosote present as a dense nonaqueous phase liquid (DNAPL). The nearly steady-state condition of the PAH concentrations observed during the last three years of the study suggests that the effectiveness of the phytoremediation system is limited by the rate of PAH dissolution from the DNAPL source.
This study evaluated the microbial degradation of naphthol, naphthalene, and acenaphthene, under aerobic, anaerobic, and denitrification conditions in soil-water systems. Chemical degradation of naphthol and naphthalene in the presence of a manganese oxide was also studied. Naphthol, naphthalene, and acenaphthene were degraded microbially under aerobic conditions from initial aqueous-phase concentrations of 9, 7, and 1 mg/liter to nondetectable levels in 3, 10, and 10 days, respectively. Under anaerobic conditions naphthol degraded to nondetectable levels in 15 days, whereas naphthalene and acenaphthene showed no significant degradation over periods of 50 and 70 days, respectively. Under denitrification conditions naphthol, naphthalene, and acenaphthene were degraded from initial aqueous-phase concentrations of 8, 7, and 0.4 mg/liter to nondetectable levels in 16, 45, and 40 days, respectively. Acclimation periods of approximately 2 days under aerobic conditions and 2 weeks under denitrification conditions were observed for both naphthalene and acenaphthene. Abiotic degradation of naphthalen and naphthol were evaluated by reaction with manganese oxide, a minor soil constituent. In the presence of a manganese oxide, naphthalene showed no abiotic degradation over a period of 9 weeks, whereas the aqueous naphthol concentration decreased from 9 mg/liter to nondetectable levels in 9 days. The results of this study show that low-molecular-weight, unsubstituted, polycyclic aromatic hydrocarbons are amenable to microbial degradation in soil-water systems under denitrification conditions.
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Three polycyclic hydrocarbons, benz(a)anthracene, 3-methylcholanthrene and 7,12-dimethylbenz(a)anthracene, have been studied in a cell-mediated mutagenesis system using BHK 21 cells to metabolize the hydrocarbons and V-79 cells as targets for detecting induced cytotoxicity and mutation. In large-scale experiments, the DNA of V-79 cells was analyzed by column chromatography to determine the nature and true extent of reaction of hydrocarbons with dexoyribonucleosides. Products with DNA formed by the two carcinogenic compounds were qualitatively very similar to those reported to occur in vivo and in primary cell cultures. Binding indices were calculated from the tritium content of DNA-hydrocarbon products, related to overall metabolism, for these two compounds together with benzo(a)pyrene and 7-methylbenz(a)anthracene using data from a previous study. These values reflected differences in carcinogenic potency between the compounds. Induced mutation frequencies were related to the extent of DNA reaction with each compound. At equivalent extents of DNA reaction with hydrocarbon products, levels of induced mutation were not significantly different.
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Polycyclic aromatic compounds such as polycyclic aromatic hydrocarbons or aromatic amines presently are considerably underestimated with regard to the formation of environmentally caused cancer diseases. The individual urinary metabolite profile raising from the PAH inhaled is invariant. This holds for tar-pitch aerosol exposed Wistar rats as well as for PAH-exposed workers. Significant individual differences of the urinary metabolite profile can be observed in different individuals. The differences reflect the different individual enzyme equipment. There is an individual correlation between the PAH-masses inhaled and the masses of their metabolites excreted in the urine; e.g. the excretion of phenanthrene varies from 5% to 20% for different coke workers. The PAH metabolite profile analysis appears to be a suitable tool to estimate the individual cancer.risk at PAH-exposed working places since the PAH-induced malign transformation is caused by specific PAH metabolites.
A mortality study was carried out among the workers of a plant that had produced ferrochromium and stainless steel, and was still producing stainless steel, in order to determine whether exposure to chromium compounds, to nickel compounds, and to polycyclic aromatic hydrocarbons (PAH) could result in a risk of lung cancer for the exposed workers. The cohort comprised 2269 men whose vital status were recorded between 1 January 1952 and 31 December 1982. The smoking habits of 67% of the cohort members were known from medical records. The observed numbers of deaths were compared with the expected ones based on national rates with adjustment for age, sex, and calendar time. A low mortality, achieving statistical significance, was found from all causes (observed = 137, standardised mortality ratio (SMR) = 0.82) and from benign respiratory diseases (observed = one, SMR = 0.15). With regard to mortality from lung cancer, a non-significant excess appeared in the whole cohort (observed = 12, SMR = 1.40). Among the exposed workers, however, a significant lung cancer excess was found (observed = 11, SMR = 2.04) that contrasted with a low SMR (0.32) in the non-exposed group. This excess is unlikely to be explained by smoking, as the tobacco consumption of these two groups was similar. No trend was observed for mortality from lung cancer either according to time since first exposure, or according to duration of exposure. A nested case-control study clearly suggested that this excess of deaths from lung cancer was attributable to former PAH exposures in the ferrochromium production workshops rather than to exposures in the stainless steel manufacturing areas.
Mytilus edulis were collected intertidally from three locations in Halifax Harbor, Nova Scotia, on five occasions during spring and summer 2000. Bioindicators of health (lipid content), condition and gonad indices (CI and GI), and sex ratio, as well as vitellins, were compared with the bioaccumulation of polycyclic aromatic compounds (PACs) including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), coprostanol, and metals. Twice as many male as female mussels were collected from a downtown site (M8) close to numerous raw sewage effluents and a naval dockyard. Males from M8 had a high lipid content, and females had a delayed production of vitellins. These mussels also displayed the highest levels of PACs, coprostanol, Ag, and Sn. Coprostanol and silver are sewage markers in sediments, and their presence in mussels confirms exposure to sewage effluents. Female mussels were more abundant in an area outside the industrialized part of the harbor that had higher marine traffic (M14); displayed higher levels of vitellins in gonads; had similar time trends for CI and GI; and had some similar metals compared with mussels from M8. The lowest variability in biomarkers was observed at a site in a mostly residential arm of the harbor (M12), which was expected to be more pristine based on an earlier investigation. Compared to mussels in M14, the mussels of M12 had the lowest condition indices and PCB concentrations and low but similar levels of lipids, PACs, and coprostanol. They also displayed the highest concentrations of Cd, Cu, Pb, and Hg, and females had the highest gonad indices early in the season.
Breast cancer is the second leading cause of cancer death among American women. Known risk factors account for only approximately one-third of the 182,000 new cases diagnosed each year in the United States. There is both concern and debate over the contribution of environmental exposures related to lifestyle, occupation, and ambient pollution, particularly in high risk areas such as Long Island, NY and the rest of the northeastern United States. Biomarkers such as carcinogen-DNA adducts can help to explore the role of environmental risk factors for breast cancer by documenting DNA damage from specific carcinogens directly in human tissue. In this pilot study, a total of 31 breast tissue samples were analyzed by the 32P-postlabeling method for carcinogen-DNA adducts characteristic of complex mixtures of aromatic compounds (such as polycyclic aromatic hydrocarbons) and tobacco smoke. The samples included tumor and tumor-adjacent tissues from 15 women with breast cancer and normal tissue samples from 4 women undergoing breast reduction. Among the breast cancer cases, the mean aromatic/hydrophobic-DNA adduct level in all tissues assayed was 5.3 +/- 2.4 (SD) adducts/10(8) nucleotides compared to 2.3 +/- 1.5 among the samples from the noncancer patients. Breast tissue (tumor and/or nontumor) from 30% (5 of 15) of women with breast cancer displayed a pattern of adducts (referred to as a diagonal zone of radioactivity) associated previously, in studies of other tissues, with exposure to tobacco smoke. The 5 positive samples were from current smokers; tissue samples from the 8 nonsmoking cases did not show this characteristic pattern (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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A systematic method for the identification of aza-arenes in coal-derived oil was developed. The basic nitrogen-containing substances were extracted with 6 M hydrochloric acid and fractionated sequentially by using gel chromatography and thin-layer chromatography (TLC) on an alumina plate. The aza-arenes in these fractions were separated by using glass capillary gas chromatography. Individual compounds in the column effluent were trapped in a system consisting of a valve for flow switching and a trapping tube made from a glass capillary. The fluorescence spectra of nanogram to subnanogram amounts of trapped compounds were measured. Some attempts were made to identify components based on their TLC RF values and their fluorescence spectra, in addition to their mass spectra.
An 800-850 degrees F solvent-refined coal-II liquid was fractionated into chemical classes to obtain the aliphatic hydrocarbons, polycyclic aromatic hydrocarbons (PAH), nitrogen-containing polycyclic aromatic compounds (NPAC), and hydroxy-substituted PAH (hydroxy-PAH). The isolated NPAC fraction was refractionated by chemical class both before and after undergoing a nitrosation reaction. The nitrosated and non-nitrosated refractionated NPAC fractions were further subfractionated into secondary amine (pyrroles), primary amine-enriched (amino-PAH), and tertiary amine (azaarene) classes. The PAH and hydroxy-PAH composition of the NPAC fraction increased upon nitrosation, whereas the amino-PAH fraction composition decreased upon nitrosation. Nitrosation of standards indicated the amino-PAH compounds reacted to form parent PAH, chloro-substituted PAH, and methoxy-substituted PAH when analyzed by high-resolution gas chromatography (GC) and GC/mass spectrometry (MS). Some easily oxidized PAH compounds reacted to form ketones and quinones. All other standard reference compounds, chosen to be representative of the major chemical classes of compounds present in coal liquefaction materials, were unchanged by the nitrosation reaction. The amino-PAH of the nitrosated NPAC fraction reacted to form parent and some chloro-substituted PAH when analyzed by low-voltage direct-probe MS in addition to the methods given above. Epidermal carcinogenesis studies with the PAH, NPAC, nitrosated NPAC, and hydroxy-PAH fractions isolated from the 800-850 degrees F coal liquid indicated the PAH and NPAC were the most important determiners of skin carcinogenesis, with the PAH giving a higher response than the NPAC. The tumorigenicity of the NPAC was drastically reduced by nitrosation, probably due to the destruction of the amino-PAH upon nitrosation.