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Biomedical subjects

J Lewtas

Publications and source records attributed to J Lewtas.

At least 37 records · Page 2Linked to original sources
PubMed1995

Metabolic activation of the genotoxic environmental contaminants 2- and 3-nitrofluoranthene in variants of Salmonella typhimurium TA98.

The mutagenic environmental pollutants 2-nitrofluoranthene (2-NFA) and 3-nitrofluoranthene (3-NFA), labelled with 3H and 14C respectively, were incubated with Salmonella typhimurium strain TA98, its nitroreductase-deficient variant TA98NR and its O-acetytransferase-deficient variant TA98/1,8-DNP6, to investigate the activity of these metabolic pathways under conditions approximating those of the Ames assay, hence their contribution to mutagenic potency. 2-Aminofluoranthene (2-AFA) was the major metabolite of 2-NFA (4 microM) in all three TA98 variants, isolated by reverse-phase HPLC and identified by UV-vis and NMR spectroscopy and mass spectrometry. 2-AFA was formed more slowly in TA98NR (65 pmol/h/ml resting phase bacterial broth, 1 to 2 x 10(9) bacteria/ml) than in TA98 (295 pmol/h/ml) or TA98/1,8-DNP6 (82 pmol/h/ml). 2-Acetamidofluoranthene (2-AAFA) was also identified in incubations with TA98 (80 pmol/h/ml), TA98NR (21 pmol/h/ml), and TA98/1,8-DNP6 (8 pmol/h/ml). 3-Aminofluoranthene (3-AFA, confirmed by UV-vis and NMR spectroscopy and mass spectrometry) was formed by all three variants from 3-NFA (4 microM): TA98, 1.76 nmol/h/ml; TA98NR, 0.55 nmol/h/ml; TA98/1,8-DNP6, 2.93 nmol/h/ml. 3-Acetamidofluoranthene (3-AAFA) was not detected in any of the variants. 3-AFA and 3-AAFA were less mutagenic than 3-NFA, and required S9 for activation. Mutagenicity of 3-NFA relative to initial nitroreduction rate was similar in TA98 and in TA98NR, but almost 10-fold lower in TA98/1,8-DNP6; hence O-acetylation considerably enhances the mutagenicity of reduction products of 3-NFA. Mutagenicity of 2-NFA relative to initial nitroreduction rate was similar in TA98 and in TA98/1,8-DNP6; the bacterial genotoxicity of 2-NFA is therefore largely independent of O-acetyltransferase activity. Ratios of mutagenicity to nitroreduction rate were similar in TA98 for 2-NFA and 3-NFA; differences in the potency of these isomers arise primarily from their respective suitabilities as substrates for nitroreductase enzymes.

Acetylation↗
PubMed1995

Cancer biomarkers in human atherosclerotic lesions: detection of DNA adducts.

Since somatic mutations are suspected to contribute to the pathogenesis not only of cancer but also of atherosclerotic plaques, we measured DNA adducts in the smooth muscle layer of atherosclerotic lesions in abdominal aorta specimens taken at surgery from seven patients. DNA adducts were evaluated in three laboratories by means of different molecular dosimetry methods, including: (a) HPLC/fluorescence, which specifically identifies the DNA adducts of the anti-benzo(a)pyrene (BPDE) isomer; (b) two- and three-dimensional synchronous fluorescence spectrophotometries, which detect DNA adducts of BPDE and other reactive metabolites of polycyclic aromatic hydrocarbons; and (c) 32P postlabeling, which reveals the presence of a variety of types of DNA adducts. The HPLC/fluorescence method provided for the first time evidence for the presence of BPDE-DNA specific adducts in three of six specimens tested. Synchronous fluorescence spectrophotometry displayed broad areas of fluorescence in all seven specimens, thereby suggesting the occurrence not only of BDPE-DNA but also of other DNA adducts with similar fluorescence characteristics. All specimens were also positive at 32P postlabeling, which revealed multiple spots detectable following enrichment either with nuclease P1 or butanol, indicative of the presence of different aromatic DNA adducts. Thus, the data obtained by applying typical cancer biomarkers provide further support to the hypothesis that there may be similarities between the carcinogenic and the atherogenic processes, and in particular that genetic alterations caused by DNA-binding agents in the artery wall may be detected in atherosclerotic lesions.

Aged↗
PubMed1994

Outcome of polyarteritis nodosa and Churg-Strauss syndrome. An analysis of twenty-five patients.

OBJECTIVE: To compare outcome in patients with polyarteritis nodosa (PAN) and patients with Churg-Strauss syndrome (CSS) followed up at a single center. METHODS: A retrospective data review of 13 patients with PAN and 12 patients with CSS who were followed up at a vasculitis clinic. Outcome measures included a global damage index, disability and pain dimensions of the Health Assessment Questionnaire, and mortality rate. RESULTS: Compared with patients with CSS, patients with PAN had a significantly higher mean damage index score (5.15 versus 2.42; P = 0.011), a higher disability score (1.09 versus 0.16; P = 0.007), and a higher pain score (1.04 versus 0.01; P = 0.017). Patients with PAN had more relapses (relative risk = 5.07; P < 0.000) and a higher mortality rate (31%) compared with patients with CSS (8%). CONCLUSION: PAN and CSS differ in their morbidity and mortality; therefore, they should be considered as distinct clinical entities.

Adult↗
PubMed1994

Comparison of DNA adduct levels in human placenta from polychlorinated biphenyl exposed women and smokers in which CYP 1A1 levels are similarly elevated.

Previous studies demonstrated that cigarette smoking is associated with high elevations in levels of both cytochrome P450 1A1 (CYP1A1) and DNA adducts in human placenta. To date, the identity of the smoking related DNA adducts is not known. The DNA adducts identified in placenta of smokers could result from chemicals present in cigarette smoke, substances formed by CYP 1A1 metabolic activation of endogenous compounds, noncigarette related exposures or a combination of these processes. Exposure to contaminated rice oil containing large doses of polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) also resulted in massive elevation of CYP 1A1 in human placenta but formation of DNA adducts directly from this exposure has not previously been reported. The purpose for comparing the two populations was to test the hypothesis that if CYP 1A1 induction results in the metabolic activation of endogenous compounds, then DNA adducts should also be present in PCB/PCDF exposed tissues exhibiting high CYP 1A1 activity and some of the adducts detected in the placental DNA from smokers may be identified as those derived from the metabolic activation of endogenous compounds. To test this hypothesis, we measured DNA adducts using 32P-postlabeling to analyze placental DNA from women exposed to PCB/PCDF and from cigarette smokers where levels of CYP 1A1 were similarly elevated. There was no evidence of DNA adducts among specimens obtained from PCB/PCDF exposed individuals. These data suggest that CYP 1A1 induction alone (in the absence of cigarette smoking) does not induce the formation of DNA adducts detectable by this approach, and that smoking related adducts are not a consequence of CYP 1A1 induction mediated activation of endogenous compounds or xenobiotics other than cigarette smoke.

Aryl Hydrocarbon Hydroxylases↗
PubMed1994

Human exposure to complex mixtures of air pollutants.

Human exposure to complex mixtures of polycyclic organic matter (POM) from the products of incomplete combustion contribute to the potential lung cancer risk in urban areas. The most ubiquitous emission sources outdoors in populated areas are residential motor vehicles and residential heating, while environmental tobacco smoke is usually the major combustion source in indoor air. In addition to these urban combustion sources, there are industrial and municipal sources that may also have a significant impact on human exposure to carcinogenic agents due to their high DNA adduct and tumor initiating potency. This review focuses on new approaches to assess human exposure to POM using source apportionment, personal exposure monitoring, and biomarker methods.

Air Pollutants↗
PubMed1994

Formation of DNA adducts in rat lung following chronic inhalation of diesel emissions, carbon black and titanium dioxide particles.

Exposure of rats to diesel emissions results in the development of lung tumors. The objective of this study was to determine whether the polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs or other polycyclic organic matter adsorbed to diesel particles induces the formation of DNA adducts in the lung when compared to particles with little or no adsorbed organic matter. Rats were exposed to diesel emissions containing particles with over 30% solvent-extractable adsorbed organic matter and to particles with < 0.1% adsorbed organic matter (carbon black particles and TiO2). Wistar rats were exposed to diesel emissions (7.5 mg/m3) for 2 months, 6 months and 2 years and for 2 years to carbon black (11.3 mg/m3) and TiO2 particles (10.4 mg/m3) to compare tumorigenic response and DNA adduct formation in the lung. Two versions of the 32P-postlabeling assay for the detection of DNA adducts were used to tentatively identify nitrated-amine or arylamine adducts formed relative to other nitro PAH based on the demonstrated sensitivity of these adducts to nuclease P1 treatment. Total adduct levels were determined for peripheral lung tissue DNA as detected in a diagonal radioactive zone. One major adduct which migrated outside this region (adduct 1) and a nuclease P1-sensitive adduct (adduct 2) were quantitated separately. Adduct 1 increased significantly over time in the filtered air exposed animals but decreased markedly at the 2 year time points regardless of particle type, presumably as a result of adduct dilution through de novo cell synthesis or cell proliferation invoked in response to particle loading and/or effect on the endogenous synthesis or degradation of DNA reactive moieties. The nuclease sensitive adduct (adduct 2), possibly resulting from exposure to nitro-PAHs, was detected in diesel-exposed rats but was not detected in the rats exposed to TiO2 and carbon black. No significant elevation in PAH-derived adducts, relative to the filtered air controls, was observed in the rodents exposed to diesel emission. Our data suggest that long-term contact with these particles may result in a cell proliferative response, enhanced degradation of I-compounds not related to cell proliferation, and/or synthesis of I-compounds, irrespective of the differences in organic content associated with the three particle types. This response may be an important factor in explaining the reported similarity in tumorigenic response in rodents exposed to diesel emissions, carbon black and TiO2 particles.

Administration, Inhalation↗
PubMed1994

Exposure and risk from ambient particle-bound pollution in an airshed dominated by residential wood combustion and mobile sources.

A major field study was conducted in Boise, Idaho, during the heating season of 1986 to 1987 as part of the Integrated Air Cancer Project. Filter samples were systematically collected in residences and in the ambient air across the community to characterize the particle-bound pollutants. The extractable organic matter (EOM) from the filter samples was apportioned to its source of origin, either residential wood combustion (RWC) or mobile sources (MS). Two composite samples, with apportioned contributions from RWC and MS, were prepared from the Boise ambient samples and tested for tumor-initiation potency. A comparative potency lung cancer risk estimate has been made based on the two ambient composite samples from this airshed. In addition, a microenvironmental exposure model was developed from the Boise data and from national survey data to estimate the exposure to EOM from RWC and MS. In this paper, the microenvironmental model is extrapolated to provide an estimate of the average annual exposure and dose in Boise to EOM from RWC and MS. The annual model considers actual pollutant levels in Boise, historical changes in RWC usage and meteorological dilution factors and the likely activities in the various microenvironmental zones and their resultant inhalation rates. Combined with the lifetime risk estimates, the average annual dose suggests a risk of about 4 x 10(-4) based upon the composite ambient samples. Despite the fact that RWC accounts for 73% of the EOM on an annual average basis, it accounts for only about 20% of the estimated lifetime risk.

Air Pollution↗
PubMed1994

Primary angiitis of the CNS diagnosed by angiography.

Sixteen patients (8 female, 8 male) with primary angiitis of the CNS (PACNS), were followed prospectively in a vasculitis clinic. Diagnosis was by angiography in patients without underlying disease. Median age at diagnosis was 36.5 years, and median duration of follow-up was 28 months. Onset was acute in 14 patients (88%), with 3.5 weeks (median) from onset symptoms to diagnosis. Three women developed symptoms within 3 weeks postpartum. The most frequent symptoms were severe headaches (12, 75%), stroke (6, 30%), transient ischaemic attack (TIA) (4, 28%), seizures (7, 44%), visual aberration (3, 19%), and cognitive impairment (5, 31%). Laboratory data included high ESR (2, 13%), leucocytosis (8, 80%), thrombocytosis (1, 6%), positive antinuclear antibody titre (3, 15%), and high levels of complement (5, 31%). Lumbar puncture was performed in 12 patients (75%). CSF analysis was abnormal in five patients (42%). EEG was abnormal in 5/9 patients. The major CT/MRI scan findings were cerebral haemorrhage (4, 25%), brain infarcts (5, 31%), brain atrophy (2, 13%) and non-specific lesions (2, 13%). Four patients had normal studies. All patients received corticosteroids (CS), and five were treated with oral cyclophosphamide. Two patients relapsed despite CS and cyclophosphamide therapy. All patients are alive, and at the last assessment, eight had a permanent neurological deficit, which included paresis (3, 19%), neurocognitive abnormalities (2, 13%), visual loss (2, 13%) and seizure activity (5, 31%). Our data suggest a non-progressive, non-fatal course in those PACNS patients diagnosed angiographically and treated with CS with or without cyclophosphamide.

Adult↗
PubMed1993

An evaluation of the comparative metabolism and kinetics of 1-nitropyrene by rabbit, rat, and hamster tracheal epithelial cells.

The comparative metabolism of 1-nitropyrene was studied in isolated rabbit, rat, and hamster tracheal epithelial cells commonly used in neoplastic transformation assays. The maximum total metabolite production for all species was attained at 2.0 x 10(6) cells and 4 hr incubation, with no significant increase after 20 hr. The majority of the metabolites produced by tracheal epithelial cells from each species were released into the surrounding medium. The metabolites retained by tracheal epithelial cells were qualitatively identical to those identified in the medium but were present at lower concentrations. The apparent Km for the metabolism of 1-nitropyrene by tracheal epithelial cells was in the order of rabbit (5.1 microM) < hamster (9.1 microM) < rat (13 microM). The apparent V/K value for the metabolism of 1-nitro-pyrene by tracheal epithelial cells was also in the order of rabbit (2.0 nmol/hr/mg protein) > hamster (1.6 nmol/hr/mg protein) > rat (0.48 nmol/hr/mg protein). Intrinsic clearance of the previously characterized mutagenic metabolites (3-OH-1-NAAP, K-DHD, 10-OH-1-NP, 1-AMP, and phenols 6- or 8-OH-1-NP) produced by tracheal epithelial cells at their approximate Km values also indicated that rabbit tracheal cells were more active in the production of these metabolites than either hamster or rat tracheal cells. Although the metabolism of 1-NP in isolated tracheal epithelial cells of these three species was qualitatively similar, rabbit tracheal cells are the most active in metabolizing 1-NP. These results are consistent with the possibility that tracheal epithelial cells may be a target tissue for NO2-PAHs carcinogenesis.

Animals↗
PubMed1993

Airborne carcinogens.

Air pollution has been recognized as a cancer risk for many years. More than 2,800 different chemicals have been identified in the air or emission sources. Only about 10% of these chemicals have been evaluated in bioassays for genetic or carcinogenic effects. Hydrocarbons, nitrogen-containing organics, and halogenated organics account for nearly 60% of the airborne chemicals that have been studied in long term animal cancer bioassays or short-term genetic bioassays. The sources that emit the highest number of these potentially carcinogenic chemicals are sources involving combustion (e.g., tobacco smoke, automobile exhaust, and coal combustion). Quantitative estimates of the risk of airborne carcinogens in outdoor air consistently show that polycyclic organic matter (POM) from products of incomplete combustion (PICs) make the largest single contribution to human cancer risk. Although the POM emissions from various air pollution sources are chemically similar and induce cancer by a similar genotoxic mechanism, the cancer risk per unit of exposure of these emissions may vary by several orders of magnitude. Among these combustion sources motor vehicle emissions account for the greatest cancer risk in outdoor air. Environmental tobacco smoke (ETS) and radon are the major sources of cancer risk from indoor exposures. There are, however, many uncertainties in identifying the important airborne carcinogens and quantitating the human cancer risk of air pollution. One important uncertainty is the role of atmospheric transformation products in human cancer.

Air Pollutants↗
PubMed1993

Complex mixtures of air pollutants: characterizing the cancer risk of polycyclic organic matter.

Complex mixtures of polycyclic organic matter (POM) are used to illustrate the scientific problems and issues associated with characterizing the comparative risk of related complex mixtures. The complexity of mixtures in which the active components are not well characterized present special challenges, which include identifying the critical components of mixtures, their sources, and the appropriate biomarker(s) of exposure and dose; developing the appropriate experimental models for dose-response assessment; species extrapolation; and developing a scientific basis for predicting from one mixture to another. Strategies for addressing these issues include bioassay-directed chemical characterization of bioactive components of complex mixtures, apportionment methods to determine the source of biological activity and risk, DNA adduct methods to determine tissue exposure and target dose of mixtures, and comparative approaches to determining the relative similarity, potency, and risk of complex mixtures. Epidemiological data are available for humans exposed to POM from coke ovens, coal roofing tar, coal smoke, aluminum smelters, and cigarette smoke. These emissions are characterized and compared to POM from automotive emissions (diesel and gasoline), woodstove emissions, residential oil furnace emissions, and ambient air particles. The tumor potency and estimated cancer risks for these POM mixtures ranges over nearly three orders of magnitude.

Air Pollutants↗
PubMed1993

Detection and comparison of DNA adducts after in vitro and in vivo diesel emission exposures.

Development of methods to evaluate certain classes of polycyclic aromatic compounds (PAC) detected in complex mixtures to which humans are exposed would greatly improve the diagnostic potential of 32P-postlabeling analysis. Identification of DNA adduct patterns or specific exposure-related marker adducts would strengthen associations between observed DNA adducts and exposures to different environmental pollutants (e.g., kerosene, cigarette smoke, coke oven, and diesel). We have compared diesel-modified DNA adduct patterns in various in vitro and in vivo rodent model systems and compared them to DNA reactive oxidative and reductive metabolites of 1-nitropyrene. The formation of nitrated polycyclic aromatic hydrocarbon (nitrated PAH) DNA adducts, derived from the metabolism of diesel extract constituents, was enhanced relative to other PAH-derived DNA adducts via xanthine oxidase-catalyzed nitroreduction. These adducts were detectable only by the butanol extraction version of the postlabeling analysis. Five major DNA adducts were detected in human lymphocytes treated in vitro with diesel extract. A major adduct detected in human lymphocytes treated in vitro with diesel extract comigrated with a major adduct detected in lymphocyte DNA treated with benzo[a]pyrene (BaP) alone. Other adducts that co-migrated with the major BaP-derived adducts were detected in skin and lung DNA isolated from rodents topically treated with (50 mg) diesel extract and the major adduct detected in calf thymus DNA treated with rat liver S9 and diesel particle extract. Postlabeling of lung DNA isolated from rodents exposed via lung inhalation for 24 months to diesel combustion emissions resulted in the formation of a major nuclease-P1-sensitive DNA adduct that did not co-migrate with the major BaP-diol epoxide adduct.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

DNA adducts as biomarkers for assessing exposure to polycyclic aromatic hydrocarbons in tissues from Xuan Wei women with high exposure to coal combustion emissions and high lung cancer mortality.

The high lung cancer rate in Xuan Wei, China, is associated with smoky coal use in unvented homes, but not with wood or smokeless coal use. Smoky coal combustion emits higher polycyclic aromatic hydrocarbon (PAH) concentrations than wood combustion. This study used DNA adducts as biomarkers for human exposure to PAH from combustion emissions. DNA adducts were determined by enzyme-linked immunosorbent assays (ELISA) in placentas and peripheral and cord white blood cells (WBC) from Xuan Wei women burning smoky coal or wood and from Beijing women using natural gas. Color ELISA gave positive results in 58, 47, and 5% of the placentas from Xuan Wei women burning smoky coal without and with chimneys, and from Beijing women, respectively. Fluorescence ELISA indicated that 46, 65, 56, and 25% of placentas were positive from Xuan Wei women who lived in houses without and with chimneys, Xuan Wei women burning wood, and Beijing controls, respectively. Peripheral WBC samples were positive in 7/9, 8/9, and 3/9 for the Xuan Wei women who lived in houses without and with chimneys and Beijing women, respectively. PAH-DNA adducts were detected in a higher percentage of placentas from Xuan Wei women living in houses exposed to smoky coal or wood emissions than from those of the Beijing controls. No dose-response relationship was observed between the air benzo[alpha]pyrene concentrations and DNA adduct levels or percentage of detectable samples. The results suggest that DNA adducts can be used as a qualitative biomarker to assess human exposure to combustion emissions.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1993

Comparison of DNA adducts from exposure to complex mixtures in various human tissues and experimental systems.

DNA adducts derived from complex mixtures of polycyclic aromatic compounds emitted from tobacco smoke are compared to industrial pollution sources (e.g., coke ovens and aluminum smelters), smoky coal burning, and urban air pollution. Exposures to coke oven emissions and smoky coal, both potent rodent skin tumor initiators and lung carcinogens in humans, result in high levels of DNA adducts compared to tobacco smoke in the in vitro calf thymus DNA model system, in cultured lymphocytes, and in the mouse skin assay. Using tobacco smoke as a model in human studies, we have compared relative DNA adduct levels detected in blood lymphocytes, placental tissue, bronchoalveolar lung lavage cells, sperm, and autopsy tissues of smokers and nonsmokers. Adduct levels in DNA isolated from smokers were highest in human heart and lung tissue with smaller but detectable differences in placental tissue and lung lavage cells. Comparison of the DNA adduct levels resulting from human exposure to different complex mixtures shows that emissions from coke ovens, aluminum smelters, and smoky coal result in higher DNA adduct levels than tobacco smoke exposure. These studies suggest that humans exposed to complex combustion mixtures will have higher DNA adduct levels in target cells (e.g., lung) as compared to nontarget cells (e.g., lymphocytes) and that the adduct levels will be dependent on the genotoxic and DNA adduct-forming potency of the mixture.

Adult↗
PubMed1993

DNA adduct profiles and levels in placenta, blood and lung in relation to cigarette smoking and smoky coal emissions.

Tobacco smoking and indoor smoky coal combustion emissions lead to exposures to complex environmental mixtures that have been associated with increased lung cancer mortality rates in the USA and Xuan Wei County, China, respectively. Human exposures to benzo[a[pyrene (BaP) present in smoky coal emissions are 20-200 times greater than exposure to BaP from smoking 1-2 packs of cigarettes per day. We compared DNA adducts resulting from cigarette smoking and coal smoke exposures in blood cells, placental syncytial nuclei, whole placental tissue homogenates and lung cells. Postlabelling analysis of DNA isolated from placental tissue of smokers revealed multiple adducts as a diagonal radioactive zone. DNA adduct levels for both white blood cells (WBC) and lymphocyte DNA were approximately 2.5-fold higher in smokers than in non-smokers. One smoking-related adduct was detected in both WBC and lymphocyte DNA, but no exposure-related adducts were detected in either WBC DNA or placental tissue DNA isolated from coal smoke-exposed individuals, despite higher exposure to BaP and aromatic organics. In contrast, discrete adducts unrelated to smoking status were detected, by 32P-postlabelling analysis, in DNA from syncytial nuclei isolated from placental villus samples from smokers and non-smokers. One major placental syncytial adduct co-migrated with a major BaP-derived DNA adduct. DNA adduct levels were approximately four-fold higher in bronchoalveolar lavage (BAL) cells from coal smoke-exposed individuals compared to unexposed individuals and suggest that DNA-reactive intermediates concentrate in the respiratory tract and may not be detectable in whole WBC or placental tissue homogenates. Our findings also suggest that the distribution and concentration of placental DNA adducts may be dependent on the site at which the placenta is sampled.

Adolescent↗
PubMed1993

Systemic vasculitis following influenza vaccination--report of 3 cases and literature review.

Influenza vaccination is a widely accepted practice particularly among the elderly and high risk individuals. Minor and transitory side effects following the vaccination are common while systemic complications are infrequently reported. We describe 3 patients who developed systemic vasculitis following influenza vaccination. With increasing use of influenza vaccination, attention should be drawn to the possible expression of systemic adverse effects such as vasculitis.

Aged↗