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Biomedical subjects

K Norpoth

Publications and source records attributed to K Norpoth.

At least 19 recordsLinked to original sources
PubMed1999

p53 mutations and codon 213 polymorphism of p53 in lung cancers of former uranium miners.

PURPOSE: There is a high prevalence of G-->T transversions of p53 in lung cancers of smokers. One study has reported a special "hotspot" mutation at codon 249 of p53 in lung cancers of former uranium miners. The aim of our study was to look for mutational spectra of p53 in former German uranium miners with lung cancers. METHODS: We investigated 16 patients with lung cancer who had worked as uranium miners in Germany and 13 lung cancer patients without a mining history of the same region. By means of the polymerase chain reaction and sequencing we looked for mutations in exons 5 7 of the p53 gene. RESULTS: We could not find any suggestion of hotspot mutations. The only G-->T mutation in former uranium miners was detected in the only nonsmoker. In 3 patients (19% of the total) we found a codon 213/3 polymorphism. CONCLUSIONS: The results indicate that G-->T transversions do not seem to be very common mutations in p53 in lung cancers probably caused by radiation. Therefore, p53 may be mutated early in lung cancer development if radiation exposure is a critical factor in carcinogenesis. In accordance with studies of thyroid cancer patients in the Chernobyl region, our results may indicate an overrepresentation of codon 213/3 polymorphism in p53 in radiation-caused cancers.

Codon↗
PubMed1998

Elevated DNA single-strand breakage frequencies in lymphocytes of welders exposed to chromium and nickel.

DNA damage (alkaline filter elution) and sister chromatid exchange (SCE) frequencies were measured in lymphocytes of 39 welders and 39 controls. The welders showed a significantly higher rate of DNA single-strand breakages and significantly elevated SCE values. These results are not in accordance with those of a former study in which only DNA-protein cross-links were measured. The different results may be explained on the basis of different exposure levels for chromium(VI) and nickel. Both methods are not specific but sensitive enough to measure genotoxic damage after occupational exposure to chromium(VI) and nickel in the range of threshold values for the workplace on a collective basis. Additionally, the results indicate that DNA single-strand breakage and DNA-protein cross-links show different increases depending on the exposure levels for chromium and nickel.

Adult↗
PubMed1997

DNA single strand breakage, DNA adducts, and sister chromatid exchange in lymphocytes and phenanthrene and pyrene metabolites in urine of coke oven workers.

OBJECTIVES: To investigate the specificity of biological monitoring variables (excretion of phenanthrene and pyrene metabolites in urine) and the usefulness of some biomarkers of effect (alkaline filter elution, 32P postlabelling assay, measurement of sister chromatid exchange) in workers exposed to polycyclic aromatic hydrocarbons (PAHs). METHODS: 29 coke oven workers and a standardised control group were investigated for frequencies of DNA single strand breakage, DNA protein cross links (alkaline filter elution assay), sister chromatid exchange, and DNA adducts (32P postlabelling assay) in lymphocytes. Phenanthrene and pyrene metabolites were measured in 24 hour urine samples. 19 different PAHs (including benzo(a)pyrene, pyrene, and phenanthrene) were measured at the workplace by personal air monitoring. The GSTT1 activity in erythrocytes and lymphocyte subpopulations in blood was also measured. RESULTS: Concentrations of phenanthrene, pyrene, and benzo(a)pyrene in air correlated well with the concentration of total PAHs in air; they could be used for comparisons of different workplaces if the emission compositions were known. The measurement of phenanthrene metabolites in urine proved to be a better biological monitoring variable than the measurement of 1-hydroxypyrene. Significantly more DNA strand breaks in lymphocytes of coke oven workers were found (alkaline filter elution assay); the DNA adduct rate was not significantly increased in workers, but correlated with exposure to PAHs in a semiquantitative manner. The number of sister chromatid exchanges was lower in coke oven workers but this was not significant; thus counting sister chromatid exchanges was not a good variable for biomonitoring of coke oven workers. Also, indications for immunotoxic influences (changes in lymphocyte subpopulations) were found. CONCLUSIONS: The measurement of phenanthrene metabolites in urine seems to be a better biological monitoring variable for exposure to PAHs than measurement of hydroxypyrene. The alkaline filter elution assay proved to be the most sensitive biomarker for genotoxic damage, whereas the postlabelling assay was the only one with some specificity for DNA alterations caused by known compounds.

Adult↗
PubMed1995

Nasal cancer in leather workers: an occupational disease.

Nasal cancer has a number of causative agents; exposures to most of the established nasal carcinogens occur in the workplace. An increased risk of nasal cancer has been ascertained in shoe-making and shoe-repairing, but the results for leather goods manufacture and leather tanning don't provide adequate evidence of carcinogenicity. Findings from two epidemiological studies carried out in Italy (a case/control study and a case/series report) add further information on this issue. The case/control study was performed in the provinces of Siena (Tuscany), Verona and Vicenza (Venetia) including 96 cases and 378 controls. A significant increased risk (Odds Ratio: 6.8; 90% C.I. = 1.9-25) of sinonasal cancer was found for the employ in the whole leather industry; Odds Ratio of 8.3 (C.I. = 1.9-36) and 5.0 (C.I. = 0.92-28) were associated with shoe-making and leather tanning. The case/series report is based on 110 patients accepted in some Italian hospitals during last three years (1990-1993): 26 cases had worked in the leather industry; adenocarcinoma is the most frequent type observed. Chromium salts and natural tannins are indicated as possible aetiological agents.

Case-Control Studies↗
PubMed1995

Biomonitoring of urinary aromatic amines and arylamine hemoglobin adducts in exposed workers and nonexposed control persons.

The renal excretion of arylamines in occupationally exposed and nonexposed subjects was measured by a gas chromatography-electron capture detector method. Additionally, in the occupationally exposed persons hemoglobin adduct levels of arylamines were determined by a liquid chromatography-electrochemical detector method, together with the individual acetylator status. The aromatic amines aniline, p-toluidine, 2-naphthylamine, and 4-chloro-o-toluidine were detected in the urine of nonsmoking subjects who were not occupationally exposed to arylamines. Significantly higher concentrations of aniline, o-toluidine, m-toluidine, 2-naphthylamine, and 4-methyl-1,3-phenylenediamine could be observed in the urine of smoking control persons in comparison to nonsmokers. Comparison of smokers and nonsmokers in a group of workers primarily exposed to aniline and 4-chloroaniline revealed significant differences (P < 0.05) in the formation of 4-aminodiphenyl hemoglobin adducts and in the renal excretion of 2-naphthylamine. The slow acetylators in this group produced significantly more hemoglobin adducts of aniline and 4-chloroaniline than did the fast acetylators. In slow acetylators among the smoking workers there was a significant increase in the formation of 4-aminodiphenyl hemoglobin adducts and in the renal excretion of 4-chloroaniline and m-toluidine. The results indicate that there are influences of smoking habits and acetylator status on the levels of arylamine hemoglobin adducts as well as urinary arylamine concentrations. Hemoglobin adducts seem to be good parameters for monitoring aniline and 4-chloroaniline exposure at the workplace, especially if the acetylator polymorphism can be taken into account. 4-Aminodiphenyl hemoglobin adducts might be good parameters for monitoring individual smoking habits. The determination of urinary arylamine concentrations provides additional information concerning acute exposures to aromatic amines.

Amines↗
PubMed1995

32P-postlabeling analysis of DNA adducts in different populations.

Blood samples were obtained from different populations exposed occupationally or by lifestyle habits to polycyclic aromatic hydrocarbons (PAH). DNA adducts were determined by 32P-postlabeling assay either in white blood cells (WBC) or lymphocytes. The level of DNA adducts ranged from 1.5 per 10(9) nucleotides in one of the control groups up to 7.1 per 10(9) nucleotides in one group of PAH-exposed workers. Comparison of the adduct thin layer chromatography (TLC) profiles revealed individual variation in both pattern and level of DNA adducts. Significant differences of adduct levels were detected between one group of PAH-exposed coke-oven workers and the corresponding control group. Only a weak influence of the smoking habits on the amount of adducts was detectable in occupationally exposed or unexposed individuals.

Adult↗
PubMed1994

DNA-protein cross-links and sister chromatid exchange frequencies in lymphocytes and hydroxyethyl mercapturic acid in urine of ethylene oxide-exposed hospital workers.

The lymphocytes of 25 hospital workers exposed to ethylene oxide and of a standardized control group were investigated for DNA damage (measured by alkaline filter elution) and sister chromatid exchange (SCE) frequencies. Additionally, the excretion of hydroxyethyl mercapturic acid (HEMA) in the 24-h urine of ten workers and ten control persons was determined. The peak levels of ethylene oxide in air during the first 8 min after opening of the sterilization unit were measured. Peak levels of ethylene oxide in the air of up to 417 ppm after opening of the sterilization unit were detected. In the alkaline filter elution assay we found significantly reduced elution rates in the exposed workers, indicating DNA-protein cross-links. The reduction of the elution rates through HVLP filters correlated significantly with the exposure classification (low, medium, high) (r = -0.45, P < 0.05) and the ethylene oxide peak level after opening of the sterilization unit (r = -0.42, P < 0.05). The SCE frequencies in the standardized control group were significantly elevated. With respect to (n = 78) historic control SCE values of our institute, the SCE values of the disinfectors were not significantly elevated (6.54 vs 6.27). The ethylene oxide-exposed workers did not have a greater percentage of high-frequency SCE cells. The mean HEMA concentration in the urine of the exposed workers was significantly elevated, but there were wide variations in HEMA concentrations and no correlation to ethylene oxide exposure. We conclude that the alkaline filter elution assay may be a sensitive parameter for ethylene oxide-exposed workers.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcysteine↗
PubMed1994

Concentrations of benzene in blood and S-phenylmercapturic and t,t-muconic acid in urine in car mechanics.

Different parameters of biological monitoring were applied to 26 benzene-exposed car mechanics. Twenty car mechanics worked in a work environment with probably high benzene exposures (exposed workers); six car mechanics primarily involved in work organization were classified as non-exposed. The maximum air benzene concentration at the work places of exposed mechanics was 13 mg/m3 (mean 2.6 mg/m3). Elevated benzene exposure was associated with job tasks involving work on fuel injections, petrol tanks, cylinder blocks, gasoline pipes, fuel filters, fuel pumps and valves. The mean blood benzene level in the exposed workers was 3.3 micrograms/l (range 0.7-13.6 micrograms/l). Phenol proved to be an inadequate monitoring parameter within the exposure ranges investigated. The muconic and S-phenylmercapturic acid concentrations in urine showed a marked increase during the work shift. Both also showed significant correlations with benzene concentrations in air or in blood. The best correlations between the benzene air level and the mercapturic and muconic acid concentrations in urine were found at the end of the work shift (phenylmercapturic acid concentration: r = 0.81, P < 0.0001; muconic acid concentration: r = 0.54, P < 0.05). In conclusion, the concentrations of benzene in blood and mercapturic and muconic acid in urine proved to be good parameters for monitoring benzene exposure at the workplace even at benzene air levels below the current exposure limits. Today working as a car mechanic seems to be one of the occupations typically associated with benzene exposure.

Acetylcysteine↗
PubMed1994

Genotoxic and cytotoxic effects of 4-aroyl-1-nitrosohydrazine-carboxamides on O6-alkylguanine-DNA alkyltransferase-positive and -negative human cell lines.

Five different representatives (I-V) of a new class of bifunctional alkylating agents, the 4-aroyl-1-nitrosohydrazinecarboxamides ("nitrososemicarbazides"), were evaluated for their potential interaction with DNA and for their cytotoxic activity in vitro to O6-alkylguanine-DNA alkyltransferase-positive (Mer+) and -negative (Mer-) human cell lines. The HeLa MR cell line (Mer-) showed up to 20-fold higher sensitivity at IC50 (dose that inhibits colony formation by 50%) to agents I-V than did the HeLa S3 cell line (Mer+) in a colony-formation assay. These data were compared to those obtained by treatment of the two cell lines with carmustine, a currently used antitumor drug. In Mer+ cells comparable results to those with carmustine were obtained with compounds III, IV and V; in Mer- cells compounds I and II showed nearly the same effects as carmustine. Whether compounds I-V produce DNA strand breaks and/or DNA-protein cross-links was investigated using an alkaline filter elution technique. In this assay all compounds produced DNA single-strand breaks; no correlation could be detected between the strand breakage frequency and cytostatic, mutagenic and antitumor activity.

Carmustine↗
PubMed1994

Sister chromatid exchange frequencies in lymphocytes of oral cancer patients seem to be influenced by drinking habits.

Sister chromatid exchange (SCE) values were determined in the lymphocytes of 24 oral cancer patients before therapy and in the lymphocytes of 24 control persons standardized with respect to sex, age and smoking habits. Oral cancer patients showed significantly elevated SCE values (mean 7.82 versus 6.42). In both groups the highest SCE values were found in the subgroups with the highest alcohol consumption. A significant correlation between SCE and gamma-glutamyltranspeptidase (GGT) values by Spearman correlation analysis was detected in the combined group (cancer patients and control persons) (n = 32, r = 0.40, P = 0.023). The SCE values in the oral cancer patients were weakly correlated (Pearson) to DNA adduct levels (n = 22, r = 0.39, P = 0.068) and DNA single-strand breakage frequencies (n = 12, r = 0.56, P = 0.054) in lymphocytes. The correlation (Pearson) between SCE values and DNA strand breakage values in lymphocytes was significant (n = 10, r = 0.67, P = 0.036) in smoking cancer patients. The increase of SCE values with respect to alcohol drinking habits underlines epidemiologic findings that alcohol is an important co-carcinogen in many cancers, especially in oral cancers. Because of the influences on SCE and adduct levels in lymphocytes, alcohol drinking habits should be controlled as broadly as possible in biomarker studies.

Adult↗
PubMed1993

Production and characterization of monoclonal antibodies to N7-phenylguanine.

N7-Phenylguanine, a base adduct possibly formed after arylation of DNA by benzene oxide, the first reaction metabolite during benzene metabolism, was synthesized in our laboratory and used as reference for the production and characterization of monoclonal antibodies. 2-Hydroxymethyl-7-phenylhypoxanthine, a molecule structurally similar to N7-phenylguanine, was coupled by a linker molecule to different carrier proteins. The resulting conjugate was used to immunize BALB/c mice, the spleen cells of which were fused with mouse P3X63-Ag8.653 myeloma cells to obtain monoclonal antibodies. Several hybridoma lines were cultivated in defined media and characterized as to sensitivity and specificity by an enzyme-linked immunosorbent assay (ELISA). Competitive ELISA demonstrated that all antibodies showed a very high affinity for N7-phenylguanine but had a lower affinity towards various other samples including N7-chlorophenylguanines and C8-, N2-and O6-phenylguanine. As little as about 20 pg N7-phenylguanine could be detected with one of the most sensitive antibodies, CE6/G11, with a colorimetric end point while the detection limit could be lowered to about 10 pg N7-phenylguanine when a fluorescent end point was used. The detection limit of other methods used to determine N7-phenylguanine so far is 10 ng for gas-chromatography/mass-spectrometry and 1 ng for high-pressure liquid chromatography. Thus the use of specific monoclonal antibodies seems to be the most sensitive method for the detection of N7-phenylguanine.

Animals↗
PubMed1993

Genotoxic effects of subacute treatments with wood dust extracts on the nasal epithelium of rats: assessment by the micronucleus and 32P-postlabelling.

Human exposure to wood dust has been epidemiologically linked to a number of enhanced incidences of various neoplasias, including those of the nose. Among different suspected woods, long-term exposure to the dust of beech (Fagus silvatica) is strongly associated with development of these tumors. Experimentally, it has been shown that a simple alcoholic extract of beech wood dust is mutagenic toward some bacteria and tumorigenic on mouse skin. For the present study, different groups of male Wistar rats were treated with aqueous, ethanol, or methanol extract of untreated beech wood dust via nasal drip at three concentrations for 48 h. Animals were killed 24 h after the last treatment and the nasal tissues were isolated to be examined for possible induction of micronuclei and DNA adducts. A clear dose-dependent increase in the number of micronuclei (P < 0.01) was observed after treatment of rats with each alcoholic extract of wood dust. In contrast, no DNA adducts could be detected with these extracts using the 32P-postlabelling technique. No increased number of micronucleated cells was found with solvents alone or with aqueous extract of dust. These data might support the early hypothesis that wood dust per se contains some in vivo genotoxic and thus possibly carcinogenic components extractable by an alcohol.

Animals↗
PubMed1993

DNA strand breakage and DNA adducts in lymphocytes of oral cancer patients.

In lymphocytes of 12 oral cancer patients (and two control groups) the frequencies of DNA single-strand breaks and DNA-protein cross-linking were determined by alkaline filter elution. We found elevated DNA elution rates, which must be interpreted as an increased strand breakage frequency. There were significant correlations between the DNA strand breakage frequency and smoking habits. Using the 32P-postlabelling assay we determined the DNA adduct level in lymphocytes of 23 oral cancer patients (and two control groups). No significant influence of smoking habit on the DNA adduct level could be detected. There was a significant correlation between the DNA adduct level and the gamma-glutamyltranspeptidase (GGT) value, suggesting systemic influences of alcohol drinking habits on the adduct level.

Adult↗
PubMed1993

Studies on guanine adducts excreted in rat urine after benzene exposure.

Investigations with [14C]benzene indicate the formation of base adducts in vivo. Experiments to separate adducts from urine of [14C]benzene-exposed rats suggest the excretion of eight labeled compounds different from benzene metabolites. In order to obtain information about their structure we synthesized N7-, O6-, C8- and N2-phenylguanine. With regard to their chromatographic properties we compared these phenylguanines with products obtained by alkylation of guanine by metabolites of unlabeled and 14C-labeled benzene in vivo with HPLC with UV detection and liquid scintillation counting. Furthermore GC/MS and ELISA techniques were used to detect N7-phenylguanine. Phenylguanines could not be identified in collected DNA fractions. The labeled compounds detected in urine of [14C]benzene-exposed rats also showed deviations from the HPLC elution patterns of our reference substances. Even N7-phenylguanine, formerly suspected to be a urinary metabolite of benzene in the rat, could not be detected with these refined HPLC methods. With GC/MS a compound was found in trace amounts in concentrated rat urine samples, which had a similar fragmentation pattern to N7-phenylguanine. These data could not be confirmed by a sensitive immunological assay (ELISA). No N7-phenylguanine was detected in purified rat urine samples. The results suggest the excretion of a hydroxylated phenylguanine which may be formed in liver or bone marrow DNA by highly reactive hydroxylated intermediates. The OH group might be lost because of the high temperatures during GC/MS measurements. A hydroxy group at the phenyl-ring of N7-phenylguanine will cause other elution properties in HPLC compared to N7-phenylguanine.

Animals↗