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K Golka

Publications and source records attributed to K Golka.

At least 37 records · Page 2Linked to original sources
PubMed2000

Induction of unscheduled DNA synthesis in primary human urothelial cells by the mycotoxin ochratoxin A.

Ochratoxin A (OTA) is a widespread contaminant in human staple food. Exposure of humans to this mycotoxin is a matter of concern because OTA is a known rodent carcinogen. As the urothelium is one target tissue of this mycotoxin, primary cultured human urothelial cells (HUC) from adults and children were used to analyze the induction of unscheduled DNA synthesis (UDS) by OTA. HUC were isolated from the ureters or renal pelves of two nephrectomized adults and of two children with ureteropelvic junction stenosis and cultured under serum-free conditions. After a confluency of 70-80% was reached, cell proliferation was suppressed by arginine-deficient medium (ADM), and UDS was assessed autoradiographically by 3H-thymidine incorporation upon exposure to OTA (10-2000 nM), ethyl methanesulfonate (EMS, 5 mM, positive control), or dimethyl sulfoxide (DMSO, 0.2%, solvent control). In control cultures the level of UDS was low. Exposure to EMS resulted in an induction of UDS (2-to 5-fold compared to control), thus allowing the sensitive detection of repair resulting from induction of DNA lesions in all four specimens, and demonstrating that repair of EMS-induced DNA lesions can take place under the chosen culture conditions. In two HUC cultures derived from adults, a significant induction of UDS was observed in the concentration range of 50-500 nM OTA. The highest fraction of cells in repair (CIR) was found at 50 nM OTA for the HUC from the older male (50% CIR). The maximum response in the other specimens from the adult female and the 7-year-old boy were seen at OTA concentrations of 500 and 250 nM, respectively. In contrast to all other specimens, no significant induction of UDS by OTA was found in the HUC cultures derived from an infant's urothelium. Signs of cytotoxicity were observed above 500 nM OTA in all cultures. The varying susceptibility toward OTA observed in vitro may hint at varying predispositions of individuals in vivo.

Adult↗
PubMed2000

Subjective symptoms due to solvent mixtures, dioxin, and toluene: impact of exposure versus personality factors.

In this study, we analyse the impact of personality factors on the frequency of self-reported symptoms for workers under different exposure conditions. Reported symptoms may depend on the level and type of exposure, as well as on personality factors such as trait anxiety of the worker or his general sensitivity with regard to the environment. The employed data stems from three studies: The first study contains information of 60 workers who suspected to be exposed to polychlorined dibenzodioxins and dibenzofuranes (Lifetime Weighted Average Exposure, LWAE, as an index for contact with the substances). The second study concerns 40 workers who are exposed to different concentrations of solvent mixtures in paint manufacturing (LWAE of total hydrocarbons about 10 ppm). The third study includes repeated measurements of two subgroups of workers from rotogravure printing plants who are exposed to different concentrations of toluene: a "high" exposure group (n = 129, LWAE about 46 ppm, current exposure 25 ppm) and a "low" exposure group (n = 96, LWAE for toluene about 9 ppm, current exposure 3 ppm). Trait anxiety, environmental sensitivity, and self-reported symptoms are measured by validated questionnaires and age as well as verbal intelligence are controlled. To determine the effect of the individual characteristics and the different exposures on self-reported symptoms, frequency analyses and variance analyses are conducted and linear models are fitted. For all analyses, trait anxiety explains the highest share of the variance. If there is no effect of the exposure on the reported symptoms (dioxin and low-level toluene study), trait anxiety seems to have a larger explanatory power in comparison with those studies where the exposure has an effect on the reported symptoms (solvent-mixture and high-level toluene study). Neurotoxicological risk analysis has to account for the detected dependence of self-reported symptoms on personality traits: assessments for elevated symptoms should not only be linked to the intensity of exposure but also related to benchmarks derived from the normal variability of personality factors.

Adaptation, Psychological↗
PubMed1999

Polymorphisms of the xenobiotic-metabolizing enzymes CYP1A1 and NAT-2 in systemic sclerosis and lupus erythematosus.

The etiology of systemic autoimmune diseases, such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is still unknown. In several cases, however, xenobiotics (i.e. drugs and occupational agents) were identified as etiologic agents and associations with certain polymorphic alleles of xenobiotic-metabolizing enzymes have been reported. Cytochrome P4501A1 (CYP1A1) and N-acetyltransferase 2 (NAT-2) are xenobiotic-metabolizing enzymes of phase 1- and phase 2-metabolism, respectively. CYP1A1 may activate drugs and other chemicals to reactive metabolites. NAT-2 is the most important enzyme in acetylation of aromatic amines, and thus may be responsible for detoxification of many of these compounds. Two polymorphisms of the human CYP1A1 gene, a point mutation in the 3' flanking region of the gene (Msp1) and a mutation in exon 7 leading to an isoleucine-valine-exchange in the heme-binding region of the enzyme, have been described and may lead to a higher basal and inducible enzyme activity. With respect to NAT-2, several alleles which combine for the two phenotypes "fast" and "slow" acetylators have been described. We analyzed the gene frequencies of the CYP1A1 polymorphisms and the phenotypes of NAT-2 in patients suffering from idiopathic SLE or SSc. CYP1A1 polymorphisms were analyzed in genomic DNA by PCR, whereas NAT-2 phenotypes were measured by the caffeine method. For CYP1A1 polymorphisms, 106 patients have been typed until now. The SLE group (n = 68) exhibited a significant increase (p < 0.05) in the mutant Val-allele (OR = 2.59) when compared to controls (n = 184). However, no significant differences in allele frequencies for MspI in the SLE group and for both CYP1A1 polymorphisms in the SSc group could be observed. Regarding the NAT-2 phenotype, patients suffering from SLE (n = 88) 75% and SSc (n = 26) 80.2%, respectively, were slow acetylators compared to 55% slow acetylators in the healthy German population (p < 0.05). The observed increased frequencies of the CYP1A1 mutant Val-allele and the slow actylator phenotype in idiopathic autoimmune disease support our concept that in slow acetylators non-acetylated xenobiotics may accumulate and are subsequently metabolized by other enzymes into reactive intermediates. Thus, enhanced formation of reactive metabolites could alter self-proteins presented to the immune system thus stimulating autoreactive T cells which induce autoimmunity.

Alleles↗
PubMed1999

[Occupational risk factors for bladder carcinoma. A case control study].

Aim of this case-control study, performed on 412 male bladder cancer cases and 414 controls with benign prostatic hyperplasia in a former area of coal, iron and steel industries in Germany, was to identify occupations with an increased bladder cancer risk. In bladder cancer cases, smokers were overrepresented (58.3%) compared to controls (35.2%). The percentage of patients who had stopped smoking for at least 10 years did not differ in cases (10.2%) and controls (9.7%). Significantly elevated smoking-adjusted bladder cancer odds ratios (MH) were observed in painters and lacquers (MH 2.24, 95% CI 1.07-5.13), chemistry-related occupations (MH 2.44, 95% CI 1.05-5.67), coke plant workers (MH 2.89, 95% CI 1.16-7.16) and hard coal miners (MH 2.33, 95% CI 1.52-3.58). Significantly decreased smoking-adjusted bladder cancer odds ratios (MH) were observed in businessmen (MH 0.64, 95% CI 0.45-0.92) and office personnel (MH 0.58, 95% CI 0.41-0.81). In these two groups a relevant exposure to occupational bladder carcinogens is not likely.

Aged↗
PubMed1997

Solvent exposure and ratings of well-being: dose-effect relationships and consistency of data.

Ratings on analog scales for dimensions of well-being provide information about the acute state of well-being during solvent exposure. In a study of volunteers and workers exposed to solvents, tension, tiredness, complaints, and annoyance were rated on seven-point scales. Dose-effect relationships were analyzed for several scenarios; data were collected in diaries during work hours. In two studies, 40 volunteers in an exposure laboratory were exposed to ethanol by inhalation at levels between 80 and 1900 parts per million (ppm). In two other studies, 32 volunteers were exposed to acetone and ethyl acetate in single exposures (1000 and 500 ppm, respectively) and combined exposures (500 ppm acetone + 200 ppm ethyl acetate). A field study of 8 exposed workers and 8 nonexposed controls involved exposures of up to 2100 ppm acetone. Dose-effect relationships were shown for ratings of annoyance by correlations of 0.36 (ethanol) and 0.58 (acetone). Similar coefficients were found for ratings of complaints. The dimensions tension and tiredness showed no stable relationship with exposure. The consistency of ratings was assessed by means of correlations between the ratings given during periods of nearly equal exposures. Ratings of annoyance for the different studies between the periods of nearly equal exposure showed average correlations from 0.68 to 0.84. For the ratings of complaints, the coefficients were 0.53 to 0.81. The coefficients for tension had similar stabilities; those for tiredness were lower.

Acetates↗
PubMed1997

[Clinical relevance of acetylator phenotyping in 196 urothelial tumor patients].

A total of 196 patients with urothelial tumours were phenotyped for N-acetyltransferase 2 by the molar ratio of two caffeine metabolites excreted in urine. The proportion of "slow" acetylators, who are genetically predisposed to urothelial tumours if they have been exposed to aromatic amines in the past, in the entire group was 55%, within the range in a normal population. Among 40 patients with assumed former occupational exposure to aromatic amines, 65% were "slow" acetylators. Invasiveness, histopathological grading of the urothelial tumour at the time of first diagnosis, and course were not related to acetylator phenotype.

Acetylation↗
PubMed1997

Influence of polymorphisms of GSTM1 and GSTT1 for risk of renal cell cancer in workers with long-term high occupational exposure to trichloroethene.

Suspected nephrocarcinogenic effects of trichloroethene (TRI) in humans are attributed to metabolites derived from the glutathione transferase (GST) pathway. The influence of polymorphisms of GSTM1 and GSTT1 isoenzymes on the risk of renal cell cancer in subjects having been exposed to high levels of TRI over many years was investigated. GSTM1 and GSTT1 genotypes were determined by internal standard controlled polymerase chain reaction. Fourty-five cases with histologically verified renal cell cancer and a history of long-term occupational exposure to high concentrations of TRI were studied. A reference group consisted of 48 workers from the same geographical region with similar histories of occupational exposures to TRI but not suffering from any cancer. Among the 45 renal cell cancer patients, 27 carried at least one functional GSTM1 gene (GSTT1 +) and 18 at least one functional GSTT1 gene (GSTT1 +). Among the 48 reference workers, 17 were GSTM1 + and 31 were GSTT1 +. Odds ratio for renal cell cancer were 2.7 for GSTM1 + individuals (95% CI, 1.18-6.33; P < 0.02) and 4.2 for GSTT1 + individuals (95% CI, 1.16-14.91; P < 0.05), respectively. The data support the present concept of the nephrocarcinogenicity of TRI.

Aged↗
PubMed1997

A note on the physiological background of the ethylene oxide adduct 7-(2-hydroxyethyl)guanine in DNA from human blood.

A newly developed high-performance liquid chromatography (HPLC) method involves derivatization with phenylglyoxal and fluorescence detection, using 7-methylguanine as internal standard. The physiological background of the adduct 7-(2-hydroxyethyl)guanine in DNA isolated from human blood was determined by this method. In five persons the range of the adduct was between 2.1 and 5.8 pmol/mg DNA (mean 3.2). This finding is consistent with previous data obtained by others, using different analytical methods, and points to an intrinsic carcinogenic risk due to endogenous ethylene oxide.

Chromatography, High Pressure Liquid↗
PubMed1997

N-Acetyltransferase 2 (NAT2) and Glutathione S-Transferase µ (GSTM1) in Bladder-cancer Patients in a Highly Industrialized Area.

The study was designed to assess occupational and non-occupational risk factors in patients with urothelial carcinomas in an area of former coal, iron, and steel industries, with special regard to the impacts of polymorphic enzymes involved in the metabolism of aromatic amines (N-acetyltransferase 2, NAT2) and of polycyclic aromatic hydrocarbons (glutathione S-transferase µ, GSTM1). Inpatients with bladder cancer (n = 179) were interviewed for occupations ever engaged in for more than six months, and for bladder cancer risk factors in general. NAT2 was phenotyped by high-pressure liquid chromatography of caffeine metabolites in urine. The NAT2 status was additionally evaluated by genotyping 88 of these patients. Eighty-nine patients were genotyped for GSTM1. Of the 179 bladder-cancer patients, 115 (64%) were slow acetylators. In 70% of the subgroup of 89 patients, GSTM1 was negative, suggesting an impact of polycyclic aromatic hydrocarbons (PAHs) in bladder-cancer carcinogenesis in the general population in this area. Contrary to an ordinary distribution of the acetylator status in underground coal miners (18 slow acetylators out of 32), GSTM1 was negative in 16 of 19 of these coal miners. Five of six coke-oven workers were slow acetylators; GSTM1 was negative in all four genotyped coke-oven workers. Twelve of 17 patients formerly exposed to colorants were slow acetylators. Distributions of NAT2 (59% slow acetylators) and GSTM1 (54% GSTM1 negative) were normal in businessmen and administrative officers among the occupationally non-exposed bladder-cancer patients. The results are consistent with the view that a slow-acetylator status and lack of the GSTM1 gene are individual risk factors for bladder cancer in persons occupationally exposed to aromatic amines and PAHs. Aromatic amines may be connected with induction of bladder cancer in persons who have been in contact with azo dyes and in coke-oven workers. PAHs may also contribute to elevated bladder-cancer risks in coke-oven workers and in underground coal miners.

Journal Article↗
PubMed1997

Solvent Exposure, Shiftwork, and Sleep.

The effects of different conditions of occupational exposure to organic solvents on subjective sleep quality were studied with and without shiftwork. Laboratory studies showed that four hours of daytime exposure to ethanol (400, 800 ppm) by inhalation led to blood ethanol levels below 0.01 per thousand and had marginal effects on the following night's sleep. Exposures to acetone (1,000 ppm), ethyl acetate (400 ppm), and a solvent mixture (acetone 500 ppm, ethyl acetate 200 ppm) increased the subjective depth of sleep. In a field study with eight hours of exposure, during three different work shifts, dose-response relationships between acetone concentrations during the shiftwork and the depth of sleep were found. Nevertheless, the solvent-exposed shift workers reported a reduced sleep quality, mainly in connection with daytime sleep, in comparison with non-exposed shift workers. The effects of solvent exposure during shiftwork on sleep varied with time of day of the exposure.

Journal Article↗
PubMed1996

Preexistence of chronic tubular damage in cases of renal cell cancer after long and high exposure to trichloroethylene.

Substantially more cases of tubular damage were found among renal cell carcinoma patients who had been exposed to high levels of trichloroethylene over many years than among renal cell carcinoma patients who had not been exposed to trichloroethylene. This supports the hypothesis (Goeptar et al. 1995) that chronic tubular damage may be regarded as a necessary precondition for trichloroethylene to exert a nephrocarcinogenic effect. The findings also indicate that the urine protein patterns identified with SDS-PAGE may represent a valuable parameter for effect biomonitoring of persons exposed to high levels of trichloroethylene over many years.

Carcinoma, Renal Cell↗
PubMed1996

Comparative genotyping and phenotyping of glutathione S-transferase GSTT1.

Only limited information is available so far concerning the human glutathione S-transferase isoenzyme class theta encoded by the GSTT1 gene. The aim of the study was to characterize individuals in respect to a polymorphic deletion of the GSTT1 gene and to validate these results with the phenotypical determination of the "conjugator status" according to Hallier et al. (1993). Determination of the GSTT1 genotype was done in 40 healthy adults by using an assay based on internal standard controlled polymerase chain reaction. The GSTT1-1 phenotype was determined by measuring the erythrocyte conjugating activity towards methyl chloride using a gas chromatographic assay. Genotypically, 34 individuals out of 40 were classified as GSTT1 positive; the remainder were negative. These results could be confirmed by phenotyping in all but one case. In the present study the frequency of "nonconjugators" was 15%. Our study demonstrates the reliability of the suggested PCR assay for GSTT1 genotyping which is easier to perform than the phenotyping assay and is not affected by confounding factors.

Adult↗
PubMed1996

Glutathione S-transferase GSTM1 and GSTT1 null genotypes as potential risk factors for urothelial cancer of the bladder.

One-hundred-and-thirteen patients with cancer of the urinary bladder (cases) were examined with respect to the frequency of null genotypes of the polymorphic glutathione S-transferases GSTM1 and GSTT1. The allelic background in the German population of the area was evaluated by analysing 170 newborns (controls). The frequency of GSTM1 and GSTT1 null genotypes in this population, using methods based upon internal standard controlled polymerase chain reaction (PCR), was 0.54 and 0.18 respectively. An elevated relative bladder cancer risk of GSTM1 null genotype carriers was indicated by comparison of this background with the data of the bladder cancer cases (OR = 1.81; 95% CI [1.10, 2.98]; p = 0.019). The frequencies of the GSTT1 null genotype in the total group of bladder cancer cases versus controls did not differ statistically. However, a significantly higher relative risk of bladder cancer for the GSTT1 null genotype was detected in the cases-subgroup of non-smokers (OR = 3.84; 95% CI [1.21, 12.23]; p = 0.023). Thus, the GSTT1 null genotype might represent a minor risk factor for human bladder cancer which should be further investigated.

Adult↗
PubMed1996

Occupational history and genetic N-acetyltransferase polymorphism in urothelial cancer patients of Leverkusen, Germany.

OBJECTIVES: The study was designed to realize possible shifts in the ratio of slow to fast acetylators within a group of 196 urothelial cancer patients in an area with earlier benzidine production. METHODS: The subjects were interviewed for occupational and nonoccupational risk factors. The patients were phenotyped for N-acetyltransferase 2 (NAT2) by Grant's caffeine test. A subgroup of 54 patients was additionally genotyped for NAT2. RESULTS: The antimode in the NAT2 phenotyping with the caffeine test (AFMU: IX ratio) was 1.0, as evidenced by additional genotyping of the subgroup of 54 patients. The prevalence of slow acetylators in the entire group of bladder cancer patients was 55%, in accordance with published figures for European populations. In a subgroup of 40 patients with occupational histories as workers in chemical or rubber industries 65% were slow acetylators. In a further subgroup of 28 cases having specifically worked at chemical production sites of the local chemical industry, 68% were slow acetylators. CONCLUSIONS: In contrast to earlier studies, this study shows no increased prevalence of slow acetylators among urothelial cancer patients in comparison with the normal population. However, in subgroups of cases with a likelihood of past occupational contacts with aromatic amines, there was a trend towards a higher representation of slow acetylators. This finding is in accordance with observations of others that the percentage of slow acetylators in urothelial cancer patients is generally decreasing, possibly because the production of benzidine and benzidine-based dyes ceased in the early 1970s.

Acetylation↗
PubMed1995

A note on individual differences in the urinary excretion of optical enantiomers of styrene metabolites and of styrene-derived mercapturic acids in humans.

Urine samples from 20 male workers in the polyester industry exposed by inhalation to styrene concentrations ranging from 29 to 41 ppm were investigated. Excretion products of styrene metabolism, mandelic acid and mercapturic acids, were purified from the urine over an extraction column packed with Porapak Q, with subsequent ether elution. The optical enantiomers R- and S-mandelic acid were then determined by thin layer chromatography (TLC) using chiral plate material and selective staining with vanadium pentoxide. Quantitative analysis of these compounds was performed using commercial reference substances. Styrene-specific mercapturic acids were analyzed by a modified TLC method, using synthesized reference substances. The concentration of racemic mandelic acid in the individual urine samples ranged from 80 to 1610 mg/l, and the ratio of the R- and S-enantiomers ranged from 0.7 to 2.2. These individual variations are not explained by differences in individual styrene exposure levels, or by differences in the concentration of the urine samples (in relation to creatinine excretion). Styrene-specific mercapturic acids were detected in the urine of only 1 of the 20 workers, at a concentration much lower than expected from previous investigations by others in humans and laboratory animals, in which less specific analytical methods had been used. The results point to marked interindividual differences in metabolism of styrene, probably related to enzyme polymorphisms.

Acetylcysteine↗
PubMed1994

[Urothelial diseases as an occupational disease].

The number of urothelial tumors of the lower urinary tract caused by occupational exposure is expected to markedly exceed the number of diseases which are actually compensated. The German compensation system for diseases is explained using the example of disease number 1301 which applies to bladder diseases due to aromatic amines. A standard procedure for the evaluation of the percentage of disability ("MdE") caused by tumors of the urinary bladder is presented. Important working areas which are associated with an elevated tumor risk of the lower urinary tract are mentioned. Cancerogenic aromatic amines can also be liberated in the human organism from soluble, i. e. bioavailable, azo dyes by reductive cleavage. Therefore, as a first step, a detailed work history (starting from the beginning of apprenticeship) must be obtained in all cases of urothelial tumors because of the very long latency time of tumors of the urothelium which can be up to fourty years and higher.

Carcinoma, Transitional Cell↗