Biomedical subjects

K Hemminki

Publications and source records attributed to K Hemminki.

At least 253 records · Page 14Linked to original sources

PubMed1995

DNA adducts caused by tamoxifen and toremifene in human microsomal system and lymphocytes in vitro.

DNA-binding of tamoxifen and toremifene was studied in rat in vivo, in human and rat microsomes in vitro, and in cultured primary human lymphocytes by 32P-postlabelling. Only tamoxifen caused DNA adducts in rat liver. Both compounds induced adducts in both rat and human microsomal systems and in cultured lymphocytes. The levels of adducts in microsomes and lymphocytes were low, ca. 1 adduct/10(9) nucleotides. Toremifene showed lower binding in each system, and in lymhocytes adducts were only detected at a cytotoxic dose level.

Animals↗

PubMed1995

Relationship between hprt mutant frequency, aromatic DNA adducts and genotypes for GSTM1 and NAT2 in bus maintenance workers.

We have studied the mutant frequency in the human gene for hypoxanthine-guanine phosphoribosyl transferase (hprt) using the T-cell cloning assay, the aromatic DNA adduct level using the 32P-postlabelling assay, and related the levels of these biomarkers to the genotypes for glutathione transferase (GST mu) and N-acetyltransferase (NAT2) in non-smoking bus maintenance workers exposed to diesel exhaust. No difference in mutant frequency was observed between the 47 exposed (8.6 x 10(-6), age range 27-65) and the 22 control individuals (8.4 x 10(-6), age range 23-61), while the difference in adduct level (3.2 versus 2.3 x 10(-8)) was highly significant (P = 0.0009). Both mutant frequency and adduct level were highest in the 16 most heavily exposed workers. Overall, a significant increase of mutant frequency was observed with adduct level (P = 0.008) as well as with age (P < 0.0001). The age dependence was higher in the GSTM1-negative slow acetylators (3.1%/year) as compared to the three other genotype combinations (2.4-2.5%/year). There was no significant difference in mutant frequency or in adduct level between the GSTM1-negative (49.3% of the population) and positive individuals, or between the slow (60.9% of the population) and rapid acetylators. Among the slow acetylators, however, a significantly higher adduct level (P = 0.03) was obtained for the GSTM1-negative individuals as compared to the GSTM1-positive individuals. These results suggest a possible role of both GST mu and NAT2 for individual susceptibility to carcinogen exposure.

Adult↗

PubMed1995

DNA adducts in biomonitoring.

Application of methods to the measurement of DNA adducts in occupational and environmental studies was surveyed. The methods included the 32P-postlabeling assay, immunoassay, mass spectrometry, and synchronous fluorescence spectroscopy. Methods for detecting excreted urinary RNA and DNA adducts were also discussed. When the techniques have been applied in occupational settings with complex exposures, identification and quantitation of the adduct levels have not been possible. At present emphasis is being placed on the determination of specific adduct levels. This can often be achieved by adding a purification step before the determination of adducts. Inasmuch as humans differ in their metabolic capacity, it has become feasible to determine adducts in humans who are polymorphic in their xenobiotic metabolism.

DNA Adducts↗

PubMed1995

The molecular epidemiology of growth signal transduction proteins.

Cellular proteins involved in growth signal transduction pathways represent potential molecular epidemiologic biomarkers for various disease processes of toxicologic interest, particularly cancer. In many instances, the proteins gain access to the extracellular environment and thus can be detected in easily accessible biological fluids such as serum or plasma. This paper reviews the experience with selected examples of such proteins, including growth factors, growth factor receptors, G proteins, and nuclear DNA-binding proteins, as serum or plasma biomarkers of disease.

Biomarkers↗

PubMed1995

Cancer incidence among Finnish workers exposed to halogenated hydrocarbons.

Epidemiologic studies and long-term carcinogenicity studies in experimental animals suggest that some halogenated hydrocarbons are carcinogenic. To investigate whether exposure to trichloroethylene, tetrachloroethylene, or 1,1,1-trichloroethane increases carcinogenic risk, a cohort of 2050 male and 1924 female workers monitored for occupational exposure to these agents was followed up for cancer incidence in 1967 to 1992. The overall cancer incidence within the cohort was similar to that of the Finnish population. There was an excess of cancers of the cervix uteri and lymphohematopoietic tissues, however. Excess of pancreatic cancer and non-Hodgkin lymphoma was seen after 10 years from the first personal measurement. Among those exposed to trichloroethylene, the overall cancer incidence was increased for a follow-up period of more than 20 years. There was an excess of cancers of the stomach, liver, prostate, and lymphohematopoietic tissues combined. Workers exposed to 1,1,1-trichloroethane had increased risk of multiple myeloma and cancer of the nervous system. The study provides support to the hypothesis that trichloroethylene and other halogenated hydrocarbons are carcinogenic for the liver and lymphohematopoietic tissues, especially for non-Hodgkin lymphoma. The study also documents excess of cancers of the stomach, pancreas, cervix uteri, prostate, and the nervous system among workers exposed to solvents.

Adult↗

PubMed1995

Validity aspects of exposure and outcome data in reproductive studies.

Some validity aspects related to various sources on pregnancy outcome and exposure are discussed. Register-based data on outcome and exposure are compared with workers' own reports. The problems in the use of personal interview data on pregnancies are related to the possible selection in recognition and reporting the pregnancy outcome. The best way of avoiding misclassification of outcome is to resort to medical records whenever possible. Misclassification of exposure is most likely a common reason for discrepancies in results in reproductive studies. The misclassification of exposure deflates the power of the study to detect the true difference between exposed and nonexposed subjects, particularly when the prevalence of exposure is low. It is of great importance to confirm, if possible, the exposure status by using two or more independent sources of data.

Bias↗

PubMed1995

Time to pregnancy among women occupationally exposed to lead.

A retrospective time-to-pregnancy study was conducted among women biologically monitored for exposure to lead. The women were participants of a previous study on spontaneous abortion. They were classified into exposure categories on the basis of questionnaire information, and individual blood lead (B-Pb) measurements. The adjusted incidence density ratios (IDR) of clinically recognized pregnancies were .93 (95% confidence interval [CI] .56 to 1.57) for very low (B-Pb < .5 mumol/L), .84 (CI .48 to 1.45) for low (B-Pb .5 to .9 mumol/L), and .80 (CI 0.42 to 1.54) for higher (B-Pb > or = 1.0 mumol/L) exposure compared with no exposure, in the discrete proportional hazards analysis. Exposure to inorganic lead was not associated with fecundability at current, low-exposure levels. The suggestive finding among the eight most heavily exposed women (B-Pb 1.4 to 2.4 mumol/L, IDR .53; CI .19 to 1.52) should be confirmed or refuted in a larger study.

Abortion, Spontaneous↗

PubMed1995

Reproductive effects of chemical exposures in health professions.

Numerous chemical substances are handled by persons working in the health care sector. At exposure levels that may occur in the occupational setting, some of these substances are potentially harmful to the reproductive processes. Among the potentially harmful substances are anesthetic gases, antineoplastic agents, and sterilants. The epidemiological evidence of increased risks for adverse reproductive effects (eg, subfertility, spontaneous abortions, congenital defects) from such exposure is not unequivocal. However, due to the toxic potential, exposures should be kept at a minimum, and this may be especially important for workers who are pregnant or are planning to achieve pregnancy.

Abortion, Spontaneous↗

PubMed1995

Tumour necrosis factor-alpha (TNF-alpha) in patients who have asbestosis and develop cancer.

OBJECTIVES: Concentrations of tumour necrosis factor-alpha (TNF-alpha) were assayed by radioimmunoassay in serum samples collected between 1981 and 1987 from 111 patients with asbestosis who were at a high risk of cancer. Follow up of these patients until 1993 showed that 38 had developed cancer (27 lung, three mesotheliomas, and eight diverse malignancies). RESULTS: The mean serum concentrations of TNF-alpha given in fmol/100 microliters serum in all the cases with cancer (14.1) and the cases with lung cancer (13.6) were significantly higher (P < 0.05) than the mean concentrations in the exposed controls (10.5). A positive increase was considered to be any value that was > 2 SDs above the mean of the exposed controls. 22% (six of 27) of the cases with lung cancer were positive compared with 4% (three of 73) of the exposed controls, a significant difference (P < 0.001). The serum concentrations of TNF-alpha correlated moderately with cancer (r = 0.3), lung cancer (r = 0.3), and Neu oncoproteins and epidermal growth factor receptor (EGFR) (r = 0.3, 0.5 respectively). Also, there was a significant correlation between development of cancer and severity or progression of asbestosis. There was no correlation between the concentrations of TNF-alpha and severity or progression of asbestosis. CONCLUSIONS: These results showed high concentrations of TNF-alpha in the patients who had cancer. TNF-alpha may offer an auxiliary method in early diagnosis of cancers related to asbestosis.

Adult↗

PubMed1995

Excess lung cancer among workers exposed to lead.

OBJECTIVE: Studies on experimental animals suggest that inorganic lead is a carcinogen. The purpose of the study was to examine whether occupational exposure to lead increases the risk of cancer. METHODS: The study population comprised 20,700 workers who had been biologically monitored for their blood lead (B-Pb) concentrations during 1973-1983. The mortality and cancer incidence rates were followed among the monitored workers and compared with those of the Finnish general population. An internal comparison of the cancer incidence rates was also done between subcohorts formed according to individual B-Pb levels. Questionnaire-based information was also collected on lifetime occupational history and potential confounders, and exposure history was assessed on an individual basis with a nested case-referent design for lung cancer. RESULTS: The internal comparison within the cohort showed a 1.4-fold increase in the overall cancer incidence and a 1.8-fold increase in the incidence of lung cancer among those who had ever had a blood lead level of > or = 1.0 mumol.l-1. In the case-referent study, an increased odds ratio for lung cancer was found for concomitant exposure to lead and engine exhaust. The odds ratio for squamous-cell carcinoma of the lung was increased even when the blood lead level had been slightly elevated. Bias or confounding did not explain the risks. CONCLUSIONS: The results suggest that exposure to lead increases the risk of lung cancer. Co-exposure to engine exhaust and lead may be associated with the risk.

Adult↗

PubMed1995

Serum oncoproteins in asbestosis patients.

Using ELISAs, we determined the concentrations of transforming growth factor alpha (TGF-alpha), the extracellular domain of the erbB-2 receptor (erbB-2 ECD), and mutant p53 protein in stored serum samples of asbestosis patients with and without cancer and control subjects (without asbestosis or cancer). The percentage of individuals in these three groups with increased serum concentrations of TGF-alpha, erbB-2 ECD, and mutant p53, respectively, were: asbestosis patients with cancer, 36%, 16%, 19%; asbestosis patients without cancer, 38%, 19%, 6%; control subjects, 0%, 5%, 10%. Although differences in serum positivity for these oncoproteins were apparent among these groups, the differences did not achieve statistical significance (P > 0.05). In several of the cancer cases, increased concentrations of TGF-alpha, erbB-2 ECD, and mutant p53 were also detected in the stored serum samples collected years before the clinical diagnosis of disease.

Asbestosis↗

PubMed1995

Studies of biomarkers in aluminum workers occupationally exposed to polycyclic aromatic hydrocarbons.

Evaluation of biomarkers for genotoxic exposure are important for future use of such biomarkers in cancer prevention. We have studied a group of aluminum plant workers for a period of 2.5 years. The level of polycyclic aromatic hydrocarbons (PAHs) has been monitored at the work place (cathode relining). During the study period, urine and blood were sampled up to seven times from the same workers. Mean level of urinary 1-hydroxypyrene varied from 1.08 to 2.44 mumol/mol creatinine in the exposed groups compared with 0.36 and 0.20 mumol/mol creatinine in the two reference groups. For a group of 14 workers the intraindividual variation of urinary 1-hydroxypyrene was analyzed. The relative standard deviation of the values was < or = 0.50 for half of the workers; the relative standard deviation was calculated for individual values divided by mean of each time point. Polycyclic aromatic hydrocarbon-DNA adducts in white blood cells from exposed and nonexposed workers were measured by both immunoassay and 32P-postlabeling. By 32P-postlabeling mean values of 12.0 adducts/10(8) and 10.8 adducts/10(8) nucleotides were found in a PAH-exposed group and a reference group, respectively. Intraindividual variation of PAH-DNA adducts was also analyzed.

Adult↗

PubMed1995

[Estimation of aromatic DNA adduct levels in laryngeal tumors in relation to cancer staging].

Genotoxical agents as PAH, nitrosamines, aromatic amines located in tobacco smoke are responsible for disorders of structure and function of DNA chromosomes, proteins and also initiation of carcinogenesis. DNA adducts are recognized as measure of the biological effective dose of exposure to environmental genotoxicant. So far most studies on DNA adducts after human exposure to tobacco smoke have ben carried out on white blood cells, lungs and oral cavities tissue. The aim of this work was estimation of relationship between state of neoplastic disease (TNM system) and number of aromatic DNA adducts. The subject were 37 patients with primary larynx tumor. In every case histopathological investigation revealed squamous cell carcinoma. There were 33 total and 4 partial laryngectomies performed. From tumour and nontumour larynx tissue DNA was isolated. Analysis of DNA adducts was performed by the 32P-postlabelling method. The results were characterized by individual differentiation. The highest level of DNA adducts was found in larynx tumour cells. In case of strong smokers (30-40 cigarettes per day) the level of aromatic adducts was higher then in non- or ex-smokers. In both tissues (tumour and non-tumour) the highest level of aromatic adducts was in T3 stage, the lowes in cause of T2 stage. In tissues with T4 stage the level of DNA adducts was intermediate. One has been observed decrease tendency in level of DNA adducts which is connected with increase of TNM stage.

Adult↗

PubMed1994

A 32P-postlabelling assay for DNA adducts induced by cis-diamminedichloroplatinum(II).

A 32P-postlabelling method was developed to measure cisplatin-DNA adducts. Platinated oligonucleotides with different chain lengths were enzymatically digested with deoxyribonuclease I, snake venom phosphodiesterase (SVPD) and prostatic acid phosphatase. We found that SVPD was not able to cut the phosphodiester bond immediately 5' to the platinated nucleotide. As a result the adducts had an attached 5' unmodified nucleotide, while the unmodified nucleotides were digested to nucleosides. This is a facile enrichment procedure for the adducts, because the normal nucleosides lacking the 3'-phosphate are not substrates for T4 polynucleotide kinase. Instead, the adduct fragments containing an unmodified nucleotide at their 5' end can be phosphorylated by T4 polynucleotide kinase and [-32P]ATP. This method was also shown to be suitable for the detection of cisplatin-adducts in platinated calf thymus DNA.

Chromatography, High Pressure Liquid↗

PubMed1994

Detection of increased amounts of the extracellular domain of the c-erbB-2 oncoprotein in serum during pulmonary carcinogenesis in humans.

Over-expression of the c-erbB-2 oncogene-encoded p185 protein product has been implicated in the pathogenesis of a wide variety of human malignancies, including lung cancer. Over-expression of p185 can be detected immunologically by quantification of the extracellular domain of p185 (c-erbB-2 oncopeptide) in extracellular fluid in vitro and in serum in vivo. An enzyme-linked immunosorbent assay (ELISA) for the c-erbB-2 oncopeptide was used to examine banked serum samples of 11 pneumoconiosis patients who subsequently developed lung cancer and serum samples from 11 hospital controls matched for age, sex, ethnic group and smoking as well as 55 unmatched general population controls. The mean serum level for the c-erbB-2 oncopeptide in human neu units/ml in the lung cancer cases (1,756 +/- 549 HNU/ml) was statistically significantly elevated (p < 0.001) in comparison to the mean level in the matched controls (976 +/- 488 HNU/ml) or the general population controls (888 +/- 655 HNU/ml). Defining a positive elevation of the serum c-erbB-2 oncopeptide as any value more than 2 standard deviations above the mean of the matched controls, 64% (7 of 11) of the lung cancer cases were positive compared to 0% (0 of 11) matched controls and 5% (3 of 55) of the unmatched controls. In addition, 4 of the 7 c-erbB-2 oncopeptide-positive cancer cases had positive serum samples prior to the time of disease diagnosis (average = 35 months). These results suggest that serum c-erbB-2 oncopeptide may be elevated at an early stage of pulmonary carcinogenesis and that further prospective study of the utility of this biomarker is warranted.

Aged↗

PubMed1994

Reaction kinetics of alkyl epoxides with DNA and other nucleophiles.

1,2-Epoxy alkanes from C3 to C8 were reacted with DNA, deoxyguanosine and 4-(p-nitrobenzyl) pyridine (NBP). DNA was hydrolyzed at neutral pH to release 7-alkylguanines. The products were analyzed by HPLC. The epoxides reacted largely according to the chain length, shorter epoxides being more reactive. Substitutions through carbon 1 predominated. Reactivity with NBP was almost equal between the epoxides.

Alkanes↗

PubMed1994

Exposure of bus and taxi drivers to urban air pollutants as measured by DNA and protein adducts.

Urinary 1-hydroxypyrene, lymphocyte DNA adducts, serum protein-bound PAH and hemoglobin-bound alkene adducts were analysed from 4 groups of non-smoking men: urban and suburban bus drivers, taxi drivers and suburban controls. The only differences between the groups were in DNA adducts between suburban bus drivers and controls, and in DNA adduct and plasma protein PAH-adducts between taxi drivers and controls.

Air Pollutants↗

PubMed1994

Aromatic DNA adducts in larynx biopsies and leukocytes.

Larynx cancer is strongly associated with tobacco smoking. The objective of this work was an analysis of aromatic DNA adducts in tumour and non-tumour larynx cells by means of the 32P-postlabelling method. Peripheral blood leukocytes were used as a reference tissue. The presence of aromatic DNA adducts was demonstrated in all the studied tissues obtained after surgery of larynx tumours. The highest level of DNA adducts was found in larynx tumour cells, followed by non-tumour larynx cells, which exceeded that found in leukocytes almost 2.5 times. Large interindividual differences were detected between subjects. The adduct level in tumour/non-tumour correlated only moderately. However a high correlation was found between the level of DNA adducts in larynx (tumour and non-tumour) cells and that in leukocytes.

Adult↗