[Genetic and immune-toxicologic studies on abnormal thyroid functions in hospital employees exposed to cytostatic drugs]. / Citosztatikus kezelést végzo kórházi dolgozók pajzsmirigy-elváltozásainak géntoxikológiai és immuntoxikológiai vonatkozásai.

INTRODUCTION: Environmental exposure to harmful chemicals may produce severe consequences. AIM: The aim of the authors was to perform geno- and immune-toxicological monitoring in female employees occupationally exposed to cytostatic agents in hospitals and compare the findings to those obtained from controls. METHOD: Altogether 642 women working in hospital who were occupationally exposed to cytostatic drugs and 262 control women participated in the study. Frequency of chromosome aberrations, immune phenotype and activation of lymphocytes, and the production of reactive oxygen-species in neutrophil granulocytes were determined. RESULTS: Markedly higher number (n=39) of thyroid alterations was observed among exposed subjects as compared to controls (n=3). In persons with abnormal thyroid functions, the frequency of chromosome aberrations (3.69%) was significantly higher (3.69%) than in exposed subjects without thyroid alterations (2.43%) and in controls (1.70% and 1.60% in control subjects with and without thyroid alterations, respectively). Significantly increased ratio of helper T lymphocytes and decreased ratio of cytotoxic T cells and transferrin-receptor (CD71) expressing B cells were observed in exposed subjects having abnormal thyroid functions as compared to controls. In addition, the ratio of B cells, CD71 expressing T cells and production of reactive oxygen-intermediates was significantly decreased in exposed subjects with thyroid alterations in comparison to exposed subjects without thyroid alterations. CONCLUSIONS: The results indicate increased geno- and immune-toxic effects among exposed subjects having thyroid alterations. Further data are needed to clearly establish the underlying pathophysiological mechanism of this finding.

[Use of comet assay for the risk assessment of oil- and chemical-industry workers]. / Comet assay alkalmazása olaj- és vegyipari exponált dolgozók kockázatbecslésében.

INTRODUCTION: The comet assay is a fluorescent microscopic method that is able to detect DNA strand-breaks even in non-proliferative cells in samples with low cell counts. AIM: The aim of the authors was to measure genotoxic DNA damage and assess oxidative DNA damage caused by occupational exposure in groups exposed to benzene, polycyclic aromatic carbohydrates and styrene at the workplace in order to clarify whether the comet assay can be used as an effect marker tool in genotoxicology monitoring. METHOD: In addition to the basic steps of the comet assay, one sample was treated with formamido-pirimidine-DNA-glycolase restriction-enzyme that measures oxidative DNA damage. RESULTS: An increase was observed in tail moments in each group of untreated and Fpg-treated samples compared to the control. CONCLUSIONS: It can be concluded that occupational exposure can be detected with the method. The comet assay may prove to be an excellent effect marker and a supplementary technique for monitoring the presence or absence of genotoxic effects.

Immunotoxicity monitoring of hospital staff occupationally exposed to cytostatic drugs.

The aim of our study was to investigate the immunotoxicity of occupational cytostatic drug exposure, and to assess the possible effect of confounding factors, such as age and smoking. In this human study, the immunotoxic effect of antineoplastic drugs was investigated among 306 nurses working in oncology chemotherapy units. Results were compared to 98 non-exposed women. The immune status of the subjects was characterized by immune phenotyping of peripheral blood lymphocytes by flow cytometry, using monoclonal antibodies against surface antigens (CD3, CD4, CD8, CD19, CD25, CD45, CD56 and CD71). The killing ability of neutrophil leukocytes was assessed by the measurement of reactive oxygen intermediate production. Occupational exposure to antineoplastic drugs caused shifts in the major lymphocyte subpopulations, resulting in a statistically significant increase in the ratio of B cells. Cytostatic drug exposure also manifested itself in a decreased frequency of CD25 positive, activated T lymphocytes, and increased oxidative burst of neutrophil granulocytes, both of which may have a functional impact on the immune system of exposed subjects. In the younger subjects exposure also caused a shift in T cell subpopulations: a reduction in the cytotoxic T cell population lead to an elevated Th/Tc ratio. In the exposed group, smoking increased activation of T lymphocyte subpopulations. In conclusion, we have demonstrated that low dose occupational cytostatic drug exposure is immunotoxic, and age and smoking modify the effect of exposure.

Formaldehyde-induced chromosomal aberrations and apoptosis in peripheral blood lymphocytes of personnel working in pathology departments.

Peripheral blood lymphocytes (PBL) of 37 formaldehyde-exposed women from four pathology departments in Hungary were investigated to collect data on the effects of occupational exposures to formaldehyde and to find a possible relationship between in vivo formaldehyde-induced apoptosis and genotoxic effects. The subjects were divided into two groups: 16 donors exposed to formaldehyde together with various organic solvents, and 21 subjects exposed mainly to formaldehyde. The results were compared with 37 controls (all women) without known occupational exposure. Ambient air concentrations of formaldehyde were measured in three work places, and ranged from 0.23 to 1.21mg/m(3) (mean 0.9mg/m(3)). Measures of genotoxicity included the determination of the frequencies of chromosomal aberrations (CA), sister-chromatid exchange (SCE), HPRT mutations (variant frequency, VF) and the measurement of UV-induced unscheduled DNA-repair synthesis (UDS). The percentages of premature centromere division (PCD) and of cells with a high frequency of SCE (HF/SCE) were also scored. Apoptosis and cell proliferation were determined by flow cytometry. In both formaldehyde-exposed groups, the apoptotic activity and the CA levels in PBLs were significantly higher than in controls. The CA were mostly breaks of the chromatid type. In the second group, which was mainly exposed to formaldehyde, CA were slightly lower in comparison with the group exposed to formaldehyde and solvents, which may be attributed to a different rate of elimination of damaged lymphocytes as a consequence of formaldehyde-induced apoptotic activity. In the second group, a significant decrease of VF and a non-significant increase in HF/SCE were found compared with the control and the other group. In conclusion, the results demonstrate that exposure to formaldehyde induces apoptosis and CA, indicating an excess cancer risk among subjects occupationally exposed to formaldehyde. The results also emphasize the importance of the measurement of occupational air pollutants, such as formaldehyde, in order to avoid genotoxic effects in the workers.

Chemical safety and health conditions among Hungarian hospital nurses.

In the present study genotoxicological and immunotoxicological follow-up investigations were made on 811 donors including 94 unexposed controls and 717 nurses with various working conditions from different hospitals (The Hungarian Nurse Study). The nurses were exposed to different chemicals: cytostatic drugs, anesthetic, and sterilizing gases, such as ethylene oxide (ETO) and formaldehyde. The measured biomarkers were: clinical laboratory routine tests, completed with genotoxicological (chromosome aberrations [CA], sister chromatid exchange [SCE]), and immune-toxicological monitoring (ratio of lymphocyte subpopulations, lymphocyte activation markers, and leukocyte oxidative burst). The highest rate of genotoxicologically affected donors (25.4%) was found in the group of cytostatic drug-exposed nurses. Comparing geno- and immunotoxicological effect markers, we found that among genotoxicologically affected donors the frequency of helper T cell (Th) lymphocytes, the ratio of activated T and B cells increased, whereas the oxidative burst of leukocytes decreased. In hospitals with lack of protective measures increased CA yields were observed compared to those with ISO 9001 quality control or equivalent measures. Anemia, serum glucose level, thyroid dysfunctions, benign, and malignant tumors were more frequent in the exposed groups than in controls. The hygienic standard of the working environment is the basic risk factor for the vulnerability of nurses. On the basis of these results, it is suggested, that the used cytogenetic and immunological biomarkers are appropriate to detect early susceptibility to diseases. The Hungarian Nurse Study proved that the use of safety measures could protect against occupational exposure at work sites handling cytostatic drugs, anesthetic, and sterilizing gases.

[The state of health of oncology nurses characterized by genetic and immunotoxicologic biomarkers]. / Citosztatikumokkal exponált nôvérek egészségi állapotának jellemzése gén- és immuntoxikológiai módszerekkel.

Statistical data indicate a chronic shortage of work-force due to overwork, ill health state and increased risk of chronic noninfectious diseases in Hungarian health care personnel, which needs investigations in order to decrease the risk. Nurses of oncology units, often exposed to carcinogens when preparing and handling cytostatic drugs, are especially at high risk. In the present publication we report a complex clinical, geno- and immunotoxicology risk assessment of altogether 500 nurses, performed during the last 10 years at various oncology units in Hungary. The obtained results indicate that the health status of nurses at oncology units is better than the Hungarian average, especially of hypertonia and type II diabetes. However, the prevalence of iron deficiency anemia and different thyroid gland diseases is significantly higher than those of the controls matched for sex and age. The results suggest that iron deficiency can potentiate the resistance to insulin, i.e. the persistence of iron deficiency may increase the serum glucose levels and thus the risk of diabetes. Among the studied geno- and immunotoxicology biomarkers, the frequency of chromosome aberrations, sister chromatid exchange and B lymphocytes was significantly increased compared to the matched controls. The obtained alterations demonstrate the occupational exposure of the nurses to cytostatic drugs, thus the introduction of more strict hygienic controls and compliance with the European Union chemical safety regulations is necessary.

Risk management among benzene-exposed oil refinery workers.

Ten benzene-exposed oil refinery workers were genotoxicologically monitored in an annual follow-up study between 1990 and 2003 and compared with 87 industrial and 26 matched controls. Each of the exposed subjects suffered from several intercurrent non-infectious diseases such as joint, rheumatic, gastric and dental problems, as well as kidney and liver dysfunctions. The structural chromosome aberration (CA) yields of the exposed donors suggested a dose-dependent response to the mean peak benzene concentrations in the ambient air. Sister chromatid exchange (SCE), high-frequency SCE, DNA repair, and cell proliferation data also indicated the presence of genotoxic exposure at the workplace. The results of the biological and genotoxicological monitoring indicated the need of intervention (primary prevention of occupational exposure-related chronic non-infectious diseases) including the introduction of zero tolerance of benzene emission, health control, and education with motivation to change life-styles. The decrease in CA frequencies considered as the most established genotoxicological effect markers indicated the positive changes due to the achieved zero tolerance at the workplaces. The results also demonstrated the effectiveness of a trilateral co-operation between the health services, the employer and the employee in order to reduce the risk of the exposure-related intercurrent non-infectious diseases and to prevent further deterioration of the health state of the workers.

[Biomarker indicators of chemoprevention among subjects occupationally exposed to metals]. / A kemoprevenció biomarker indikátorai fémexponáltak körében.

Chemoprevention with chelating agent Humetta for three months was performed, due to anaemia and other haematologic disorders, immunotoxicological alterations and/or increased chromosome aberration rate among galvanisers and goldsmiths occupationally exposed to precious and heavy metals. Twenty-two of altogether 47 subjects took part voluntarily in the chemoprevention, and the rest of the subjects served as untreated controls. Complex clinical laboratory testing including detailed anamneses; genotoxicological and immunotoxicological monitoring were performed before and after administration of chemopreventive agent. After chemoprevention a significant improvement was observed in anaemia and serum glucose levels, while a less marked improvement was found in serum cholesterol levels and liver functions. Altered chromosome aberration and apoptotic cell fraction also tended to normalise after treatment. Immunological parameters were not affected by the treatment. The obtained results may suggest that chemoprevention with chelating agents as Humetta can help in the prevention of harmful effects of occupational exposures to metals.

Lymphocyte phenotype analysis and chromosome aberration frequency of workers occupationally exposed to styrene, benzene, polycyclic aromatic hydrocarbons or mixed solvents.

The aim of our study was to investigate the immunotoxicity of benzene, styrene and polycyclic aromatic hydrocarbon exposure, to establish the correlation between immunological and genotoxicological parameters, and to assess the possible effect of confounding factors such as age and smoking. The immune status of the donors was characterized by measuring the surface antigens of peripheral lymphocytes. The studied antigens were the following: CD3, CD4, CD8, CD14, CD19, CD25, CD38, CD45, CD45RO, CD54, CD56, CD62L, CD71 and HLA-DR. In our studies, we compared the immunological and genotoxicological parameters (chromosome aberration, sister chromatid exchange frequency, unscheduled DNA synthesis) of the different groups with healthy controls. Analysis revealed changes in the expression of surface antigens on peripheral lymphocytes in correlation with exposure. Confounding factors, such as smoking, increased the proportion of CD4 positive T lymphocytes and influenced the surface expression of several antigens. In our investigation the occurrence of chromosome aberrations negatively correlated with CD25 (IL-2R) expression in both CD4 and CD8 positive T cells. The presented data suggest that solvents such as benzene, styrene and PAHs activate peripheral lymphocytes, and cause changes in the incidence of CD25+/CD4+ T lymphocytes that may represent a distinct subset of immune-regulatory T cells.