Sister chromatid exchanges and micronuclei in peripheral lymphocytes of shoe factory workers exposed to solvents. (Articles).We examined sister chromatid exchanges (SCEs) and micronuclei (MN; cytokinesis-block method) in cultured peripheral lymphocytes Lymphocytes
Small white blood cells that bear the major responsibility for carrying out the activities of the immune system; they number about 1 trillion. from 52 female workers of two shoe factories and from 36 unexposed age- and sex-matched referents. The factory workers showed an elevated level of urinary hippuric acid hippuric acid /hip·pu·ric ac·id/ (hi-pur´ik) C6H5·CO·NH·CH2·COOH, formed by conjugation of benzoic acid and glycine.
hippuric acid , a biomarker of toluene toluene (tōl`yēn') or methylbenzene (mĕth'əlbĕn`zēn), C7H8 exposure, and workplace air contained high concentrations of various organic solvents such as toluene, gasoline, acetone acetone (ăs`ĭtōn), dimethyl ketone (dīmĕth`əl kē`tōn), or 2-propanone (prō`pənōn), CH3COCH3 , and (in one of the plants only) ethylacetate and methylenediphenyl diisocyanate. The shoe factory workers showed a statistically significant higher frequency of micronucleated binucleate bi·nu·cle·ate or bi·nu·cle·ar
Having two nuclei. lymphocytes in comparison with the referents. This finding agreed with three preliminary MN determinations (each comprising 27-32 shoe workers and 16-20 controls) performed in one of the plants 2-5 years earlier. The shoe factory workers also had a lower average level of blood hemoglobin than the referents. In contrast, no difference was found between the groups in SCE SCE (in Scotland) Scottish Certificate of Education
SCE n abbr (= Scottish Certificate of Education) → Schulabschlusszeugnis in Schottland analysis. Smokers showed significantly higher mean frequencies of SCEs per cell and high frequency cells (HFC 1. (networking) HFC - Hybrid Fiber Coax.
2. (hardware) HFC - hydrofluorocarbon. ) than nonsmokers. Aging was associated with increased MN rates and reduced cell proliferation. Polymorphism of the glutathione S-transferase M1 gene (GSTM GSTM Gatespace Telematics (supplier of systems and components for telematics)
GSTM General System Test Module 1) did not affect the individual level of SCEs; but in smoking shoe workers an effect of the occupational exposure on the frequency of micronucleated cells could be seen only in GSTM1 null subjects. The low prevalence of the glutathione S-transferase T1 (GSTT GSTT Generation Skipping Transfer Tax
GSTT Geological Society of Trinidad & Tobago 1) null genotype precluded the evaluation of the influence of GSTT1 polymorphism. Our results show that the shoe factory workers have experienced genotoxic genotoxic /ge·no·tox·ic/ (je´no-tok?sik) damaging to DNA: pertaining to agents known to damage DNA, thereby causing mutations, which can result in cancer.
adj. exposure, which is manifest as an increase in the frequency of MN, but not of SCEs, in peripheral lymphocytes. The exposures responsible for the MN induction could not be identified with certainty, but exposure to benzene in gasoline and methylenediphenyl diisocyanate may explain some of the findings. Key words: glutathione S-transferase M1, glutathione S-transferase T1, micronuclei assays, shoe factory workers, sister chromatid exchange assays, solvent exposure. Environ Health Perspect 110:399-404 (2002). [Online 11 March 2002]
During the last few years, genotoxicity Genotoxic substances are a type of carcinogen, specifically those capable of causing genetic mutation and of contributing to the development of tumors. This includes both certain chemical compounds and certain types of radiation. biomarkers have received considerable interest as tools for detecting human genotoxic exposure and effects, especially in health surveillance programs dealing with occupational exposure to chemical carcinogens Carcinogens
Substances in the environment that cause cancer, presumably by inducing mutations, with prolonged exposure.
Mentioned in: Colon Cancer, Rectal Cancer . Currently, only cytogenetic cytogenetic /cy·to·ge·net·ic/ (-je-net´ik)
1. pertaining to chromosomes.
2. pertaining to cytogenetics.
pertaining to or originating from the origin and development of the cell. end points in peripheral blood lymphocytes Peripheral Blood Lymphocytes (PBL): These are the mature lymphocytes (small white immune cells) that are found circulating in the blood, as opposed to organs, such as the lymph nodes, spleen, thymus, liver or bone marrow. These cells consist of T cells, NK cells and B cells. allow a reasonable epidemiologic evaluation of cancer predictivity. The largest databases are available for chromosomal aberrations (CA); high CA level has been associated with increased cancer risk (1,2). Evaluations have also been performed for lymphocyte lymphocyte: see blood; immunity.
Type of leukocyte fundamental to the immune system, regulating and participating in acquired immunity. Each has receptor molecules on its surface that bind to a specific antigen. sister chromatid exchanges (SCEs) and micronuclei (MN), but thus far these biomarkers have not been shown to predict cancer (1,2). These findings may reflect the relatively small databases, the comparatively young cohorts, and variation in techniques, which have made it difficult to standardize individual SCE and MN values obtained from different sources. In a few years, accumulation of more uniform data will make it possible to reassess the value of both SCEs and MN. In the meantime Adv. 1. in the meantime - during the intervening time; "meanwhile I will not think about the problem"; "meantime he was attentive to his other interests"; "in the meantime the police were notified"
meantime, meanwhile , SCEs and MN are used as biomarkers of genotoxic exposure, as simpler alternatives to CA analysis. In the present study, we applied these methods to monitor solvent-exposed workers from two Bulgarian shoe factories.
People employed in the shoemaking industry are at an increased risk of leukemia and nasal cancer (3), and an excess of mortality due to other types of cancer has also been reported (4-6). Workers in shoe and boot factories are exposed to a mixture of organic solvents, among which toluene and acetone are usually the most common. Neither of these solvents is considered a genotoxin ge·no·tox·in
A chemical or other agent that damages cellular DNA, resulting in mutations or cancer.
[New Latin geno-, gene (from Greek genos, race, offspring; see or a carcinogen carcinogen: see cancer.
Agent that can cause cancer. Exposure to one or more carcinogens, including certain chemicals, radiation, and certain viruses, can initiate cancer under conditions not completely understood. ; the weight of evidence from human in vivo in vivo /in vi·vo/ (ve´vo) [L.] within the living body.
Within a living organism.
in vivo adv. studies suggests that exposure to toluene does not cause somatic cell somatic cell
Any cell of a plant or an animal other than a germ cell. genotoxic damage (7), although this view has been questioned by recent studies of rotogravure rotogravure: see printing. printers (8,9).
The glues and gasoline used in shoe manufacture may contain benzene, which could be responsible for some of the cancers found in shoe workers. Benzene is a well-known clastogen that requires metabolic activation to be mutagenic mutagenic
inducing genetic mutation. . The genotoxic metabolites Metabolites
Substances produced by metabolism or by a metabolic process.
Mentioned in: Interactions are also thought to play an important role in benzene myelotoxicity and leukemogenesis leu·ke·mo·gen·e·sis
Induction, development, and progression of a leukemic disease.
the process of generation of myeloid cell lines in bone marrow and extramedullary sites; a critical feature in myeloproliferative . The quinone quinone
Any member of a class of cyclic organic compounds comprising a six-membered unsaturated ring (see saturation) to which two oxygen atoms are bonded as carbonyl groups (−C=O; see functional group). metabolites of benzene can break chromosomes by inducing reactive oxygen species reactive oxygen species,
n molecules and ions of oxygen that have an unpaired electron, thus rendering them extremely reactive. Many cellular structures are susceptible to attack by ROS contributing to cancer, heart disease, and cerebrovascular disease. but may also act as aneuploidogens, causing microtubule microtubule
Tubular structure enclosed by a membrane found within animal and plant cells. Of varying length, they have several functions. They help give shape to many cells and are major components of cilia and flagella, participate in the formation of the spindle during disruption (10,11). Recent investigations have indicated that structural CA are increased in shoe factory workers exposed to benzene and toluene (12,13).
In a preliminary study of the genotoxic effects of occupational exposure to organic solvents, using the alkaline Comet assay, we did not detect any increase in DNA DNA: see nucleic acid.
or deoxyribonucleic acid
One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. damage in cryopreserved peripheral blood peripheral blood Cardiology Blood circulating in the system/body mononuclear leukocytes from a group of women employed in the two Bulgarian shoe factories (14).
Here we report results of lymphocyte SCE and MN analyses in a larger group of shoe workers from the same plants. We also present MN data from three other cross-sectional studies conducted 2-5 years earlier than the last sampling. In all cases, the concentrations of toluene, gasoline, acetone, ethylacetate, and methylenediphenyl diisocyanate (MDI (1) (Multiple Document Interface) A Windows function that allows an application to display and lets the user work with more than one document at the same time. ) in workplace air and the concentration of hippuric acid (HA) in the urine were determined. To evaluate whether genetically determined individual variations in xenobiotic xen·o·bi·ot·ic
Foreign to the body or to living organisms. Used of chemical compounds.
A xenobiotic chemical.
any substance, harmful or not, that is foreign to the animal's biological system. metabolizing capacity modified individual susceptibility to the possible genotoxic effects of the occupational exposure, we examined the subjects for their glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) genotypes.
Materials and Methods
Subjects studied. We conducted four independent biomonitoring studies of Bulgarian shoe factory workers in 1992, 1993, 1995, and 1997. In the first three years, only workers from plant B (Gabrovo) were examined; the last survey also included subjects from plant A (Sofia). In 1997, we examined 33 workers from plant A and 19 from plant B. The control group consisted of 36 unexposed women from the administrative staff of these plants. The subjects represented about half of the staff in each factory and were chosen randomly. In general, the workers participated in the study only once, except for a few individuals who were included in two or three of the samplings. All subjects gave written informed consent and were interviewed for personal data, duration of employment, and smoking habits. The characteristics of the studied groups are summarized in Table 1. The subjects were all women, except eight control subjects and three exposed workers enrolled in 1992. In all cases, the numbers of smokers among the controls and the exposed subjects were adequately matched, except in the 1993 study, where the number of smokers was higher among the controls than among the exposed. In the shoe factory workers, the total duration of occupational exposure gradually increased during the follow-up period; the difference in the average time of employment in the plant between the first and the last sampling was 3 years.
Exposure measurements. We used special diffusive dif·fu·sive
Characterized by diffusion.
dif·fu monitors (Hygitest Co., Sofia, Bulgaria) placed at breath level to obtain workplace vapor samples. The average concentrations of gasoline and methylenediphenyl diisocyanate (MDI) were measured by express linear-colorimetric method. We measured environmental levels of toluene, acetone, and ethylacetate with an infrared gas chromatography gas chromatography (GC)
Type of chromatography with a gas mixture as the mobile phase. In a packed column, the packing or solid support (held in a tube) serves as the stationary phase (vapour-phase chromatography, or VPC) or is coated with a liquid stationary phase analyzer Miran 1B2 (Foxboro, MA, USA). We monitored these substances in workplace air according to the Bulgarian analytic protocols (15) and Bulgarian Health Ministry's Order (16). Because the administrative staff was expected to be exposed to very low environmental levels of organic solvents, compared with the exposed workers, and given the results of earlier studies (17-19), exposure values for control subjects included in this study were taken to be zero. The mean workplace levels (milligrams per cubic meter) of some organic solvents in the shoe factories are shown in Table 2, expressed as time-weighted average (8-hr TWA) values. It is evident that the shoe workers were exposed to a complex mixture of solvents. In most cases, the concentrations of these solvents clearly exceeded the limits recommended by European and American standards (20-22).
As a biomarker of toluene exposure, urine samples were collected in the end of the working day, also from the controls, and were analyzed for HA, according to a method previously described (23). As can be seen from Table 3, the shoe factory workers showed a marked increase in the mean HA levels, with a statistically significant difference from controls [p < 0.001; analysis of variance (ANOVA anova
see analysis of variance.
ANOVA Analysis of variance, see there )] in each sampling. A significant relationship between HA concentrations in urine and toluene air levels was found in the entire population studied ([beta] = 0.651, p < 0.001). The presence of phenol phenol (fē`nōl), C6H5OH, a colorless, crystalline solid that melts at about 41°C;, boils at 182°C;, and is soluble in ethanol and ether and somewhat soluble in water. , the main urinary metabolite metabolite, organic compound that is a starting material in, an intermediate in, or an end product of metabolism. Starting materials are substances, usually small and of simple structure, absorbed by the organism as food. of benzene, was analyzed (24) in urine samples from 29 shoe factory workers and 16 controls included in the 1992 study. As there were no differences between these groups in urinary phenol levels (exposed: 0.12 [+ or -] 0.03 mmol/L; controls: 0.10 [+ or -] 0.02 mmol/L; detailed data not shown), the workers did not appear to be exposed to high levels of benzene. However, urinary phenol may not reliably indicate lower benzene exposures from gasoline, but these benzene levels may have genotoxic effects.
We analyzed the glues used in these plants in 1997 for benzene content, using a gas chromatograph with a mass-spectrometric detector (Hewlett-Packard 6890/5972A, Wilmington, DE, USA). We detected no benzene traces in these glues.
Blood collection. Heparinized venous blood venous blood
n. Abbr. v
Blood that has passed through the capillaries of various tissues other than the lungs, is found in the veins, in the right chambers of the heart, and in pulmonary arteries, and is usually dark red as a result of a samples were drawn from each donor, and hemoglobin values were measured in Bulgaria by standard methods. In the 1992, 1993, and 1995 studies, the blood samples were processed in Bulgaria, and blood cultures were set up in a few hours after sampling. To carry out the 1997 study, the blood samples were sent to Barcelona and were put in culture within 48 hr after the collection. Briefly, the blood samples were centrifuged at 170 g for 5 min, the plasma was removed, and RPMI RPMI Rapid Prototyping & Manufacturing Institute
RPMI Roswell Park Memorial Institute
RPMI Royal Park Memorial Institute (culture medium) 1640 culture medium (GIBCO GIBCO Grand Island Biological Company (tissue culture media enterprise) , Eragny, France) was added to each blood pellet to attain its initial volume.
Sister chromatid exchanges. We performed the SCE assay only for blood samples obtained in 1997, following standard methodology (25). Briefly, two whole-blood lymphocyte cultures were set up for each donor, and the cultures were incubated covered from light for 72 hr in the presence of 5-bromodeoxyuridine (BrdU; final concentration 8 [micro]g/mL). The cultures were treated with colcemid for the last 2 hr, and the cells were then harvested, treated with hypotonic hypotonic /hy·po·ton·ic/ (-ton´ik)
1. denoting decreased tone or tension.
2. denoting a solution having less osmotic pressure than one with which it is compared. solution (0.075 M KCl) for 20 min, and fixed three times with methanol-glacial acetic acid acetic acid (əsē`tĭk), CH3CO2H, colorless liquid that has a characteristic pungent odor, boils at 118°C;, and is miscible with water in all proportions; it is a weak organic carboxylic acid (see carboxyl group). . Microscopic slides were prepared from the fixed cells by air drying, and the slides were stained by the fluorescence-plus-Giemsa procedure (26). We purchased BrdU and Hoechst 33258 from Eastman Kodak (Rochester, NY, USA), and Giemsa from Merck (Darmstadt, Germany).
For each donor, we analyzed 50 metaphases (25/replicate) on coded slides to determine the frequency of SCEs per cell. The analysis was conducted by two scorers, one per replicate. We estimated the percentage of high frequency cells (HFC) for each individual using the pooled distribution of all SCE measurements. We defined HFC as cells with SCE number over the 95th percentile of the distribution of SCEs per cell in the whole population. We examined 100 metaphases to calculate the proliferation rate index (PRI PRI: see Institutional Revolutionary party.
(Primary Rate Interface) An ISDN service that provides 23 64 Kbps B (Bearer) channels and one 64 Kbps D (Data) channel (23B+D), which is equivalent to the 24 channels of a T1 line. ) (27).
Micronuclei. Whole blood cultures for the cytokinesis-block MN test were established according to Surralles et al. (28), with some minor adaptations to the specific conditions of the Sofia and Barcelona laboratories. In both cases, the cultures were incubated at 37 [degrees] C for 72 hr and, at 44 hr after initiation of the cultures, cytochalasin-B (Sigma Chemicals, St. Louis, MO, USA) was added at a concentration of 6 [micro]g/mL. The cells were harvested, treated with a mild hypotonic solution (0.075 M KCl) for 2-3 min, and gently fixed three times using methanol/acetic acid (5:1) solution. Air-dried preparations were made, and the slides were stained in a 10% (v/v) solution of Giemsa in phosphate buffer (pH 6.8) for 20 min.
We examined 1,000 binucleate cells for each subject on coded slides (the same scorer in Barcelona and Bulgaria), and the total numbers of MN and the frequency of binucleate cells with MN (BNMN) were scored. We scored 500 lymphocytes to evaluate the percentage of cells with 1, 2, 3, or 4 nuclei, and we calculated the cytokinesis-block proliferation index (CBPI CBPI Competency-Based Performance Improvement ) according to Surralles et al. (29).
Genotype analysis. We used genomic DNA extracted from leukocytes by standard methods as a template in the GSTM1 and GSTT1 genotype analyses, as described elsewhere (30). Briefly, the GSTM1 and GSTT1 genotypes were determined simultaneously in a multiplex polymerase chain reaction polymerase chain reaction (pŏl`ĭmərās') (PCR), laboratory process in which a particular DNA segment from a mixture of DNA chains is rapidly replicated, producing a large, readily analyzed sample of a piece of DNA; the process is (PCR PCR polymerase chain reaction.
polymerase chain reaction
Polymerase chain reaction (PCR) ) approach using [beta]-globin specific primers in addition to the GSTM1 and GSTT1 specific primer pairs. The presence of the [beta]-globin specific signal verified the proper functioning of the PCR reaction, whereas the absence of GSTM1 and GSTT1 specific amplification products revealed the corresponding null genotypes.
Statistical analysis. For the cross-sectional studies performed in 1992-1997, all variables analyzed were compared with the normal distribution by the Kolmogorov-Smirnov test of goodness of fit Goodness of fit means how well a statistical model fits a set of observations. Measures of goodness of fit typically summarize the discrepancy between observed values and the values expected under the model in question. Such measures can be used in statistical hypothesis testing, e. . The distributions of our data did not significantly depart from normality (p > 0.05) in any case, so parametric tests were adequate for the statistical analysis.
For each independent study, the effects of various factors on HA, hemoglobin, BNMN, and SCEs were simultaneously assessed by the ANOVA. These factors were occupational exposure, smoking, and, if available, GST GST
Greenwich sidereal time
GST (in Australia, New Zealand, and Canada) Goods and Services Tax genotypes, and we considered the age of the subjects as a covariate. To determine the relationship between solvent exposure levels and both HA and hemoglobin data, we applied a multiple regression Multiple regression
The estimated relationship between a dependent variable and more than one explanatory variable. analysis in the whole population. To this effect, from those subjects sampled several times, only the latest results were included in the analysis. Because of the low prevalence of the GSTT1 null genotype, GSTT1 genotype was not included as an independent variable in the analysis. The results were analyzed using the CSS (1) See Cascading Style Sheets.
(2) (Content Scrambling System) The copy protection system applied to DVDs, which uses a 40-bit key to encrypt the movie. : STATISTICA/W (StatSoft, Tulsa, OK, USA) statistical package.
As shown in Table 3, the hemoglobin values of shoe factory workers were reduced compared those of nonexposed women. This difference, apparently stemming from the occupational exposure, reached statistical significance (p < 0.001) in the ANOVA.
In 1992-1995, we used the MN assay to assess whether the occupational exposure of the shoe factory workers could exert some genotoxic effects. We observed significant increases in the mean frequency of BNMN of the exposed groups each year in comparison with the respective control groups (Figure 1). Especially noteworthy was the constant increase in the mean frequency of BNMN in the exposed groups from 1992 (38.00, SD 20.18) to 1995 (55.2, SD 17.1), whereas control subjects consistently showed similar basal mean values (from 18.6, SD 6.3 to 22.0, SD 10.0).
In the last study, carried out in 1997 and involving both factories, the MN assay confirmed our previous positive findings. Table 4 shows the MN and SCE results, separately for nonsmokers and smokers, among the controls and exposed workers. In the multiple ANOVA, occupational exposure (plant A, plant B, and controls) constituted a statistically significant (p < 0.001) source of variation for the BNMN values. The post hoc least squares difference test showed that workers of plant B had a clearly higher BNMN frequency (p < 0.001) than controls or plant A workers, but also plant A workers differed significantly (p = 0.035) from the controls. We detected no effect on cell-cycle kinetics, measured as CBPI, as a consequence of the solvent exposure.
In the SCE assay (Table 4), we were not able to detect any genotoxic effect related to occupational exposure. We found no correlation between MN and SCEs. The occupational exposure was associated with a slight decrease in PRI (p = 0.048).
Age was a significant covariate (p = 0.006) in the multiple analysis of variance of the 1997 BNMN data, reflecting an age-dependent increase in BNMN frequency. Age appeared to be partially associated with a decreased cell proliferation, as indicated by its significant effect on PRI (p = 0.001); CBPI was not affected by age. In the same analysis, smoking did not significantly affect BNMN frequencies in the 1997 study. However, both the mean frequency of SCEs per cell (p = 0.006) and the mean number of. HFC (10 = 0.004) were increased by smoking. This smoking-related effect was stronger among the controls than among plant A workers (p < 0.05 in both cases; t-test), but it did not attain statistical significance among plant B workers.
In agreement with reported frequencies for Caucasian populations, the prevalence of GSTM1 and GSTT1 null subjects in the 1997 study was 56.8% and 13.6%, respectively (Table 5). When the few GSTT1 null subjects were removed for a subsequent ANOVA (including occupational exposure, smoking, and GSTM1 genotype as independent factors and age as a covariate), neither the MN nor the SCE assay outcome was significantly affected by the GSTM1 genotype. However, considering plant A and B workers together, the post hoc least squares difference test indicated a higher BNMN frequency in the exposed than the controls in GSTM1 null subjects among both smokers (p = 0.006) and nonsmokers (p = 0.003), but in GSTM1 positive subjects only among nonsmokers (p = 0.017). Tables 6 and 7 show the average of BNMN, CBPI, SCEs, HFC, and PRI values for GSTM1 positive and GSTM1 null subjects among the different subgroups.
The present study showed an increased frequency of MN in peripheral lymphocytes of shoe factory workers exposed to a mixture of organic solvents. In plant B, where lymphocyte MN frequencies were followed up over 5 years, all four samplings yielded the same result. Although the shoe factory workers did not show any effects in the frequency of SCEs, HFC, or DNA breakage, as measured earlier by the Comet assay (14), our findings indicate the presence of genotoxic exposure at the workplace. This would appear to act via an aneugenic or clastogenic mechanism that does not involve DNA breakage readily detectable by the Comet assay and that does not efficiently lead to SCE formation.
In interpreting these findings, one must consider that although there are several examples of MN induction in human binucleated bi·nu·cle·ate also bi·nu·cle·at·ed or bi·nu·cle·ar
Having two nuclei.
Adj. 1. binucleated - having two nuclei
binuclear, binucleate lymphocytes by known clastogenic exposures in vivo, evidence that the in vivo effects of an aneugen can be expressed in the first in vitro in vitro /in vi·tro/ (in ve´tro) [L.] within a glass; observable in a test tube; in an artificial environment.
In an artificial environment outside a living organism. division of a binucleated cell is scanty (31,32). The binucleated cells that are exclusively analyzed in the cytokinesis-block MN assay have, by definition, completed their first in vitro mitosis, and most MN observed in such cells have been formed in the culture. Thus, an in vivo MN inducer inducer /in·duc·er/ (in-dldbomacs´er) a molecule that causes a cell or organism to accelerate synthesis of an enzyme or sequence of enzymes in response to a developmental signal.
n. would have to be able to initiate its effect in the resting [G.sub.0] lymphocyte. Further studies of the shoe factory workers using CA analysis or an MN assay incorporating pancentromeric fluorescence in situ hybridization Fluorescence in situ hybridization (FISH)
A technique for diagnosing DiGeorge syndrome before birth by analyzing cells obtained by amniocentesis with DNA probes. FISH is about 95% accurate. or antikinetochore antibodies to identify the contents of the MN will be useful in identifying the nature of the exposure that produced the excess MN.
Although the glues used in the factories did not contain measurable amounts of benzene, there probably was benzene in the gasoline used as solvent. The air concentrations of gasoline were high, and benzene may well be the principal agent responsible for the observed genotoxic effects. In factory B, the levels of MDI (measured as diisocyanate) were very high and could explain some of the genotoxic effects. MDI is highly reactive and induced CA in human lymphocytes in vitro (33). MN frequencies were clearly higher in plant B than in plant A, and this could be caused by MDI, since diisocyanate was not found at all in plant A. Even in plant B, diisocyanate was not discovered during the first three sample collections. Thus, although it may not be possible to point out a single genotoxic agent at the workplace, benzene in gasoline and MDI may explain some of the findings. A possible indication of the heavy organic solvent exposure of the workers was the consistently lowered blood hemoglobin level, which we also observed in the previous study (14). Anemia and other hematologic hematological, hematologic
pertaining to or emanating from blood cells.
total and differential white cell counts, hematocrit estimation, erythrocyte count. abnormalities have been associated with organic solvent exposure in Bulgarian petroleum workers (34).
Several investigations have suggested an increased sensitivity of the GSTM1 null genotype to genotoxicity induced by various exposures, including tobacco smoke (35-47). Such an association was not, however, unequivocally demonstrated in most of the few studies where SCEs or MN were used as biomarkers (48-58). Nevertheless, our MN results appear to support the increased sensitivity of the GSTM1 null genotype, because in smokers an occupational exposure effect could be seen only among GSTM1 null subjects. Although this finding is based on a few individuals, it could indicate, for example, that smoking induces GSTM1 activity in GSTM1-proficient individuals, which would protect them from t&e genotoxic effects of the occupational exposure. Smoking is not known to markedly induce GSTM1 in humans in vivo. At present, the possible effect of GSTM1 genotype on MN formation is not well understood. Our previous studies suggested that the baseline level of MN is decreased in GSTM1 null subjects (55).
In one investigation, the GSTM1 null genotype was described to increase SCEs in smokers, although the difference to GSTM1 positive smokers was quite small (0.23 SCEs/cell) and was statistically significant only in heavy smokers (0.53 SCEs/cell) (48). An increase of this magnitude may have been undetected in the present study. An effect of GSTM1 polymorphism on the baseline level of SCEs in nonsmokers was reported by Cheng et al. (59,60), but this finding has not been reported in other studies (52-54,57), and it was not supported by our data.
In contrast, there is some evidence that the GSTT1 null genotype is associated with an increased baseline frequency of SCEs (61-64) and possibly also CA (54,65). This finding does not appear to be explained by smoking or other known exposures. Unfortunately, we could not properly evaluate the effects of GSTT1 polymorphisms because of the low frequency of the GSTT1 null genotype.
In conclusion, our results indicate that the shoe factory workers studied have experienced genotoxic exposure, which is manifested as an increase in the frequency of MN, but not of SCEs, in peripheral lymphocytes. The workers also showed a reduction in blood hemoglobin values. Although high air concentrations of several organic solvents were found at the factories, the exposures responsible for the MN induction could not be identified with certainty. Exposure to benzene in gasoline and MDI may explain some of the findings.
Table 1. Characteristics of the exposed shoe workers and control subjects studied. Age, years Year, group No. (mean [+ or -] SD) 1992 Controls 16 35.3 [+ or -] 7.9 Exposed 32 38.8 [+ or -] 9.4 1993 Controls 19 40.2 [+ or -] 7.8 Exposed 27 38.2 [+ or -] 8.0 1995 Controls 20 38.4 [+ or -] 10.3 Exposed 27 38.4 [+ or -] 8.3 1997 Controls 36 43.7 [+ or -] 8.2 Exposed 52 40.7 [+ or -] 8.8 Duration of employment, No. of smokers Year, group years (mean [+ or -] SD) (%) 1992 Controls -- 8 (50.0) Exposed 9.7 [+ or -] 9.5 15 (46.9) 1993 Controls -- 12 (63.2) Exposed 11.1 [+ or -] 10.1 9 (33.3) 1995 Controls -- 10 (50.0) Exposed 12.3 [+ or -] 9.7 16 (59.3) 1997 Controls -- 16 (44.4) Exposed 12.8 [+ or -] 10.5 29 (55.8) Table 2. Concentrations (milligrams per cubic meter) of some solvents in workplace air of two shoe factories. (a) Year Plant Toluene 1992 B 275 [+ or -] 123 (100-410) 1993 B 235 [+ or -] 64 (68-618) 1995 B 148 [+ or -] 104 (18-320) 1997 A 76 [+ or -] 11 (66-96) B 236 [+ or -] 125 (137-412) Year Plant Gasoline 1992 B 746 [+ or -] 430 (422-1,477) 1993 B 1,334 [+ or -] 247 (450-2,800) 1995 B 300 [+ or -] 126 (150-600) 1997 A 457 [+ or -] 45 (392-526) B 468 [+ or -] 201 (283-723) Year Plant Acetone 1992 B 628 [+ or -] 363 (159-1,003) 1993 B 539 [+ or -] 252 (24-1,744) 1995 B 960 [+ or -] 955 (55-2,900) 1997 A 374 [+ or -] 17 (341-389) B 764 [+ or -] 189 (523-927) Year Plant Ethylacetate 1992 B -- (b) 1993 B -- (b) 1995 B 93 [+ or -] 82 (7-360) 1997 A -- (b) B 246 [+ or -] 105 (164-400) Year Plant Diisocyanate 1992 B -- (b) 1993 B -- (b) 1995 B 0.21 [+ or -] 0.07 (0.06-0.29) 1997 A -- (b) B 0.23 [+ or -] 0.08 (0.15-0.34) (a) Measured during an 8-hr workshift, except for diisocyanate, which was measured during a 15-min exposure. Values shown are mean [+ or -] SD (range). (b) Not used. Table 3. Urinary hippuric acid and blood hemoglobin levels in exposed shoe workers and control subjects (means [+ or -] SD). Year, group (plant) No. Hippuric acid Hemoglobin 1992 Controls 16 0.53 [+ or -] 0.28 150.50 [+ or -] 9.97 Exposed (plant B) 32 3.05 [+ or -] 2.14 123.00 [+ or -] 9.56 1993 Controls 14 0.91 [+ or -] 0.64 131.83 [+ or -] 13.59 Exposed (plant B) 26 2.97 [+ or -] 1.51 124.38 [+ or -] 11.72 1995 Controls 20 0.34 [+ or -] 0.16 141.80 [+ or -] 8.76 Exposed (plant B) 27 1.56 [+ or -] 1.55 115.04 [+ or -] 8.99 1997 Controls 36 0.48 [+ or -] 0.31 139.42 [+ or -] 12.44 Exposed (total plants A and B) 52 2.26 [+ or -] 1.63 124.06 [+ or -] 13.52 Exposed (plant A) 33 1.90 [+ or -] 1.05 128.64 [+ or -] 14.02 Exposed (plant B) 19 2.87 [+ or -] 2.22 116.11 [+ or -] 7.94 Table 4. Mean ([+ or -] SD) frequencies of BNMN and SCEs in lymphocytes of shoe factory workers of plants A and B and unexposed controls, according to smoking habit (last sampling). Micronucleus assay (a) Group No. No. BNMN/1,000 cells CBPI Controls Nonsmokers 20 24.15 [+ or -] 7.49 1.89 [+ or -] 0.16 Smokers 16 22.19 [+ or -] 8.45 1.87 [+ or -] 0.11 Plant A workers Nonsmokers 15 31.13 [+ or -] 10.01 1.93 [+ or -] 0.08 Smokers 18 25.28 [+ or -] 12.13 1.89 [+ or -] 0.09 Plant B workers Nonsmokers 8 47.25 [+ or -] 9.10 1.85 [+ or -] 0.20 Smokers 11 43.45 [+ or -] 13.47 1.95 [+ or -] 0.17 Total Controls 36 23.28 [+ or -] 7.87 1.88 [+ or -] 0.14 Plant A workers 33 27.94 [+ or -] 11.44 1.91 [+ or -] 0.09 Plant B workers 19 45.05 [+ or -] 11.69 1.91 [+ or -] 0.19 SCE assay (b) Group No. No. SCEs/cell Controls Nonsmokers 15 7.83 [+ or -] 1.04 Smokers 13 9.05 [+ or -] 1.73 Plant A workers Nonsmokers 15 7.59 [+ or -] 0.86 Smokers 18 8.47 [+ or -] 1.10 Plant B workers Nonsmokers 8 7.77 [+ or -] 0.80 Smokers 11 8.15 [+ or -] 1.34 Total Controls 28 8.40 [+ or -] 1.51 Plant A workers 33 8.07 [+ or -] 1.08 Plant B workers 19 7.99 [+ or -] 1.13 SCE assay (b) Group Percent HFC PRI Controls Nonsmokers 2.67 [+ or -] 2.47 2.26 [+ or -] 0.24 Smokers 8.37 [+ or -] 9.26 2.32 [+ or -] 0.12 Plant A workers Nonsmokers 2.53 [+ or -] 2.45 2.15 [+ or -] 0.16 Smokers 6.11 [+ or -] 5.29 2.28 [+ or -] 0.28 Plant B workers Nonsmokers 4.25 [+ or -] 3.62 2.29 [+ or -] 0.10 Smokers 5.17 [+ or -] 4.98 2.38 [+ or -] 0.10 Total Controls 5.31 [+ or -] 7.05 2.29 [+ or -] 0.19 Plant A workers 4.48 [+ or -] 4.55 2.22 [+ or -] 0.24 Plant B workers 4.76 [+ or -] 4.37 2.34 [+ or -] 0.11 (a) BNMN/1,000 cells was affected by occupational exposure (p < 0.001) and age (a covariate; p = 0.006) in analysis of variance. (b) Smoking affected no. SCEs/cell (p = 0.006) and HFC (p = 0.004) in analysis of variance. Table 5. Distribution of GSTM1 and GSTT1 genotypes among exposed shoe factory workers and control subjects in 1997. Controls Exposed Genotypes No. Percent No. Percent GSTM1 + GSTT1 + 13 36.1 19 36.5 GSTM1 + GSTT1 null 4 11.1 2 3.8 GSTM1 null GSTT1 + 16 44.5 28 53.9 GSTM1 null GSTT1 null 3 8.3 3 5.8 Total Genotypes No. Percent GSTM1 + 32 36.4 GSTM1 + 6 6.8 GSTM1 null 44 50.0 GSTM1 null 6 6.8 Table 6. Mean ([+ or -] SD) frequency of BNMN and CBPI in shoe factory workers and unexposed controls, according to smoking and GSTM1 genotype (last sampling). Group, smoking habit Genotype No. Controls Nonsmokers GSTM1 null 7 GSTM1 + 8 Smokers GSTM1 null 9 GSTM1 + 5 Plant A workers Nonsmokers GSTM1 null 7 GSTM1 + 7 Smokers GSTM1 null 11 GSTM1 + 6 Plant B workers Nonsmokers GSTM1 null 4 GSTM1 + 3 Smokers GSTM1 null 6 GSTM1 + 3 Group, smoking habit No. BNMN/1,000 cells (a) CBPI Controls Nonsmokers 22.43 [+ or -] 7.44 1.89 [+ or -] 0.21 22.38 [+ or -] 4.81 1.89 [+ or -] 0.14 Smokers 19.89 [+ or -] 8.34 1.84 [+ or -] 0.15 25.20 [+ or -] 10.03 1.89 [+ or -] 0.03 Plant A workers Nonsmokers 30.29 [+ or -] 11.24 1.91 [+ or -] 0.07 31.29 [+ or -] 10.14 1.94 [+ or -] 0.08 Smokers 27.82 [+ or -] 14.35 1.90 [+ or -] 0.07 21.17 [+ or -] 7.19 1.91 [+ or -] 0.12 Plant B workers Nonsmokers 47.50 [+ or -] 11.68 1.92 [+ or -] 0.13 48.33 [+ or -] 8.62 1.73 [+ or -] 0.29 Smokers 45.00 [+ or -] 13.83 2.00 [+ or -] 0.19 33.33 [+ or -] 12.50 1.94 [+ or -] 0.20 (a) Post hoc least squares difference test indicated a higher BNMN frequency in the exposed (plants A and B together) than the controls in GSTM1 null subjects among both smokers (p = 0.006) and nonsmokers (p = 0.003), but in GSTM1 positive subjects only among nonsmokers (p = 0.017). Table 7. Mean ([+ or -] SD) frequency of SCEs, percentage of high frequency cells, and PRI in shoe factory workers and unexposed controls, according to smoking and GSTM1 genotype (last sampling). Group, smoking habit Genotype No. No. SCEs/cell Controls Nonsmokers GSTM1 null 6 7.70 [+ or -] 1.05 GSTM1 + 5 7.86 [+ or -] 1.08 Smokers GSTM1 null 7 8.89 [+ or -] 2.08 GSTM1 + 4 8.76 [+ or -] 1.48 Plant A workers Nonsmokers GSTM1 null 7 7.49 [+ or -] 0.57 GSTM1 + 7 7.84 [+ or -] 1.07 Smokers GSTM1 null 11 8.31 [+ or -] 1.01 GSTM1 + 6 8.66 [+ or -] 1.38 Plant B workers Nonsmokers GSTM1 null 4 8.01 [+ or -] 0.86 GSTM1 + 3 7.53 [+ or -] 0.94 Smokers GSTM1 null 6 8.45 [+ or -] 1.44 GSTM1 + 3 7.05 [+ or -] 0.32 Group, smoking habit Percent HFC PRI Controls Nonsmokers 3.33 [+ or -] 3.50 2.28 [+ or -] 0.17 2.40 [+ or -] 1.67 2.20 [+ or -] 0.38 Smokers 8.00 [+ or -] 11.83 2.27 [+ or -] 0.13 7.69 [+ or -] 7.55 2.38 [+ or -] 0.06 Plant A workers Nonsmokers 2.29 [+ or -] 2.14 2.14 [+ or -] 0.16 3.14 [+ or -] 2.79 2.17 [+ or -] 0.16 Smokers 6.00 [+ or -] 3.69 2.23 [+ or -] 0.34 6.33 [+ or -] 8.24 2.38 [+ or -] 0.13 Plant B workers Nonsmokers 6.00 [+ or -] 4.32 2.28 [+ or -] 0.14 2.67 [+ or -] 2.31 2.32 [+ or -] 0.06 Smokers 5.08 [+ or -] 5.71 2.38 [+ or -] 0.09 2.67 [+ or -] 3.06 2.31 [+ or -] 0.08
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GSTP Generalised System of Tariff Preferences (United Kingdom)
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A measure of the rate of decline in the value of an option due to the passage of time. Theta can also be referred to as the time decay on the value of an option. If everything is held constant, then the option will lose value as time moves closer to the maturity of the option. deletion and cytogenetic sensitivity to diepoxybutane in lymphocytes from butadiene monomer monomer (mŏn`əmər): see polymer.
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Maria Pitarque, (1) Alexander Vaglenov, (1,2) Maria Nosko, (3) Sonya Pavlova, (4) Vera Petkova, (4) Ari Hirvonen, (5) Amadeu Creus, (1) Hannu Norppa, (5) and Ricard Marcos (1)
(1) Grup de Mutagenesi, Departament de Genetica i de Microbiologia, Edifici Cn, Universitat Autonoma de Barcelona, Bellaterra, Spain; (2) National Centre of Radiobiology radiobiology /ra·dio·bi·ol·o·gy/ (-bi-ol´ah-je) the branch of science concerned with effects of light and of ultraviolet and ionizing radiations on living tissue or organisms. and Radiation Protection, Sofia, Bulgaria; (3) Department of Hygiene and Medical Ecology, Medical University, Sofia, Bulgaria; (4) Clinical Centre of Occupational Diseases, Sofia, Bulgaria; (5) Laboratory of Molecular and Cellular Toxicology, Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland
Address correspondence to R. Marcos, Grup de Mutagenesi, Departament de Genetica i de Microbiologia, Edifici Cn, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain. Telephone: +34-93-581-20-52. Fax: +34-93-581-23-87. E-mail: firstname.lastname@example.org
We thank T. Amador, A. Corral, and G. Umbert for their expert technical assistance. The help and advice of K. Mitrunen, S. Saarikoski, and H. Wikman in the genotype analysis are much appreciated.
This investigation was supported in part by the European Union European Union (EU), name given since the ratification (Nov., 1993) of the Treaty of European Union, or Maastricht Treaty, to the
European Community (EV5V-CT92-0221), the Spanish Ministry of Education and Science (SAF SAF Safety
SAF Society of American Foresters
SAF Society of American Florists
SAF Secretary of the Air Force
SAF Second Amendment Foundation
SAF Singapore Armed Forces
SAF Students for Academic Freedom
SAF Store And Forward 95-0813; PM98-0179), and the Generalitat de Catalunya The Generalitat de Catalunya ("Government of Catalonia" ) is the institution under which the Spanish autonomous community of Catalonia is politically organised. (SGR SGR Sustainable Growth Rate
SGR Societa' di Gestione del Risparmio (Italian: Investment Management Company)
SGR Specific Growth Rate
SGR Surgeon General's Report
SGR Soft Gamma-ray Repeater 95-00512). We are grateful to the Universitat Autonoma de Barcelona for supporting M. Pitarque's stay at the Finnish Institute of Occupational Health and to the Spanish Ministry of Education and Culture, which granted a visiting research position for A. Vaglenov (SAB 1995-0689).
Received 2 November 2000; accepted 30 October 2001.