Is breast cancer cluster influenced by environmental and occupational factors among hospital nurses in Hungary? (1/202)

An unusual cluster of 8 breast cancer and 8 other malignant tumor cases (ovarian, uterus, lung, colon and brain tumors and malignant melanoma) developed in a period of 12 years among 98 nurses exposed to ethylene oxide (EtOx) for 5 15 years in a unit using gas sterilizer in a hospital of the archiepiscopal city of Eger, Hungary. EtOx concentration in air samples of the working area varied from 5 to 150 mg/m3. The question was, if there was any causal relationship between the elevated incidence of breast cancer and the EtOx exposure, the other possibility was, that this cluster appeared accidentally. EtOx is a human carcinogen, however, no increased breast cancer incidence in EtOx-exposed subjects was reported in the literature. We followed up for two consecutive years the 27 non cancer patients, EtOx-exposed nurses and 11 unexposed hospital controls with the aid of a multiple genotoxicology monitor including chromosomal aberration, sister-chromatide exchange, HPRT point mutation and DNA repair studies. The results were compared with data from 30 local historical controls, 48 historical controls from Budapest, 14 hospital controls and 9 EtOx exposed nurses from Budapest. Significantly high chromosome aberration yields (especially chromosome type exchanges) were alike detected in EtOx-exposed and the two other control groups in Eger. These results could not be interpreted as a consequence of EtOx exposure only, since in the EtOx-exposed group from Budapest, beside an increased total aberration frequency, the obtained exchange type aberration yields were as low as the historical controls. A plausible explanation can be the natural low dose radioactivity (222Rn) of the local tap-water due to a specific geological situation in Eger. The spontaneous breast cancer incidence in Hungary doubled in the last 10 years compared with the previous 20 years (1960 1980), especially in Eger. The appearance of the high breast cancer incidence in the hospital of Eger indicates the combined effect of EtOx and a more common local etiologic factor, such as the naturally radioactive tap-water. However, since the reported studies did not involve the investigation either of the genetic predisposition, or the effects of other possible environmental, occupational, and/or life style confounding factors, further studies (partly in progress) are necessary to clarify the importance of these factors.  (+info)

Molecular dosimetry of endogenous and ethylene oxide-induced N7-(2-hydroxyethyl) guanine formation in tissues of rodents. (2/202)

The formation of N7-(2-hydroxyethyl)guanine (7-HEG) in DNA was investigated previously in target and non-target tissues of F-344 rats and B6C3F1 mice exposed to >/=ISOdia>/=10 p.p.m. concentrations of ethylene oxide (EO) using fluorescence-linked high-performance liquid chromatography [V.E. Walker et al. (1992) Cancer Res., 52, 4238-4334]. In order to study the dose-responses for 7-HEG at lower exposures, a highly sensitive and specific gas chromatography coupled with high-resolution mass spectrometry (GC-HRMS) assay was developed. DNA was extracted from liver, brain, lung and spleen of B6C3F1 mice and F-344 rats exposed to 0, 3, 10, 33 or 100 p.p.m. EO for 4 weeks (6 h/day, 5 days/week). Analysis of DNA from control rodents showed that endogenous 7-HEG varied from 0.2 +/- 0.1 to 0.3 +/- 0.2 pmol/micromol guanine in tissues of rats and mice. 7-HEG exhibited tissue- and species-specific dose-response relationships in EO-exposed animals. Linear dose-response relationships were evident in mouse liver, brain and spleen at exposures between 3 and 100 p.p.m. Mouse lung exhibited a slightly sublinear response between 33 and 100 p.p.m. EO. The relationships were linear in liver and spleen of rats between 3 and 100 p.p.m. EO, but were slightly sublinear in brain and lung between 33 and 100 p.p.m. EO. The number of 7-HEG adducts present in rats exposed to 3 p.p.m. EO was 5.3-12.5 times higher than endogenous 7-HEG in unexposed controls. In contrast, mice exposed to 3 p.p.m. EO only had 1.3- to 2.5-fold greater numbers of 7-HEG adducts. The factors driving the exposure-response relationships are also likely to affect carcinogenic and mutagenic responses of rodents to EO. Likewise, a better understanding of the relationships between 7-HEG derived from low exposures to EO and endogenously formed 7-HEG may be important for the accurate extrapolation of risk to humans.  (+info)

Dose-rate effects of ethylene oxide exposure on developmental toxicity. (3/202)

In risk assessment, evaluating a health effect at a duration of exposure that is untested involves assuming that equivalent multiples of concentration (C) and duration (T) of exposure have the same effect. The limitations of this approach (attributed to F. Haber, Zur Geschichte des Gaskrieges [On the history of gas warfare], in Funf Vortrage aus den Jahren 1920-1923 [Five lectures from the years 1920-1923], 1924, Springer, Berlin, pp. 76-92), have been noted in several studies. The study presented in this paper was designed to specifically look at dose-rate (C x T) effects, and it forms an ideal case study to implement statistical models and to examine the statistical issues in risk assessment. Pregnant female C57BL/6J mice were exposed, on gestational day 7, to ethylene oxide (EtO) via inhalation for 1.5, 3, or 6 h at exposures that result in C x T multiples of 2100 or 2700 ppm-h. EtO was selected because of its short half-life, documented developmental toxicity, and relevance to exposures that occur in occupational settings. Concurrent experiments were run with animals exposed to air for similar periods. Statistical analysis using models developed to assess dose-rate effects revealed significant effects with respect to fetal death and resorptions, malformations, crown-to-rump length, and fetal weight. Animals exposed to short, high exposures of EtO on day 7 of gestation were found to have more adverse effects than animals exposed to the same C x T multiple but at longer, lower exposures. The implication for risk assessment is that applying Haber's Law could potentially lead to an underestimation of risk at a shorter duration of exposure and an overestimation of risk at a longer duration of exposure. Further research, toxicological and statistical, are required to understand the mechanism of the dose-rate effects, and how to incorporate the mechanistic information into the risk assessment decision process.  (+info)

Cellular internalization of PCL(20)-b-PEO(44) block copolymer micelles. (4/202)

The cellular internalization of polycaprolactone-b-poly(ethylene oxide) (PCL(20)-b-PEO(44)) copolymer micelles were investigated in PC12 cells cultures. The micelles were found to be internalized into PC12 cells when followed over the 4-h incubation period. Also, the internalization process was found to fulfill the basic criteria for endocytotic uptake in that it was time, temperature, pH and energy dependent. In addition, the use of other pharmacological manipulations (hypertonic treatment, Brefeldin A) provide further evidence that the mode of cellular internalization is in fact endocytotic.  (+info)

Characterization of DNA condensates induced by poly(ethylene oxide) and polylysine. (5/202)

High-molecular-weight DNA is known to collapse into very compact particles in a salt solution containing polymers like poly(ethylene oxide) [(EO)n] or polyacrylate. The biological relevance of this phenomenon is suggested by our recent finding that high concentrations of the highly acidic internal peptides found in the mature T4 bacteriophage head, as well as poly(glutamic acid) and poly(aspartic acid), can collapse DNA in a similar manner. The structure of DNAs collapsed by various methods has been studied with electron microscope. We find (EO)n collapses T4 or T7 bacteriophage DNA into compact particles only slightly larger than the size of the T4 and T7 head, respectively. In contrast, polylysine collapses DNA into different types of structures. Double-stranded DNA collapsed with (EO)n is cut by the single-strand specific Neurospora crassa endonuclease (EC 3.1.4.21) into small fragments. Extensive digestion only occurs above the critical concentration of polymer required for DNA collapse, demonstrating the (EO)n-collapsed DNA contains enzyme-vulnerable regions (probably at each fold), which are preferentially attacked. The size of the DNA fragments produced by limit-digestion with the nuclease ranges between 200 and 400 base pairs when DNA is collapsed by (EO)n. Only fragments of DNA which are larger than 600 base pairs are cut by the endonuclease in (EO)n-containing solution.  (+info)

Combined effects of gamma-radiation and ethylene oxide in human diploid fibroblasts. (6/202)

Human diploid VH-10 fibroblasts were pre-exposed to gamma-rays and then treated with ethylene oxide (EtO). In the reverse experiment, the cells were pretreated with EtO and then exposed to gamma-rays. Two different dose rates of gamma-rays were used: a low dose rate (LDR, 0.66 Gy/min) and a high dose rate (HDR, 10 Gy/min). Cell killing, mutagenicity and DNA double-strand breakage were studied in both types of experiment. The induction of mutations in the HPRT locus was studied by selection in medium containing 6-thioguanine. DNA double-strand breakage, measured as fraction of activity released (FAR), was investigated using pulsed field gel electrophoresis. Concerning mutagenesis, it was found that pre-exposure of the cells to gamma-radiation (1 Gy) followed by treatment with EtO (2.5 mMh) led to an additive co-interaction, irrespective of dose rate. On the other hand, the reverse experimental procedure (pretreatment with EtO followed by gamma-ray exposure) resulted in an antagonistic effect, which was most pronounced when the HDR was applied. In the latter case, the resultant mutant frequency was two times lower than the sum of the mutant frequencies after the individual treatments. However, the effect of the combined treatment on FAR was different: FAR increased with both combinations of agents used compared with the separate and hypothetically expected effects. Moreover, the HDR exposure led to an additional increase in FAR compared with the LDR one.  (+info)

Hemoglobin adducts from acrylonitrile and ethylene oxide in cigarette smokers: effects of glutathione S-transferase T1-null and M1-null genotypes. (7/202)

Acrylonitrile (ACN) is used to manufacture plastics and fibers. It is carcinogenic in rats and is found in cigarette smoke. Ethylene oxide (EO) is a metabolite of ethylene, also found in cigarette smoke, and is carcinogenic in rodents. Both ACN and EO undergo conjugation with glutathione. The objectives of this study were to examine the relationship between cigarette smoking and hemoglobin adducts derived from ACN and EO and to investigate whether null genotypes for glutathione transferase (GSTM1 and GSTT1) alter the internal dose of these agents. The hemoglobin adducts N-(2-cyanoethyl)valine (CEVal), which is formed from ACN, and N-(2-hydroxyethyl)valine (HEVal), which is formed from EO, and GST genotypes were determined in blood samples obtained from 16 nonsmokers and 32 smokers (one to two packs/day). Smoking information was obtained by questionnaire, and plasma cotinine levels were determined by immunoassay. Glutathione transferase null genotypes (GSTM1 and GSTT1) were determined by PCR. Both CEVal and HEVal levels increased with increased cigarette smoking dose (both self-reported and cotinine-based). CEVal and HEVal levels were also correlated. GSTM1 and GSTT1 genotypes had little effect on CEVal concentrations. GSTM1 null genotypes had no significant impact on HEVal. However, HEVal levels were significantly elevated in GSTT1-null individuals when normalized to smoking status or cotinine levels. The ratio of HEVal:CEVal was also elevated in GSTT1-null smokers (1.50 +/- 0.57 versus 0.88 +/- 0.24; P = 0.0002). The lack of a functional GSTT1 is estimated to increase the internal dose of EO derived from cigarette smoke by 50-70%.  (+info)

Biomarkers of exposure and effect as indicators of potential carcinogenic risk arising from in vivo metabolism of ethylene to ethylene oxide. (8/202)

The purposes of the present study were: (i) to investigate the potential use of several biomarkers as quantitative indicators of the in vivo conversion of ethylene (ET) to ethylene oxide (EO); (ii) to produce molecular dosimetry data that might improve assessment of human risk from exogenous ET exposures. Groups (n = 7/group) of male F344 rats and B6C3F1 mice were exposed by inhalation to 0 and 3000 p. p.m. ET for 1, 2 or 4 weeks (6 h/day, 5 days/week) or to 0, 40, 1000 and 3000 p.p.m. ET for 4 weeks. N:-(2-hydroxyethyl)valine (HEV), N:7-(2-hydroxyethyl) guanine (N7-HEG) and HPRT: mutant frequencies were assessed as potential biomarkers for determining the molecular dose of EO resulting from exogenous ET exposures of rats and mice, compared with background biomarker values. N7-HEG was quantified by gas chromatography coupled with high resolution mass spectrometry (GC-HRMS), HEV was determined by Edman degradation and GC-HRMS and HPRT: mutant frequencies were measured by the T cell cloning assay. N7-HEG accumulated in DNA with repeated exposure of rodents to 3000 p.p.m. ET, reaching steady-state concentrations around 1 week of exposure in most tissues evaluated (brain, liver, lung and spleen). The dose-response curves for N7-HEG and HEV were supralinear in exposed rats and mice, indicating that metabolic activation of ET was saturated at exposures >/=1000 p.p.m. ET. Exposures of mice and rats to 200 p.p.m. EO for 4 weeks (as positive treatment controls) led to significant increases in HPRT: mutant frequencies over background in splenic T cells from exposed rats and mice, however, no significant mutagenic response was observed in the HPRT: gene of ET-exposed animals. Comparisons between the biomarker data for both unexposed and ET-exposed animals, the dose-response curves for the same biomarkers in EO-exposed rats and mice and the results of the rodent carcinogenicity studies of ET and EO suggest that too little EO arises from exogenous ET exposure to produce a significant mutagenic response or a carcinogenic response under standard bioassay conditions.  (+info)

• 1
• 2
• 3
• 4
• 5
• 6
• 7
• 8
• 9
• 10