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Exposure to epichlorohydrin and central nervous system neoplasms at a resin and dye manufacturing plant.

This study evaluated the relationship between central nervous system neoplasms (CNSN) and exposure to epichlorohydrin (ECH) among 11 CNSN cases and 44 controls who were members of a cohort of chemical workers. Information on area of employment and potential exposure to ECH was obtained from plant personnel and medical records and from interviews with long-term employees. An elevated odds ratio (OR) for CNSN was observed for subjects who worked in the epoxy resin process line (OR = infinity, 95% confidence interval [CI] = 1.2-infinity), and in the production of anthraquinone intermediate dyes (OR = infinity, 95% CI = 1.7-infinity) and azo dyes (OR = 3.6, 95% CI = 0.6-41). Routine potential exposure to ECH was associated with CNSN (OR = 4.2, 95% CI = 0.7-26). Dose-response relationships were found with duration and with cumulative routine potential exposure to ECH (p = .11 and .08, respectively). Acute exposure to ECH requiring treatment at the plant infirmary also was associated with subsequent CNSN (OR = infinity, 95% CI = 1.5-infinity).

Adult↗

Extent of industrial exposure to epichlorohydrin, vinyl fluoride, vinyl bromide and ethylene dibromide.

Industrial hygiene studies of epichlorohydrin, vinyl fluoride, vinyl bromide and ethylene dibromide were conducted as part of an industry-wide evaluation of suspect cancer-causing chemical agents. At present there is no evidence that workers are experiencing adverse health effects at the reported exposure levels. Continued efforts to minimize worker exposure are recommended.

Air Pollutants, Occupational↗

32P-post-labelling of 7-(3-chloro-2-hydroxypropyl)guanine in white blood cells of workers occupationally exposed to epichlorohydrin.

Epichlorohydrin (ECH) is a simple 3-carbon epoxide of industrial importance. It has been shown to be genotoxic in several systems and carcinogenic in experimental animals. The aim of the present investigation was to study DNA adducts of ECH as a biomarker of occupational exposure to this chemical. 7-(3-Chloro-2-hydroxypropyl)guanine (7-CHP-guanine) was analysed in DNA from white blood cells using an anion exchange-based adduct enrichment protocol of the (32)P-post-labelling/HPLC-based assay. Blood samples were collected from seven workers handling ECH (exposed), nine workers not handling ECH but normally present in the premises where this chemical is used (potentially exposed) and 13 office and factory workers from locations in the plant where ECH is not handled (controls). 7-CHP-guanine was detected in five of the seven workers exposed to ECH (1.6-7.1 mol/10(9) mol nucleotides) and in two of the nine workers potentially exposed to ECH (0.8-1.5 mol/10(9) mol nucleotides). This adduct was not detected in any of the 13 controls. The difference in adduct levels between exposed workers and controls was statistically significant (Mann-Whitney test, P < 0.001), as was the difference between exposed workers and potentially exposed workers (P = 0.017). The recovery of 7-CHP-guanine in the (32)P-post-labelling assay was on average 48 +/- 7%, which is considerably higher than previously reported for other 7-alkylguanines. The method used had a limit of detection of approximately 0.4 mol adduct/10(9) mol nucleotides using 20 microg DNA. This study shows for the first time ECH-induced DNA adducts in humans and suggests that 7-CHP-guanine may be used as a biomarker of occupational exposure to ECH.

Adult↗

Inhalation carcinogenicity of epichlorohydrin in noninbred Sprague-Dawley rats.

Inhalation exposure experiments with the direct-acting alkylating agent epichlorohydrin (ECH) were done on noninbred male Sprague-Dawley rats. Single 6-hour exposure to ECH and follow-up for 14 days showed the median lethal concentration to be about 360 ppm. Further inhalation experiments were done with 6-hour exposure 5 days/week. A short-term 30-exposure regimen with 100 ppm ECH produced malignant squamous cell carcinomas of the nasal cavity in 15 of 140 rats and respiratory tract papillomas in 3 rats. Among 100 rats, lifetime exposure to 30 ppm yielded 1 malignant squamous carcinoma of the nasal cavity plus 1 nasal papilloma. No nasal or respiratory tract tumors were produced by lifetime exposure of 100 rats to 10 ppm. As controls, 100 air-treated and 50 untreated rats were used. A dose-rate effect was observed for ECH inasmuch as 30-day exposure to 100 ppm (3,000 ppm-days) produced 15 cancers in comparison to the 1 cancer from the lifetime exposure to 30 ppm (8,700 ppm-days) and no cancers from lifetime exposure to 10 ppm (2,500 ppm-days).

Animals↗

Decreased lung function associated with occupational exposure to epichlorohydrin and the modification effects of glutathione s-transferase polymorphisms.

Epichlorohydrin (1-chloro-2,3,-epoxypropane; ECH) is a strong irritant of the eyes, respiratory tract, and skin. Because the toxic effect of various chemicals can be modified by metabolic traits, in this study, we also investigated the influence of the glutathione S-transferase (GSTM1) and (GSTT1) genes on the toxic effect of ECH. In the GSTM1 null genotype workers, there is a dose-response of lung function tests (FEV1, FEV1/FVC, MMEF) for ECH exposure, but not in the GSTM1 non-null genotype workers. The ECH exposure was found to be significantly associated with a decreased FEV1 value (P = 0.09) and a decreased MMEF value (P = 0.053) after adjusting for other factors. The GSTM1 null genotype was found to be significantly associated with a decreased FEV1 value (P = 0.038), decreased FEV1/FVC value (P = 0.056), and decreased MMEF value (P = 0.012) after adjusting for other factors. This study indicates that obstructive lung abnormalities and small airway lung damage are associated with ECH exposure, and ECH workers with GSTM1 null-type are also associated with increased respiratory damage.

Adult↗

Comparison of contact site cancer potency across dose routes: case study with epichlorohydrin.

Risk assessment for airborne carcinogens is often limited by a lack of inhalation bioassay data. While extrapolation from oral-based cancer potency factors may be possible for some agents, this is not considered feasible for contact site carcinogens. The change in contact sites (oral: g.i. tract; inhalation: respiratory tract) when switching dose routes leads to possible differences in tissue sensitivity as well as chemical delivery. This research evaluates the feasibility to extrapolate across dose routes for a contact site carcinogen through a case study with epichlorohydrin (EPI). EPI cancer potency at contact sites is compared across three bioassays involving different dose routes (gavage, drinking water, inhalation) through the use of dosimetry models to adjust for EPI delivery to contact sites. Results indicate a large disparity (two orders of magnitude) in potency across the three routes of administration when expressed as the externally applied dose. However, when expressed as peak delivered dose, inhalation and oral potency estimates are similar and overall, the three potency estimates are within a factor of seven. The results suggest that contact site response to EPI is more dependent upon the rate than the route of delivery, with peak concentration the best way to extrapolate across dose routes. These results cannot be projected to other carcinogens without further study.

Administration, Inhalation↗

Occupational sensitization to epichlorohydrin and epoxy resin.

Sensitization to epichlorohydrin (ECH) is reported in 6 patients with occupational contact allergy. In 2 cases, an isolated positive test to ECH was found. In the remaining 4 cases, concomitant positive reactions were seen to "ICDRG epoxy resin" (MW 385) and to liquid epoxy resin (MW 370). Allergy to bisphenol A was not seen in the patients. 5 patients worked in an epoxy resin plant. Adequate preventive measures to avoid skin contact with ECH are required to prevent ECH sensitization becoming a more serious industrial hazard.

Adult↗

Testicular function among epichlorohydrin workers.

Epichlorohydrin (1,2-epoxy-3-chloropropane) (ECH) is a colourless liquid used in the production of insecticides, agricultural chemicals, epoxy resins, and many other productions. It is highly reactive and an alkylating agent suspected of possessing carcinogenic properties in man. The results of a clinical-epidemiological investigation to ascertain whether exposure to ECH may be associated with sperm count suppression among ECH production workers at two chemical plants are presented. Medical histories and physical examinations with special emphasis on the genitourinary tract were completed on each participant. Blood samples and three semen specimens were also obtained. Since no internal control group were available, the data arising from this effort were analysed for each plant (plant A, 44 men; plant B, 84 men) using a control group of 90 chemical plants workers unexposed to any agents known to be toxic to the tests who were included in previous studies. This study provides no evidence that exposure to ECH at the concentrations existing at the two plants studied is responsible for sperm count suppression.

Chemical Industry↗

Mortality of workers potentially exposed to epichlorohydrin.

An epidemiological study was undertaken to determine whether the animal carcinogen, epichlorohydrin (ECH), produces cancer in man. A total of 863 workers with probable exposure to ECH at two chemical plants during 1948-65 were followed up for deaths up to 1983. Twenty years or more after first exposure the all cancer SMR was 112.2 (22 deaths) and the SMR for leukaemia was 500.0 (three deaths), which is statistically significant. All cancer, leukaemia, and most other causes of death were related to estimated levels of exposure to ECH, except violence. The most consistent (both plants) relation was between exposure level and heart disease. Overall, the heart disease SMR 20 years or more after first exposure was 39.2 (five deaths) for low exposure and 105.4 (17 deaths) for high exposure. Limited evidence of a cardiovascular disease relation to ECH production in one other epidemiological study is supported by this study. Allyl chloride used in the production of ECH may play a part. The relation of heart disease and exposure does not appear to be an artifact, although the fact that many other causes of death were also related to exposure argues against a causal relation.

Cardiovascular Diseases↗

Morbidity prevalence study of workers with potential exposure to epichlorohydrin.

This study examined the morbidity experience from 1981 to 1988 of two cohorts (Shell cohort and Enterline cohort) of workers who had potential exposure to epichlorohydrin (ECH). The morbidity prevalence data for this study were extracted from the morbidity section of the Shell health surveillance system which included all illness and absence records in excess of five days. For both cohorts, the standardised morbidity ratios (SMRs) for all causes and all neoplasms were similar to an internal comparison group. There were no increases in heart disease morbidity for the Shell cohort (SMR = 97) or the Enterline cohort (SMR = 90). The SMRs for heart disease in the lower exposure group of the Shell cohort were 101 and 93 for the corresponding Enterline cohort. They were 92 and 87, respectively, in the higher exposure group. The increased risk of heart disease mortality reported by Enterline et al in workers more heavily exposed to ECH was not confirmed in this morbidity study. Morbidity from skin and subcutaneous tissue disorders, however, was found to be increased significantly in the Shell cohort. The SMR was 98 for the lower exposure group and 195 for the higher exposure group. A review of the original morbidity reports for each case suggested that factors unrelated to exposure to ECH such as the physical demands of a particular job, amount of time outside--for example, exposure to poison ivy--and other underlying medical conditions may be of greater importance than exposure to ECH.

Adult↗

Toxic, DNA-damaging and mutagenic activity of epichlorohydrin on human cells cultured in vitro.

Epichlorohydrin (ECHH) highly inhibited the tritiated thymidine uptake by human lymphocytes cultured in vitro, although the corresponding cell viability was unaffected. Furthermore, it elicited unscheduled DNA synthesis, acting as a DNA-damaging agent after its metabolic activation. ECHH also showed a clear toxic and mutagenic activity toward a human epithelial-like cell line, causing a decrease in cell viability and an increase in mutants resistant to 0.05 Lf/ml of diphtheria toxin.

Cell Line↗

Epichlorohydrin induced biochemical changes in the rose-ringed parakeet, Psittacula krameri Scopoli.

Intraperitoneal administration of epichlorohydrin (ECH) at the dose level of 20 and 50 mg/kg body weight inhibited spermatogenesis in the testis of parakeet during breeding season. A total load of 60 mg/kg body weight of ECH given on 3 consecutive days proved to be lethal. Testicular proteins, nucleic acids (DNA and RNA), phospholipids and acid phosphatase activity were decreased, while the lipids, total cholesterol and alkaline phosphatase activity increased after ECH administration. The results suggest that the testicular atrophy caused by ECH was associated with an alteration in the activities of macromolecules and enzymes related to specific events of spermatogenesis.

Animals↗

Increment of sister chromatid exchange frequencies (SCE) due to epichlorohydrin (ECH) in vitro treatment in human lymphocytes.

Although several studies have examined the effects on health of exposure to epichlorohydrin (ECH) through normal industrial operations and production, there is still considerable interest in its potential harmful effects on humans. The aim of the present study was to evaluate ECH effects in vitro through controlled investigations by using sister chromatid exchange (SCE), micronucleus (MN), and chromosome aberrations (CA) as the test battery. Cultures for cytogenetic tests were set up from blood samples of four healthy non-smoking and three smoking males. The experiments were performed using four different concentrations: 10(-10) M, 10(-8) M, 10(-6) M, and 10(-4) M, of ECH in DMSO. Analysis of variance showed that concentrations of ECH had significant effects on SCE/cell frequencies in the lymphocyte cultures of all donors (F=100.25, P<0.001). We were unable to find any evidence of significant increases in CA and MN frequencies in ECH-treated lymphocyte cultures with respect to the controls.

Adult↗

In vivo assessment of epichlorohydrin effects: the chorioallantoic membrane model.

BACKGROUND: Previous studies on the effects of the epichlorohydrin (ECH) epoxide demonstrated this compound's toxicity and mutagenicity and suggested a carcinogenic activity also in humans. To gain a better understanding of ECH effects in vivo, the substance was tested on developing tissues utilizing the chick embryo chorioallantoic membrane (CAM) assay. MATERIAL/METHODS: Gelatin sponges adsorbed with ECH were implanted onto nine-day CAMs. After five days the membranes were fixed, cut in serial sections, and stained with toluidine blue. Sections of the ECH-treated CAMs were also submitted to immunocytochemistry for the basal lamina glycoprotein laminin and the gap junction protein connexin 43 (Cx43). Control CAMs were treated with saline solution and submitted to identical procedures. RESULTS: ECH-treated CAMs displayed proliferation of both the epithelial layers and the mesenchyme cells and vessels. The laminin immunolabeling was interrupted beneath the ectoderm thickenings, which penetrated the mesenchyme. The endoderm showed papilloma-like formations and its laminin-positive basal membrane protruded toward the mesenchyme, together with clusters of endodermal cells. The mesenchyme showed increased numbers of cells and microvessels. These reactions were restricted to regions corresponding to the implant. Cx43 expression was strongly decreased in the ECH-treated CAMs compared with the controls, where the connexin punctate pattern regularly decorated the epithelial cell contours. CONCLUSIONS: The study confirms that ECH elicits tissue proliferation at the contact site and corroborates the suggestion of an ECH carcinogenic effect due to hallmarks of tumoral growth, such as angiogenesis, basal membrane alterations, and loss of intercellular communication via gap junctions.

Animals↗

[Specific features of the pathogenesis of epichlorohydrin eye burns and their treatment (an experimental clinico-morphological study)].

Specific features in the pathogenesis of ocular burns with a solution of an organic product, epichlorohydrin, are analyzed. Abnormalities in the vascular system anterior portion were revealed, related to the toxic effect of the agent on tissue vessels and to enhanced permeability and involvement of not only the cornea, but (and even more so) of the iris, where necrotic changes and hemorrhages eventuating in iris atrophy were detectable. Contrykal (hordox) therapy promoted a drastic inhibition of leukocytic and lymphocytic migration into burnt tissue, this resulting in a month in the formation of gentle cicatricial tissue with negligible residual inflammatory infiltration in the burn wound. Iris changes still persisted, since the drug appeared to have no effect on this process.

Animals↗

Correlation of sperm motion parameters with fertility in rats treated subchronically with epichlorohydrin.

We investigated the relationship between fertility and sperm motin endpoints in rats treated subchronically with the male reproductive toxicant, epichlorohydrin (ECH). Male rats were given ECH orally for 23 days at dosages of 0, 6.25, 12.5, or 25 mg/kg/day. They were mated twice (at 19 and 22 days) to estimate fertility by (1) detection of fertilized ova (presence of sperm head and tail or two pronuclei) 18 hours after mating and by (2) counting implants on day 14 of gestation. Both indices showed dose-related reductions (P less than 0.001). Motion parameters of cauda epididymal sperm were assessed using the CellSoft computer-assisted sperm motion analysis (CASA) system after the rats were asphyxiated on day 25. Curvilinear velocity, straight-line velocity, linearity, and amplitude of lateral head displacement were reduced in a dose-related manner. The fertility indices, percent fertilized ova, and percent implantation on day 14 of gestation were correlated significantly (r = 0.68; P = 0.0001). The following motion parameters were also correlated significantly with fertility (P less than 0.0003; r1 = percent fertilized ova and r2 = percent implantation): linearity (r1 = 0.42; r2 = 0.40), amplitude of lateral head displacement (r1 = 0.54; r2 = 0.48), curvilinear velocity (r1 = 0.53; r2 = 0.50), straight-line velocity (r1 = 0.55; r2 = 0.50), and percent motile sperm (r1 = 0.42; r2 = 0.32). These results suggest a relationship between toxicant-induced reductions in sperm motion and fertility.

Animals↗

[The genotoxic effect of epichlorohydrin and epoxy resins].

The aim of this study is the interpretation of the available bibliography concerning the present information about the mutagenic and carcinogenic effects of epichlorohydrin and epoxy resins. An intervention study on 141 exposed workers shows the necessity of an investigation about the well-timed perception of the carcinogenic risk. The development of an electrophoretic method is recommended to detect the alkylated hemoglobin by way of the biological monitoring.

Berlin↗