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PubMed1983

Genotoxicity, metabolism and blood kinetics of epichlorohydrin in mice.

Epichlorohydrin (ECH), a direct mutagen in vitro, did not induce chromosomal aberrations in bone-marrow cells of CD1 mice given single oral doses of 50 and 200 mg/kg in water. The ECH diol derivative (3-chloro-1,2-propanediol) was tested in vitro by a forward-mutation assay on the yeast Schizosaccharomyces pombe and showed a weak but significant mutagenic effect. The failure of ECH to induce mutagenic effects appears to be due to the rapid metabolic clearance of the compound in vivo. ECH blood kinetics at both doses, and at the same time the concentration of the diol, were determined. ECH rapidly disappeared from mouse blood, being no longer detectable 20 min after treatment. In contrast, 3-chloro-1,2-propanediol was measurable up to 5 h after dosage. No difference was observed in the kinetic and metabolic behavior of ECH after single and repeated doses (50 and 200 mg/kg/day for 7 days). When 3-chloro-1,2-propanediol was tested, neither glutathione depletion nor epoxide hydrolase inhibition (evaluated with both styrene-7,8-oxide and ECH as substrates) could be detected in mouse liver. Finally, no difference in ECH blood kinetics or metabolism were observed in experiments in which the compound was administered (200 mg/kg) intraperitoneally in water or orally as a solution in dimethyl sulfoxide.

Animals↗
PubMed1983

Effect of occupational exposure to epichlorohydrin on the frequency of chromosome aberrations in peripheral lymphocytes.

The relationship between the level of occupational exposure to epichlorohydrin (ECHH) and the clastogenic effect was studied on a group of 33 workers. The effect of ECHH was assessed by differences in the frequency of chromosome aberrations in peripheral blood lymphocytes in ECHH-exposed and control groups. In the group exposed to the average ECHH concentration, 0.384 mg X m-3, during the last 6 months, the cytogenetic analysis revealed 2.00 +/- 0.23% AC (aberrant cells) (0.0203 B/C, breaks per cell) as compared with 1.68 +/- 0.23% AC (0.0172 B/C) in the matching controls. These results indicate that an average concentration lower than 0.40 mg X m-3 ECHH in the working atmosphere has no significant clastogenic effect on human peripheral lymphocytes.

Adult↗
PubMed1990

Enhancement of cyclosporin production in a Tolypocladium inflatum strain after epichlorohydrin treatment.

Following treatment of conidia of the cyclosporin producer fungus, Tolypocladium inflatum, with 0.15 M epichlorohydrin, strain M6 was isolated. The new strain exhibited a similar growth rate to the parent organism but more extensive conidiation and several-fold higher overall cyclosporin production. Strain M6 reached titres of 318 mg l-1 cyclosporin A in agar cultures, whereas in liquid medium it produced 140 mg l-1 cyclosporin A and 68 mg l-1 cyclosporin C. It also maintained a steady volumetric productivity of 0.48 mg l-1 h-1 cyclosporin A over 2 weeks of submerged cultivation in maltose-based semisynthetic medium. The new strain holds potential for improved cyclosporin production due to the superior titres and demonstrated capacity to sustain elevated production of cyclosporin for periods greater than the wild type.

Chlorohydrins↗
PubMed1989

Effects of epichlorohydrin on male and female reproduction in Long-Evans rats.

Male and female Long-Evans rats were treated with epichlorohydrin (ECH) by oral gavage (males: 12.5, 25, and 50 mg/kg/day; females: 25, 50, and 100 mg/kg/day) for 21 and 14 days, respectively, prior to mating trials with untreated animals. Treated females were further dosed until delivery. Fertility was assayed in the high-dose males only and was found to be totally impaired. No measured parameters of female reproduction were changed relative to controls. Treated males showed normal copulatory behavior. Sperm morphology and percentage motile sperm were not statistically different from control values in both ejaculated and cauda epididymal samples from ECH-treated animals. The number of sperm in ejaculates was normal while cauda epididymal sperm count was slightly decreased in males at the 50 mg ECH/kg dose level. Mean curvilinear velocity, straight-line velocity, and amplitude of lateral head displacement of cauda epididymal sperm were significantly reduced by ECH at 12.5 mg/kg/day and above. Sperm track linearity was also reduced, but only at 50 mg/kg/day. Beat/cross frequency of sperm was significantly increased at 12.5 mg/kg/day and above. All of the above sperm motion parameters showed dose-dependent trends. These effects are consistent with the spermatozoal metabolic lesions reported for alpha-chlorohydrin, a metabolite of ECH.

Animals↗
PubMed1985

Carcinogenicity study with epichlorohydrin (CEP) by gavage in rats.

Weanling Wistar rats of both sexes were given epichlorohydrin by gastric intubation for 2 years, 5 times a week at dosages of 0, 2, and 10 mg/kg body weight. Mortality and body weight gain were recorded and histopathological examination for tumours was carried out; after 1 year also haematology was performed. Towards the end of the study a slight dose-related increase in mortality was observed in males, along with a decrease in mean body weight in the survivors. At pathological examination a high incidence (100% for females, 81% for males) of squamous cell carcinomas of low-grade malignancy was observed in the forestomach of animals at risk (greater than 18 months) from the 10 mg/kg group. In the 2 mg/kg group forestomach tumours were found at a lower incidence (7% for females, 14% for males), whereas this tumour was not found in control animals. Other tumours diagnosed in this study occurred at background level and were not influenced by treatment.

Animals↗
PubMed1984

In vivo and in vitro binding of epichlorohydrin to nucleic acids.

Epichlorohydrin (EC) binds to macromolecules of biological relevance in vivo: DNA is less labelled than RNA and proteins, rat organs interact more than mouse organs, stomach is the most labelled organ with liver, kidney and lung involved in decreasing order. Based on the Covalent Binding Index (CBI), EC is a weak-moderate oncogen, just as other chlorinated hydrocarbons such as 1,2-dichloroethane and carbon tetrachloride. An interaction of EC with nucleic acids (DNA and polyribonucleotides) occurs also in vitro. It is mediated either by chemical reactivity per se of the molecule (near-UV (NUV) irradiation does not photoactivate EC) and by enzymatic (microsomal and/or cytosolic) fractions, whose relative effectiveness is variable in relation to the organ tested. The best substrates for interaction are poly(G) and poly(A) when using microsomal and cytosolic fractions, respectively, whereas the labelling of double-stranded DNA is always lower. On the whole, the picture of enzyme (microsome + cytosol)-mediated in vitro interaction is similar to the pattern of in vivo binding, with the exception of rat stomach enzymes which are inactive in vitro.

Animals↗
PubMed1995

Comparison of propylene oxide and epichlorohydrin effects in two transformation tests (C3H/10T1/2 and SHE cells).

The neoplastic cell transformation induced by propylene oxide (PO) and epichlorohydrin (ECH) was studied in two in vitro assays, mouse embryo fibroblasts (C3H/10T1/2) and Syrian hamster embryo (SHE) cells. In C3H/10T1/2 cells treated with PO (2.5-10 mM), the transformation frequencies were enhanced about 2-4 times in the presence of 12-O-tetradecanoylphorbol-13-acetate (TPA), compared with the transformation frequencies in the absence of TPA. In SHE cells, an even higher increase (about 6-9 times) was reached at concentrations of 2.5-20 mM. The presence of TPA strongly influenced the ability of ECH to induce the morphological transformation at low-moderate concentrations (0.25-1 mM). At the highest concentrations applied, 1 mM in C3H/10T1/2 cells and 0.5 mM in SHE cells, 41- and 4-fold increases, respectively, were observed. In C3H/10T1/2 cells, the rad-equivalence (rad/mMh) of PO and ECH in the presence of TPA was calculated to be 36 +/- 8 and 296 +/- 65 (mean +/- S.E.), respectively.

Animals↗
PubMed2006

Geographical distribution of acute symptoms after a train collision involving epichlorohydrin exposure.

In September 2002, two freight trains collided in a northern German town. The inhabitants were potentially exposed to the probable human carcinogen epichlorohydrin. As no objective data on the level of exposure were available, we aimed to assess the geographical distribution of acute symptoms among local residents and subjects occupationally involved in the accident (e.g., firemen). A random sample of 932 adult local residents and 342 occupationally involved subjects were invited to answer a mail-in questionnaire. The main outcome measures were self-reported acute symptoms potentially associated with combustion products (e.g., irritation of the eyes, nose, or throat) and stress-related nonspecific symptoms. The main location during the first 26 h after the accident served as exposure proxy. For occupationally involved subjects, the time spent at the accident site was also used. The overall prevalence of symptoms potentially associated with combustion products was 9.8% for residents and 25.4% for occupationally involved subjects. After adjustment, subjects whose main location was close to the accident site had an increased risk for such symptoms. Among occupationally involved subjects the risk increased with duration at the accident site. Neither main location nor time at the accident site was significantly associated with non-specific symptoms. We could provide an example for designing and carrying out an epidemiologic study shortly after a local accident with potential public health impact. We could define parts of the population at increased risk for symptoms potentially specific for the exposure under study.

Accidents↗
PubMed2006

Development of a biosensor based on gilo peroxidase immobilized on chitosan chemically crosslinked with epichlorohydrin for determination of rutin.

A new reagentless biosensor for the square-wave voltammetric determination of rutin in pharmaceutical formulations was developed by immobilization of gilo (Solanum gilo) crude extract in chitosan matrix. The gilo tissue acts as a source of peroxidase. The highest biosensor performance was obtained after immobilization of the peroxidase in chemically crosslinked chitosan with epichlorohydrin and glutaraldehyde that was incorporated in a carbon paste electrode. In the presence of hydrogen peroxide this enzyme catalyses the oxidation of rutin to quinone and the electrochemical reduction of the product was obtained at a fixed potential of +124 mV versus Ag/AgCl (3.0 M KCl). The performance and factors influencing the resulting biosensor were studied in detail. The bioelectrode exhibited a linear response for rutin concentrations from 3.4x10(-7) to 7.2x10(-6) M (r=0.9998) and the recovery of rutin from the samples ranged from 96.2 to 102.4%. The detection and quantification limits were 2.0x10(-8) and 6.3x10(-8) M, respectively. The relative standard deviation was less than 1.0% for solutions containing 3.4x10(-7) to 7.2x10(-6) M rutin in 0.1 M phosphate buffer solution at pH 7.0 (n=10). The lifetime of this biosensor was 8 months (at least 500 determinations).

Benzoquinones↗
PubMed1999

Adducts with haemoglobin and with DNA in epichlorohydrin-exposed rats.

Epichlorohydrin (1-chloro-2,3-epoxypropane; ECH) is an important industrial chemical and a carcinogen in experimental animals. The main aims of the present study were to characterize the adduct formation in female Wistar rats and to identify adducts that could potentially be used in human biomonitoring studies. The total binding of radioactivity to haemoglobin in rats administered 0, 0. 11, 0.22, 0.43, or 0.97 mmol [3H]ECH/kg body weight by i.p. injection, and sacrificed 24 h after treatment, was linearly related to a dose up to 0.43 mmol/kg body weight. The binding at the highest dose was higher than predicted by extrapolation from lower doses, indicating saturation of a metabolic process for elimination of ECH. Ion-exchange chromatography of a globin hydrolysate showed one major radioactivity peak corresponding to S-(3-chloro-2-hydroxypropyl)cysteine. The half-life of this adduct was estimated as about 4 days by analysis of globin from rats administered 0.43 mmol/kg body weight and sacrificed after 1, 2 and 9 days. Crosslinking of the adduct, presumably with glutathione, appeared to be the predominant secondary reaction. Hydrolysis of N-(3-chloro-2-hydroxypropyl)valine, the primary reaction product of ECH with N-terminal valine, would give N-(2,3-dihydroxypropyl)valine. A sensitive gas chromatography/mass spectrometry method for the dihydroxypropyl adduct was used to follow its formation and removal after administration of nonlabelled ECH (0.11 mmol/kg body weight). The level of this adduct reached a maximum of about 20 pmol/g globin after a few weeks, corresponding to about 0.1% of the initial binding of ECH to globin. N-7-(3-Chloro-2-hydroxypropyl)guanine was detected in rats administered 0.97 mmol [3H]ECH/kg body weight and sacrificed 6 h after treatment. The adduct levels in haemoglobin and DNA were compared with previously reported adduct levels in male Fischer 344 rats exposed to propylene oxide. Despite its higher chemical reactivity, the capacity of ECH to alkylate macromolecules in vivo was found to be somewhat lower than that of propylene oxide.

Animals↗
PubMed1999

Effects of three epoxides--ethylene oxide, propylene oxide and epichlorohydrin--on cell cycle progression and cell death in human diploid fibroblasts.

Ethylene oxide (EtO), propylene oxide (PO), and epichlorohydrin (ECH) strongly influenced the G1/S progression in human diploid fibroblasts, VH-10. However, these epoxides did not affect substantially the G2/M progression. It was found that G1 arrest is induced by these epoxides 6-18 h after the treatment at doses above 5, 3, and 0.5 mMh for EtO, PO, and ECH, respectively. An inhibitory effect on DNA synthesis was also demonstrated at the same doses within the same time interval. On the contrary, the epoxides transiently stimulated DNA synthesis 3-18 h after the treatment with the lower doses (below 5, 3, and 0.5 mMh for EtO, PO, and ECH, respectively). This effect was manifested both as an elevated rate of DNA synthesis and as an increase in the number of cells in S-phase. Among the three studied epoxides EtO was the most effective one: the increases of the rate of DNA synthesis and of cells in S-phase were 35 and 55%, respectively. All the epoxides tested induced significant decrease of intracellular level of reduced glutathione (GSH) shortly after cell exposure. While low and moderate doses induced a transient decrease in GSH level the high doses induced its irreversible depletion. The extensive GSH depletion was related to cell death. Morphological examination of cell nuclei indicated that epoxide-treated cells die via necrosis. This conclusion is supported by the lack of such features of the apoptosis as chromatin condensation and the occurrence of so called 'apoptotic bodies'. The absence of nucleosomal fragmentation of DNA and an increase of the permeability of the plasma membrane after the epoxide treatment also indicated a necrotic form of cell death. ECH is about ten times more toxic than the two other epoxides, and it causes almost 100% necrosis at dose of 3.0 mMh.

Cell Cycle↗
PubMed1997

Monitoring of occupational exposure to epichlorohydrin by genetic effects and hemoglobin adducts.

The present work is focused on the determination of in vivo doses and studies of genetic effects in workers exposed to epichlorohydrin (ECH). The studied endpoints were hemoglobin (Hb) adducts, frequencies of hprt mutants, micronuclei in cytochalasin B blocked binucleated lymphocytes, sister chromatid exchanges (SCE) and high frequency cells (HFC). Blood samples were collected from office clerks and ECH exposed factory workers at an industrial plant in Germany. The workers were exposed to 0.11-0.23 ppm ECH in the air 45 h per week and to 0.2-2.6 ppm for 3 h per week. Some Swedish non-exposed subjects were also used for Hb adduct measurements. The genetic data, HFC and SCE, showed a significant difference between exposed and unexposed donors. In contrast to earlier studies on SCE, no impact of smoking was observed. Effects on micronuclei were on the borderline of significance, whereas there was no effect for HPRT mutants. The average Hb adduct level was higher in exposed than in non-exposed donors, although the difference was only significant when the exposed group was compared to Swedish controls. Smoking gave significantly increased adduct levels. The absence of significant correlations between individual data for Hb adducts and genetic effects, may be explained by the different periods of time covered by the responses in these endpoints. Whereas Hb adducts reflect the exposure during up to 4 months (i.e. the life span of human erythrocytes), the SCE, and particularly the HFC, seem to accumulate for years in a long-lived fraction of T-lymphocytes without DNA repair. Thus, the adduct data does not reflect the exposure backwards in time unless it can be shown that exposure conditions have remained unchanged. The origin of the background adduct levels in non-smoking control persons is at present not known.

Adult↗
PubMedDate not supplied

Teratologic evaluation of inhaled epichlorohydrin and allyl chloride in rats and rabbits.

Pregnant Sprague-Dawley rats and New Zealand white rabbits were exposed to vapors of epichlorohydrin (ECH) at concentrations of 0, 2.5 or 25 ppm or to allyl chloride (AC) at concentrations of 0, 30, or 300 ppm. Exposures were for 7 hr/day on days 6 through 15 (rats) or 6 through 18 (rabbits) of gestation. Maternal effects including decreased body weight and food consumption were observed among rats inhaling 25 ppm of ECH. No evidence of an adverse effect to the embryo or fetus was observed among rats or rabbits following exposure to ECH. In the AC study maternal toxicity occurred in both rats and rabbits treated at 300 ppm. These consisted of depressed weight gain during gestation and increases in liver weight (both species) and kidney weights (rats only). Fetuses from rats exposed to 300 ppm of AC had a slight delay in skeletal development but there were no other signs of embryotoxicity. Thus, ECH and AC were not teratogenic or embryolethal in rats or rabbits following inhalation exposure to concentrations which induced effects in the maternal animals.

Abnormalities, Drug-Induced↗
PubMed1996

Identification and quantitative determination of 3-chloro-2-hydroxypropylmercapturic acid and alpha-chlorohydrin in urine of rats treated with epichlorohydrin.

Epichlorohydrin (ECH) is used in many industrial processes. Different toxic effects of ECH were found in rodents. The metabolism of ECH was investigated before in rats using [14C]ECH. The aim of this investigation was the development of non-radioactive quantitative analytical methods for measuring two urinary metabolites of ECH, namely 3-chloro-2-hydroxypropylmercapturic acid (CHPMA) and alpha-chlorohydrin (alpha-CH). The identity of CHPMA and alpha-CH excreted in urine of rats treated with 5 to 35 mg/kg ECH was confirmed by GC-MS. The quantitative analysis of CHPMA, involving ethyl acetate extraction from acidified urine and subsequent methylation and analysis by gas chromatography-flame photometric detection (GC-FPD), showed a method limit of detection of 2 micrograms/ml. The analysis of alpha-CH based on ethyl acetate extraction and subsequent analysis by GC-ECD, showed a method limit of detection of 2 micrograms/ml. CHPMA and alpha-CH derivatives could be determined quantitatively down to concentrations of 0.5 and 0.4 micrograms/ml urine, respectively, by selected-ion monitoring GC-MS under EI conditions. Cumulative urinary excretion of CHPMA and alpha-CH by rats treated with ECH were found to be 31 +/- 10 and 1.4 +/- 0.6% (n = 13) of the ECH dose, respectively. For CHPMA, the dose-excretion relationship suggested partially saturated ECH metabolism. For alpha-CH, the doe-excretion relationship was linear. With fractionated urine collection it was found that approximately 74 and 84% of the total cumulative excretion of CHPMA and alpha-CH, respectively, took place within the first 6 h after administration of ECH. From these investigations it is concluded that the GC-FPD and GC-ECD based methods developed are sufficiently sensitive to measure urinary excretion of CHPMA and alpha-CH in urine from rats administered 5 to 35 mg/kg ECH. It is anticipated that the analysis of CHPMA and alpha-CH based on GC-MS may be sufficiently sensitive to investigate urinary excretion from humans occupationally exposed to ECH.

Acetylcysteine↗
PubMed2002

Characterization of physicochemical properties of naproxen systems with amorphous beta-cyclodextrin-epichlorohydrin polymers.

Ground mixtures of naproxen with amorphous beta-cyclodextrin-epichlorohydrin soluble (betaCd-EPS) or insoluble cross-linked (betaCd-EPI) polymers were investigated for both solid phase characterization (Differential Scanning Calorimetry, powder X-ray Diffractometry) and dissolution properties (dispersed amount method). The effect of different grinding conditions and of drug-to-carrier ratio was also evaluated. Co-grinding induced a decrease in drug crystallinity to an extent which depended on the grinding time, and was most pronounced for the cross-linked insoluble polymer, particularly in combinations at the lowest drug content. Both cyclodextrin polymers were more effective in improving the naproxen dissolution properties, not only than the parent betaCd but also than hydroxyalkyl-derivatives, and their performance was almost comparable to that of methyl-derivatives, previously found as the best carriers for naproxen. Dissolution efficiencies of naproxen from physical mixtures with betaCd-EPS, thanks to the high water solubility of this Cd-derivative, were up to three times higher than those from the corresponding products with betaCd-EPI. However this difference in their performance became much less evident in co-ground products and tended to progressively diminish with increasing the polymer content in the mixture, according to the better amorphizing power shown by betaCd-EPI during the co-grinding process. The 10/90 (w/w) drug-carrier co-ground products exhibited the best dissolution properties, giving dissolution efficiencies about 30 times higher than that of naproxen alone.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2002

Genotoxic effects of ethylene oxide, propylene oxide and epichlorohydrin in humans: update review (1990-2001).

Ethylene oxide (EtO), propylene oxide (PO) and epichlorohydrin (ECH) are important industrial chemicals widely used as intermediates for various synthetic products. EtO and PO are also environmental pollutants. In this review we summarize data published during the period 1990-2001 concerning both the genotoxic and carcinogenic effects of these epoxides in humans. The use of DNA and hemoglobin adducts as biomarkers of exposure and the role of polymorphism, as well as confounding factors, are discussed. We have also included recent in vitro data comprising genotoxic effects induced by EtO, PO and ECH in mammalian cells. The uncertainties regarding cancer risk estimation still persist, in spite of the large database collected.

Carcinogens↗
PubMed1997

Genetic toxicology of epichlorohydrin: a review.

Epichlorohydrin (ECH) is one of the more commercially important aliphatic epoxides used extensively as an industrial intermediate, a laboratory reagent, and as an insecticide. It is a volatile, colourless liquid with an ethereal odour. It behaves as an alkylating agent. Reports have shown it to cause the respiratory and dermal toxicity in animals and humans. It has also been reported to be carcinogenic in experimental models. Thus, the wide-spread use of this aliphatic epoxide is of great concern in human health problem. The purpose of this paper is to critically review and update the mutagenic and clastogenic effects of ECH based on available literature.

Animals↗
PubMed2006

[Acute effects on the health of children after accidental exposure to epichlorohydrine].

PURPOSE: In September 2002, two freight trains collided at Bad Muender, Germany. The inhabitants were potentially exposed to combustion products and to the human carcinogen epichlorohydrine (ECH). We aimed to describe the geographical distribution of and potential risk factors for acute symptoms among children residing in Bad Muender. METHODS: The parents of a random sample of children were invited to answer a mail-in questionnaire (response rate 63%). The main outcome measures were self-reported acute symptoms potentially associated with combustion products (e. g., irritation of the eyes, nose, or throat) and stress-related unspecific symptoms (e. g., gastrointestinal complaints, sleep problems, headaches). The main location during the first 26 hours after the train accident served as exposure proxy measure. In addition, potential predictors for the symptoms under study were assessed. RESULTS: The prevalence of symptoms associated with combustion products was 5.9%. Unspecific symptoms were reported for 6.3% of the children. Main location and prevalence of symptoms were not significantly associated. Physician-diagnosed asthma and nasal allergies were the main predictors of symptoms. CONCLUSION: The prevalence of acute symptoms was relatively high in a random sample of children living close to the incident. However, associations between exposure to the accident and symptoms could not be established conclusively.

Accidents↗