[Some biochemical changes during acute poisoning with epichlorohydrine].
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Amine Oxidase (Copper-Containing)↗
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Ribonuclease chemically attached to beads of epichlorohydrin cross-linked agarose.
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Animals↗
Genotoxicity of 1,3-dichloro-2-propanol in the SOS chromotest and in the Ames test. Elucidation of the genotoxic mechanism.
1,3-Dichloro-2-propanol (1,3-DCP-OH, glycerol dichlorohydrin) is of great importance in many industrial processes and has been detected in foodstuffs, in particular in soup spices and instant soups. It has been shown to be carcinogenic, genotoxic and mutagenic. Its genotoxic mechanisms are, however, not yet entirely understood. We have investigated whether alcohol dehydrogenase (ADH) catalysed activation to the highly mutagenic and carcinogenic 1,3-dichloroacetone or formation of epichlorohydrin or other genotoxic compounds play a role for mutagenicity and genotoxicity. In our studies, no indications of ADH catalysed formation of 1,3-dichloropropane could be found, although we could demonstrate a clear activation by ADH in the case of 2-chloropropenol. Formation of allyl chloride could also be excluded. We found, however, clear evidence that epichlorohydrin formed chemically in the buffer and medium used in the test is responsible for genotoxicity. No indication was found that enzymatic formation of epichlorohydrin plays a role. Additional mutagenicity and genotoxicity studies with epichlorohydrin also confirmed the hypothesis that genotoxic effects of 1,3-DCP-OH depend on the chemical formation of epichlorohydrin.
Alcohol Dehydrogenase↗
Controlled release of EGF and bFGF from dextran hydrogels in vitro and in vivo.
In the present study, dextran-epichlorohydrin hydrogels were employed as carriers for the controlled release of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). The hydrogels were synthesized from 50% (by weight) monomeric cross-linker, epichlorohydrin, containing dextran mixtures by intermolecular side-chain reaction of dextran-hydroxyl groups with epichlorohydrin-epoxy groups. The hydrogel disks of 3-mm diameter and 1.5-mm thickness have a high swelling capacity (EWC = 650%) and enough mechanical stability for the studies in vivo. Impregnation of EGF and bFGF into the dried hydrogels was carried out by use of phosphate buffered saline solution (PBS, pH = 7.4) containing 0.5 microg mL(-1) EGF and 0.1 microg mL(-1) bFGF, respectively. The in vitro release of growth factors was detected by fluorescence spectroscopy. The prolonged release of EGF is continued up to the 14th day, in comparison with a 26-day release of bFGF. The in vivo studies were realized with subcutaneously implanted hydrogels in Wistar albino rats. The rate of neovascularization was analyzed statistically using one-way analysis of significance with EGF and bFGF incorporated hydrogels. In conclusion, dextran-epichlorohydrin hydrogels were shown to be an alternative delivery system for the release of growth factors.
Animals↗
The influence of contaminants on the mutagenic activity of dibromochloropropane (DBCP).
This study investigates the possible role of impurities in dibromochloropropane in inducing mutations, and discusses the importance of contaminants in mutagenicity and carcinogenicity testing. A technical grade sample and a pure sample of DBCP (no epichlorohydrin added) were assayed in Salmonella typhimurium TA1535, with and without S-9 activation, using agar overlay procedures and dessicator procedures. Assays performed with both technical and pure DBCP without metabolic activation resulted respectively in an increase in revertants with increasing dose (0-1600 microgram/plate) when the technical grade was tested, and no substantial increase in revertants over the same dose range when the pure DBCP was tested. Distillation of technical grade DBCP yielded an initial fraction containing high amounts of epichlorohydrin (verified by GC-MS) which was highly mutagenic. The amount of epichlorohydrin in the technical DBCP sample was calculated for each dose level tested, and the number of revertants obtained in tests of the technical DBCP sample could be attributed solely to the calculated amount of epichlorohydrin in each test dose. Tests of pure and technical DBCP using a dessicator technique produced a similar differential between the technical and pure compounds in mutagenicity. Activation of both technical and pure DBCP with S-9 from Aroclor pre-treated rats resulted in high mutagenic responses, of equal magnitude, from both preparations.
Chromatography, Gas↗
Permeation of eleven protective garment materials by four organic solvents.
The resistance of 11 different protective garment materials to permeation by epichlorohydrin, perchloroethylene, trichloroethylene, and 1,2-dibromoethane were determined. Water was the collection medium in the epichlorohydrin tests with samples taken periodically and analyzed by gas chromatography. Because of the relatively low solubilities of the other three challenge liquids in water, air was used as the collection medium. The concentrations of the permeant vapors in an airstream which passed across the downstream sides of the membranes were determined automatically every 2 min with a flame ionization detector. Butyl rubber offers good protection against epichlorohydrin, with breakthrough occurring after 8 hrs. With the halogenated hydrocarbons, Viton and Vitrile provide protection for at least 12 and 24 hrs, respectively, while PVA showed no breakthrough in 24 hrs with trichloroethylene and dibromoethane. With perchloroethylene, nitrile breakthrough occurred in 5 hrs. The weight and volume changes which occurred when the materials were soaked in each of the challenge liquids were also determined. The log of these changes correlated moderately well with the log of the breakthrough time normalized by the square of the material thickness.
Epichlorohydrin↗
Interaction of halocompounds with nucleic acids.
The binding of epichlorohydrin, 1,2-dichloroethane, 1,2-dibromoethane, chlorobenzene, bromobenzene, and benzene to nucleic acids and proteins of different murine organs was studied in in vivo and in vitro systems. The extent of in vivo enzymatic activation of brominated compounds was higher than that of chlorinated chemicals. Aryl halides were bound mainly to liver DNA whereas interaction of alkyl halides with DNA of liver, kidney, and lung gave rise to similar binding extent. In vitro activation of all chemicals was mediated by microsomal P-450-dependent mixed function oxidase system which is present in rat and mouse liver and, in smaller amount, in mouse lung. Activation of alkyl halides by liver cytosolic GSH-transferases even occurred. The relative reactivity of chemicals in vivo, expressed as Covalent Binding Index (CBI) to rat liver DNA, was: 1,2-dibromoethane greater than bromobenzene greater than 1,2-dichloroethane greater than chlorobenzene greater than epichlorohydrin greater than benzene. On the whole, it agreed with in vitro activation of chemicals, with genotoxicity data from other short-term assays and also with oncogenicity of benzene, epichlorohydrin, 1,2-dichloroethane, and 1,2-dibromoethane. CBI values of chlorobenzene and bromobenzene gave the first clear evidence of genotoxicity and of possible carcinogenicity of these two chemicals.
Animals↗
Alkylation products of DNA bases by simple epoxides.
The reaction products of a series of epoxides with deoxyribonucleosides were characterized using ultraviolet, and NMR spectroscopy. The epoxides included structural analogues which are known to differ extensively in their mutagenic potency: propylene oxide, glycidol, epichlorohydrin, trichloropropylene oxide and styrene oxide. Trichloropropylene oxide, epichlorohydrin and glycidol reacted with deoxyguanosine producing a major adduct of 1,7-(or 1,9-)dialkylguanine. All of the epoxides produced a 7-alkylguanine adduct, with the possible exception of styrene oxide. Propylene oxide, glycidol and epichlorohydrin reacted with deoxyadenosine at N-6. Glycidol, trichloropropylene oxide and styrene oxide reacted with deoxycytidine at N-3. It was concluded that the structurally related epoxides tend to react largely in a uniform way with nucleic acid bases. Thus, the reaction rates rather than the major adducts explain the differential mutagenicity of the epoxides.
Alkylation↗
Construction of a cis-cyclopropane via reductive radical decarboxylation. Enantioselective synthesis of cis- and trans-1-arylpiperazyl-2-phenylcyclopropanes designed as antidopaminergic agents.
(1S,2S)-, (1S,2R)-, and (1R,2S)-1-(2,4-Dimethylphenyl)piperazyl-2-phenylcyclopropane (2a, 3, and ent-3, respectively), which were designed as conformationally restricted analogues of haloperidol (1), a clinically effective antipsychotic agent, were synthesized from chiral epichlorohydrins using the Barton reductive radical decarboxylation as the key step. (1S,2R)-1-(tert-Butyldiphenylsilyloxy)methyl-2-carboxy-2-phenylcyclopropane (5), which was prepared from (S)-epichlorohydrin ((S)-7), was converted into its N-hydroxypyridine-2-thione ester 12, the substrate for the reductive radical decarboxylation. When 12 was treated with TMS3SiH in the presence of Et3B or AIBN, the decarboxylation and subsequent hydride attack on the cyclopropyl radical intermediate from the side opposite to the bulky silyloxymethyl moiety occurred, resulting in selective formation of the corresponding reductive decarboxylation product 4-cis with the cis-cyclopropane structure. From 4-cis, the cis-cyclopropane-type target compound 3 was readily synthesized. Starting from (R)-epichlorohydrin ((R)-7), ent-3 was similarly synthesized. Epimerization of the cyclopropanecarboxamide ent-16-cis, a synthetic intermediate for ent-3, on treatment with a base prepared from Bu2Mg and i-Pr2NH in THF occurred effectively to give the corresponding trans isomer 16-trans, which was converted into 2a with the trans-cyclopropane structure.
Cyclopropanes↗
Immobilisation of catalase on the surface of biodegradable starch-based polymers as a way to change its surface characteristics.
In this study, a specific enzyme catalase was immobilised onto the surface of two different biodegradable materials, starch cellulose acetate (SCA) and starch polycrapolactone (SPCL) blends. This immobilisation was achieved by several different routes, mainly by covalent binding and an adsorption method using as activation agents epichlorohydrin, cyanogen bromide (CNBr), and aminopropyltriethoxysilane. The effect of the coupling pH of the enzyme-support reaction was determined in terms of activity recovery (%). The catalase immobilised on SCA showed higher activity recovery (%) for all the methods used as compared with results obtained with SPCL. The immobilisation process using epichlorohydrin as an activation agent and polyethylenimine as a spacer-arm enhanced the stability and the half-lives at pH 7.0, 30 degrees C, for immobilised catalase on both SCA and SPCL. The half-lives were respectively, 1162 and 870 h compared with other treatments and free enzyme (480 h). The free glycerol present in the immobilisation medium was also a factor that contributed toward the better performance regarding the long-term stability at 30 degrees C and neutral pH. The extension of the morphological modifications on the surface of the materials was observed by scanning electron microscopy. In general, the results indicated that the chemical modification with epichlorohydrin could provide a simple and rather efficient technique to modify the starch-based materials' surface that might be useful in several biomedical applications.
Absorbable Implants↗
Development of cellulose-DNA immunoadsorbent.
The aim of this study was to prepare a DNA immunoadsorbent for the specific, extracorporeal removal of anti-DNA antibodies from the blood of patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Two kinds of cellulose beads were applied as a carrier. Calf thymus DNA was covalently coupled to the carrier using the epichlorohydrin method. Efforts were focused on optimization of conditions for activation and coupling, trying to couple as much DNA as possible to a certain amount of carrier. It was found that the activation level increased with the increase of NaOH concentration and the amount of epichlorohydrin used. The mole of epichlorohydrin must be in excess of that of NaOH because excess NaOH could react further with the epoxy groups in the beads resulting in a decrease of activation level. High activation level could be obtained in a medium of 3.0 M NaOH. The DNA coupling was found to be mainly temperature and pH dependent. Using 0.1 M Tris-HCl buffer, pH 8 at a temperature of 50-90 degrees C, more than 3 mg of DNA could be coupled to 1 ml of wet beads. Prolonging the coupling reaction under 50 degrees C to 72 h resulted in the same coupling capacity as that obtained under 90 degrees C. To evaluate the adsorption ability for anti-DNA of this immunoadsorbent, batch and circulation tests were applied using SLE patient plasma. The immunoadsorbents showed excellent adsorption capacity, especially the cellulose with smaller size (200-300 microm). The incubation of 20 ml of patient's plasma with 1 ml of adsorbent resulted in an 80% decline in the anti-DNA antibody level. In the circulation tests, 30 ml of plasma was circulated through a column containing 3 ml of adsorbent. The maximum decline in anti-DNA level, 80%, was obtained after 60 min. Such high adsorption capacity and high adsorption rate suggest this immunoadsorbent may be used for treatment. For comparison, 1,4-butanediol diglycidyl ether activation method and other DNA sources were tested with the same protocol.
Adsorption↗
Primary structure and catalytic mechanism of the epoxide hydrolase from Agrobacterium radiobacter AD1.
The epoxide hydrolase gene from Agrobacterium radiobacter AD1, a bacterium that is able to grow on epichlorohydrin as the sole carbon source, was cloned by means of the polymerase chain reaction with two degenerate primers based on the N-terminal and C-terminal sequences of the enzyme. The epoxide hydrolase gene coded for a protein of 294 amino acids with a molecular mass of 34 kDa. An identical epoxide hydrolase gene was cloned from chromosomal DNA of the closely related strain A. radiobacter CFZ11. The recombinant epoxide hydrolase was expressed up to 40% of the total cellular protein content in Escherichia coli BL21(DE3) and the purified enzyme had a kcat of 21 s-1 with epichlorohydrin. Amino acid sequence similarity of the epoxide hydrolase with eukaryotic epoxide hydrolases, haloalkane dehalogenase from Xanthobacter autotrophicus GJ10, and bromoperoxidase A2 from Streptomyces aureofaciens indicated that it belonged to the alpha/beta-hydrolase fold family. This conclusion was supported by secondary structure predictions and analysis of the secondary structure with circular dichroism spectroscopy. The catalytic triad residues of epoxide hydrolase are proposed to be Asp107, His275, and Asp246. Replacement of these residues to Ala/Glu, Arg/Gln, and Ala, respectively, resulted in a dramatic loss of activity for epichlorohydrin. The reaction mechanism of epoxide hydrolase proceeds via a covalently bound ester intermediate, as was shown by single turnover experiments with the His275 --> Arg mutant of epoxide hydrolase in which the ester intermediate could be trapped.
Amino Acid Sequence↗
[Gas chromatographic determination of micro organic impurities in 3-chloro-2-hydroxypropyl trimethyl ammonium chloride].
A simple, rapid and reliable method for the determination of micro organic impurities, epichlorohydrin and 1,3-dichloropropanol, in 3-chloro-2-hydroxypropyl trimethyl ammonium chloride (CHPTMA) by gas chromatography is reported. 2-Ethylhexanol was the internal standard. Epichlorohydrin and 1,3-dichloropropanol in CHPTMA were extracted by chloroform. The gas chromatographic separation was achieved on a stainless steel column packed with 10% PEG 20M/Chromosorb W/AW and with a flame ionization detector. The ranges of recovery were 97.5%-105.0% and 93.3%-98.8%, the RSDs were 11.5% and 13.1% and the mininum detectable concentrations were 5.0 micrograms/g and 10 micrograms/g for epichlorohydrin and 1,3-dichloropropanol respectively.
English Abstract↗
Mutagenesis at the ouabain-resistance locus of 3.7.2C L5178Y cells by chromosomal mutagens.
Chemical mutagens including methyl methanesulfonate, N-methyl-N'-nitro-N-nitrosoguanidine, iodomethane, and epichlorohydrin have been classified as "chromosomal mutagens" in the L5178Y/thymidine kinase (TK) gene mutation assay by Clive and coworkers [Mutat Res 59:61-108, 1979; and "The Predictive Value of Short-Term Screening Tests in Carcinogenicity Evaluation." Amsterdam: Elsevier/North Holland, pp 103-123, 1980] who observed mutagen-dependent increases in small TK-deficient mutant colonies with detectable damage to the chromosome (11) that carries the TK locus. In this study, we tested these four chemicals for the induction of gene mutations at the ouabain-resistance (ouares) locus of 3.7.2C L5178Y cells to determine if presumptive chromosomal mutagens would go undetected at a gene locus that is unresponsive to chromosomal damage. A final concentration of 375 micrograms/ml ouabain in soft-agar medium selected against the ouabain-sensitive phenotype without loss of the mutagen-induced ouabain-resistant phenotype. Verification of the mutant phenotype was completed for six individual soft-agar ouares colonies derived from mutagen-treated cultures via growth for 10-11 days in nonselective medium followed by retesting for colony formation in selective soft-agar medium. Dose-related reproducible increases in the frequency of ouabain-resistant mutants were observed for 3.7.2C L5178Y cells that had been exposed for 3 hr to 24-46 micrograms/ml epichlorohydrin, 1.9-3.6 micrograms/ml iodomethane, 0.006-0.011 micrograms/ml N-methyl-N'-nitro-N-nitrosoguanidine and and 2.0-5.4 micrograms/ml methyl methanesulfonate. Also, treatments with EMS, which induced sufficient numbers of ouares colonies to permit analysis of colony size distribution, showed the existence of a bimodal size distribution similar to those reported for TK-deficient mutants. This discovery suggests that mutant colony size in this cell line may be independent of specific gene locus effects. We conclude that (1) chemicals that induce a high proportion of chromosomal mutants, as detected at the TK locus in earlier studies, also induce single gene mutations at the ouabain-resistance locus and (2) a bimodal distribution of mutant colony sizes in soft-agar medium after short expression periods may be a distinctive characteristic of the 3.7.2C L5178Y cell line and is not confined to the TK locus.
Animals↗
Carcinogenicity study of trichloroethylene, with and without epoxide stabilizers, in mice.
Previous analytical studies of industrial samples of trichloroethylene (TRI) have revealed the presence of mutagenic and carcinogenic epoxides which, it was proposed, might be responsible for the carcinogenicity of such samples, as demonstrated with mice in other laboratories. To test this hypothesis, Swiss mice (ICR/HA) of both sexes, bred and kept in SPF conditions, were dosed daily with TRI in corn oil by gavage (males: 2.4 g/kg, females: 1.8 g/kg) with or without the addition of epichlorohydrin (EPC, 0.8%, w/w), 1,2-epoxybutane (BO, 0,8%), or EPC + BO (0.25% + 0,25%) for 18 months. The ensuing observation period terminated at 106 weeks (from start of experiment). Gross and microscopic examination of all organs revealed a statistically significant increase in the incidence of forestomach papillomas and carcinomas after EPC-, BO-, and (EPC + BO)-stabilized samples of TRI, but not after pure, amine base-stabilized TRI. This type of tumor is believed to be induced by the direct alkylating epoxides epichlorohydrin and epoxybutane, whose industrial use in stabilizing chlorinated aliphatic hydrocarbons should be discontinued. No other significant increase in tumor incidences was found. Again, this study does not support the suggestion that trichloroethylene itself is carcinogenic under realistic exposure conditions.
Animals↗
Vinyl chloride mutagenicity via the metabolites chlorooxirane and chloroacetaldehyde monomer hydrate.
Mutagenicity tester strains of Bacillus and Salmonella were used to assay vinyl chloride in nutrient broth at a practical concentration level. Also screened without exogenous activation were seven potential metabolites of vinyl chloride in their pure forms as well as the related epichlorohydrin. Chlorooxirane, chloroacetaldehyde, chloroacetaldehyde monomer hydrate, chloroacetaldehyde dimer hydrate, chloroacetaldehyde trimer, and epichlorohydrin produced significant mutagenic acitivity in Salmonella typhimurium strains sensitive to base-pair mutation. A recombination repair deficient strain of Bacillus subtilis was inhibited in growth by these compounds, whereas excision repair deficient and wild type strains of Bacillus subtilis were relatively unaffected. On the basis of these assays a working hypothesis for the vinyl chloride carcinogenesis mechanism is proposed which involves chlorooxirane and chloroacetaldehyde monomer hydrate as the ultimate carcinogenic metabolites of vinyl chloride.
Acetaldehyde↗
Reactivity of propylene oxides towards deoxycytidine and identification of reaction products.
Deoxycytidine was reacted with four epoxides of varying alkylating rates: propylene oxide, glycidol, epichlorohydrin and trichloropropylene oxide. Deoxycytidine was chosen to compare the reactivities of these epoxides as all sites of possible alkylation, the oxygen and both nitrogens, are involved in base pairing in DNA. Reaction products were separated on HPLC. Products of the least and most reactive epoxides, propylene oxide and trichloropropylene oxide, were characterized by UV, IR, 360 MHz NMR and MS analysis. For the epichlorohydrin and glycidol reactions and all analytical separations, products were characterized by their HPLC retention times and UV spectra. While differences in reactivity among the epoxides towards specific nitrogen and oxygen sites were found, total reactivity correlated with Taft sigma-values of the substituent groups.
Alkylation↗
Industrial mutagens and potential mutagens I. Halogenated aliphatic derivatives.
The halogenated aliphatic hydrocarbons represent one of the most important categories of industrial chemicals from a consideration of volume, use categories, environmental and toxicological considerations and hence most importantly, potential population risk. The major halocarbons reviewed, primarily in terms of their occurrence, utility, stability, distribution, and levels of exposure as well as their metabolism, carcinogenicity and mutagenicity included: vinylchloride, vinylidene chloride, trichloroethylene, perchloroethylene, ethylene dichloride, ethylene dibromide, chloroprene, chloroform, carbon tetrachloride, fluorocarbons (trichlorofluoromethane and dichlorodifluoromethane), epichlorohydrin, halohydrins (2-chloro- and 2-bromoethanol) and haloethers (bis(chloromethyl); chloromethyl'-methyl; bis(2-chloroethyl)-and bis(2-chloroisopropyl)ether. In many instances, data were not available to assess world production, populations at risk and degrees of exposure. With the exception of vinylchloride, vinylidene chloride, epichlorohydrin and 2-halo ethanols, there is an acknowledged paucity of definitive mutagenicity data concerning the majority of halogenated hydrocarbons. Their ubiquitous distribution, and in a number of cases, their carcinogenicity both in man and animals, dictates the urgent need to more exhaustively investigate their potential mutagenicity.
Carbon Tetrachloride↗