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Quantification of endogenous carcinogens. The ethylene oxide paradox.

Although ethylene oxide is a proven genotoxic carcinogen in experimental animals, its human carcinogenicity is still being debated. Alkylations (hydroxyethylation) of DNA and proteins by ethylene oxide are well established. Ethylene oxide is metabolically formed from ethylene, which is a natural body constituent. Thus, endogenous sources of ethylene/ethylene oxide contribute to background alkylations of physiological macromolecules. There are now experimentally well established data sets on the background hydroxyethylations of the N-terminal valine of hemoglobin and of the 7-N position of guanine in DNA, in laboratory animals as well as in humans: A review of these data leads to the conclusion that these background levels display remarkable consistency between the different species studied and, as far as DNA adducts are concerned, also between different tissues. From the existing database it can be deduced that in rats a hemoglobin alkylation, equivalent to the level of normal background, would be caused by repetitive external atmospheric exposures to ethylene oxide (6 hr/day, 5 days/week for several weeks) of about 30 ppb. On the contrary, in the same species, a DNA alkylation, equivalent to the level of normal background, would be caused by similar repetitive exposures to ethylene oxide at about 1-2 ppm. This paradox is unresolved. It points, however, to the biological importance of endogenous DNA alkylations and questions current regulatory procedures of assessing the risk of minute doses of exogenous carcinogens.

Animals↗

Microbiological aspects of ethylene oxide sterilization. IV. Influence of thickness of polyethylene film on the sporicidal activity of ethylene oxide.

Spores of Bacillus subtilis var. niger, dried on nonhygroscopic and hygroscopic surfaces, were enclosed in one of four thicknesses of low-density polyethylene film (2, 4, 6, and 20 mils). The surfaces were then placed in a specially designed thermochemical death rate apparatus and exposed to an ethylene oxide concentration of 600 mg/liter (at 54.4 C) and 50% relative humidity. Survival data, including both spore survivor curves and decimal reduction values (expressed as D values at 54.4 C-600 mg of ethylene oxide per liter), demonstrated similar survivor patterns when the B. subtilis var. niger spores were enclosed in low-density polyethylene films 2, 4, and 6 mils thick. A comparison of these patterns with those of spores enclosed in glassine and subjected to identical exposure conditions revealed only slight variations. The use of 20-mil polyethylene film greatly increased the time required to kill B. subtilis var. niger spores under the exposure conditions.

Bacillus subtilis↗

A cohort study of mortality and cancer incidence in ethylene oxide production workers.

Ethylene oxide, important as an intermediate product in the chemical industry and for sterilising hospital equipment, is mutagenic in several organisms; carcinogenicity has been suspected although this had not been supported by clinical data. Ethylene oxide has been produced by a Swedish company since the beginning of the 1940s. This paper describes a cohort study of the mortality and the cancer incidence among full-time exposed workers in ethylene oxide production, a group of maintenance workers with intermittent exposure and a group of unexposed controls. Investigation of the production processes in the building at different times has shown that workers were exposed to ethylene dichloride, ethylene chlorohydrin, ethylene, and small amounts of bis-(2-chloroethyl) ether as well as to ethylene oxide and traces of other chemicals. The full-time exposed cohort shows a considerable excess mortality deriving mainly from increased mortality from tumours and also from diseases of the circulatory system. The cancer incidence study, including living persons with malignancies, showed a significant excess in the full-time cohort. Of the 16 patients with tumours in the two more exposed cohorts there were three cases of leukaemia, six of tumours in the alimentary tract and four of urogenital malignancy. The excess mortality and cancer incidence cannot be attributed to any particular chemical in the production process, but ethylene oxide and ethylene dichloride are the prime suspects.

Chemical Industry↗

Platelet interactions with plasma-polymerized ethylene oxide and N-vinyl-2-pyrrolidone films and linear poly(ethylene oxide) layer.

Dimethyldichlorosilane (DDS)-treated glass (DDS-glass) was modified with either poly(ethylene oxide) (PEO) films or poly(N-vinyl-2-pyrrolidone) (PNVP) films by plasma polymerization. The thickness of the plasma polymerized films was varied between 40 and 700 nm. The results showed that the hydrophilic plasma polymerized PEO and PNVP films on DDS-glass did not prevent platelet adhesion and activation. The film thickness had only marginal influence on the prevention of platelet activation. In contrast, platelet adhesion was prevented on DDS-glass absorbed with a PEO-containing block copolymer (Pluronic F-108 surfactant) even at a calculated thickness of the PEO layer of less than 40 nm. This study shows that surface hydrophilization is not sufficient for prevention of platelet adhesion and activation. The contrasting results in platelet adhesion between cross-linked plasma polymers and linear PEO-containing block copolymers may be explained qualitatively by a steric repulsion mechanism that is achieved by the conformational freedom of the linear PEO chains interacting with water.

Biocompatible Materials↗

Thermogelling poly(ethylene oxide-b-propylene oxide-b-ethylene oxide) disulfide multiblock copolymer as a thiol-sensitive degradable polymer.

We report a reverse thermogelling poly(ethylene oxide-b-propylene oxide-b-ethylene oxide) disulfide multiblock copolymer as a thiol-sensitive biodegradable polymer. The poly(ethylene oxide-b-propylene oxide-b-ethylene oxide) aqueous solutions studied in this research underwent sol-gel-sol or sol-gel-sol-gel transition depending on the molecular weight and concentration of the polymer, whereas the corresponding disulfide multiblock copolymer aqueous solutions underwent sol-gel transition as the temperature increased in a range of 0-60 degrees C. The hydrophobic dye solubilization and dynamic light scattering of the polymer aqueous solution suggest that the poly(ethylene oxide-b-propylene oxide-b-ethylene oxide)s undergo unimer (3 nm) to micelle (12 nm) transition, whereas the disulfide multiblock copolymers undergo unimer (6 nm) to aggregated polymer (600 nm) transition as the temperature increases. The gel duration increased from 6 h (poly(ethylene oxide-b-propylene oxide-b-ethylene oxide)) to more than 12 days (the corresponding disulfide multiblock copolymer) in phosphate buffer saline, and the gel duration of the latter depended on the glutathione concentration of the medium. The model drug, paclitaxel, was released from the in-situ-formed poly(ethylene oxide-b-propylene oxide-b-ethylene oxide) disulfide multiblock copolymer gel in a glutathione concentration-sensitive manner.

Biocompatible Materials↗

Solid state NMR perspective of drug-polymer solid solutions: a model system based on poly(ethylene oxide).

Poly(ethylene oxide) (PEO) was tested as a polymer matrix for solid dispersion to enhance drug bioavailability. Solid state nuclear magnetic resonance (NMR), X-ray diffraction (XRD), and transmission electron microscopy (TEM) were utilized to characterize the high miscibility between PEO and ketoprofen, a model for crystalline drugs with poor water solubility. The experimental data demonstrated that ketoprofen in the melt-processed blend formed a complete molecular dispersion within the amorphous domain of PEO, resulting in high molecular mobility of ketoprofen in the melt-processed blend that leads to enhanced dissolution rate of ketoprofen in aqueous media. Hydrogen bonds between the carboxylic group of ketoprofen and the ether oxygen of PEO, as detected by solid-state NMR, are the likely source for the high miscibility between ketoprofen and PEO. Such drug/polymer molecular interactions promote dispersion of ketoprofen into amorphous phase of PEO at temperatures well below melting points of both crystalline ketoprofen and PEO. Consequently, melt-processing temperatures can be reduced significantly to avoid thermal degradation. The processing conditions can be also flexible while maintaining reproducibility of the physico-chemical properties of the blend. Furthermore, the high degree of drug/polymer molecular interactions stabilizes the morphology of the blend during storage.

Biological Availability↗

The reactivity of ethylene oxide in contact with iron oxide fines as measured by adiabatic calorimetry.

Samples of various iron oxides suspended above ethylene oxide in an adiabatic calorimeter exhibit exothermic activity at temperatures as low as room temperature. A gamma-Fe(2)O(3) sample was found to show the highest reactivity with ethylene oxide. Ethylene oxide in combination with most of the iron oxide fines tested displayed exothermic activity below 100 degrees C. Self-heat rates near 2000 degrees C/min were observed for the gamma-Fe(2)O(3) fines while rates in excess of 100 degrees C/min were found for other fines (alpha-Fe(2)O(3) and hydrated alpha-Fe(2)O(3)). In two cases (alpha-Fe(3)O(4) and alpha-Fe(2)O(3)), pressurization rates above 1000 psi/min took place. No reactivity was observed for ethylene oxide with the FeO. Thermal inertia effects in commercial operation, such as heat uptake by the equipment to which fines are attached, are presumed to be a factor in limiting the occurrence of related exotherms in ethylene oxide manufacturing facilities.

Disinfectants↗

Physico-chemical and toxico-hygienic aspects of using ethylene oxide for the sterilization of articles for medical use. Part 2. Toxicity and risk of ethylene oxide entering the organism by non-inhalation routes.

Results of investigation of toxicity of ethylene oxide (EO) entering the organism by routes other than inhalation (subcutaneous, intramuscular, intraperitoneal, intravenous) have demonstrated that the substance causes intoxication characterized by polytropic effect on many vitally important organs and systems. The changes in most of the indices under study show a phasic character and dose-time dependence. In both the acute and chronic effect, impairment of the state of the nervous system, the liver, kidney, blood and reactivity of the organism come to the foreground. After one single entrance, EO becomes manifest as a low-risk (class 4) compound (Limac for subcutaneous, intraperitoneal and intravenous routes being 5.0, 0.5 and 1.0 mg/kg, respectively); after repeated exposure as a high-risk (class 2) compound (Limchr for subcutaneous and intraperitoneal route being 1.0 and 0.1 mg/kg, respectively). In comparison with the subcutaneous route, the intravenous and intraperitoneal routes are more dangerous. The obtained parameters of EO toxicometry can be used as a basis for the calculation of safe levels of residual quantities of the compound in articles for medical use.

Animals↗

Release of gas residues from an ethylene oxide sterilized haemodialyser.

Ethylene oxide, a toxic gas used as sterilant for medical devices, is absorbed in plastic materials. The gas is desorbed from the sterilized devices occasionally leading to injuries to the users. A photoionization detector, being specific and sensitive, is used for measurement of liberated ethylene oxide from a haemodialyser. The detector, used as a flow through cell direct connected to the haemodialyser, enables measurement of ethylene oxide in quantities ten times smaller than the maximum daily exposure.

Ethylene Oxide↗

Human skin in vitro percutaneous absorption of gaseous ethylene oxide from fabric.

Ethylene oxide, a colourless gas at ordinary room temperature and pressure, is widely used as a fumigant, coming in contact with clothing and human skin. It is genotoxic in somatic and germ cells. [1,2-14C]Ethylene oxide and fabric discs were sealed in a glass container; the fabric discs were then removed and placed on human skin mounted in glass diffusion cells. Percutaneous absorption was 1.3% of the dose when the fabric/skin surface was open to surrounding air, and increased to 46.0% when the surface was occluded with latex glove material. The absorption was rapid, occurring within the first 0-4 hr assay period. Absorbed chemical was confirmed to be unchanged ethylene oxide in the receptor fluid. This study also serves as a model for exposure of fabric/skin to any potentially hazardous gas.

Administration, Cutaneous↗

[Decontamination of some spices by ethylene oxide. Development of 2-chloroethanol and ethylene glycol during the preservation].

After the disinfection by ethylene oxide and storage by ethylene oxide in definite conditions of 16 spices (parsley, chervil, tarragone, chive, thyme, rosemary, coriander, nutmeg, mace, cinnamon, allspices, clove, pepper), the authors observed the fast loss of residual ethylene oxide and ethyleneglycol. On the contrary, the persistence of 2-chloroethanol was followed up for 6 months. They turn their attention to the toxicity of this compound to ensure the protection of customers.

Disinfection↗

Temperature and concentration effects on supramolecular aggregation and phase behavior for poly(propylene oxide)-b-poly(ethylene oxide)- b-poly(propylene oxide) copolymers of different composition in aqueous mixtures, 1.

The phase behavior (temperature vs composition) and microstructure for the two binary systems Pluronic 25R4 [(PO)19(EO)33(PO)19]-water and Pluronic 25R2 [(PO)21(EO)14(PO)21]-water have been studied by a combined experimental approach in the whole concentration range and from 5 to 80 degrees C. The general phase behavior has been identified by inspection under polarized light. Precise phase boundaries have been determined by analyzing 2H NMR line shape. The identification and microstructural characterization of the liquid crystalline phases have been achieved using small-angle X-ray scattering (SAXS). The isotropic liquid solution phases have been investigated by self-diffusion measurements (PGSE-NMR method). 25R2 does not form liquid crystals and is miscible with water in the whole concentration range; with increasing temperature, the mixtures split into water-rich and a copolymer-rich solutions in equilibrium. 25R4 shows rich phase behavior, passing, with increasing copolymer concentration, from a water-rich solution to a lamellar and copolymer-rich solution. A small hexagonal phase, completely encircled in the stability region of the water-rich solution, is also present. In water-rich solutions, at low temperatures and low copolymer concentrations, the copolymers are dissolved as independent macromolecules. With increasing copolymer concentrations an interconnected network of micelles is formed in which micellar cores of hydrophobic poly(propylene oxide) are interconnected by poly(ethylene oxide) strands. In copolymer-rich solutions water is molecularly dissolved in the copolymer. The factors influencing the self-aggregation of Pluronic R copolymers (PPO-PEO-PPO sequence) are discussed, and their behavior in water is compared to that of Pluronic copolymers (PEO-PPO-PEO sequence).

Macromolecular Substances↗

Heritable translocation and dominant-lethal mutation induction with ethylene oxide in mice.

Ethylene oxide was studied for induction of dominant-lethal mutations and heritable translocations in male mice. The chemical was prepared in water and injected intraperitoneally. The dominant-lethal study was conducted using a single injection of 150 mg/kg (maximum tolerated dose); in the heritable translocation study males were injected daily on weekdays for 5 weeks with 60 or 30 mg/kg dose per day. Results clearly showed that ethylene oxide is effective in inducing dominant-lethal mutations and that the 4 stocks of untreated females used do not differ or may differ only slightly in the ability of their eggs to repair ethylene oxide-induced lesions in male germ cells. Increases in the frequencies of heritable translocations were also observed at the 2-dose levels. These frequencies did not deviate significantly from those expected on the basis of dose-square kinetics.

Animals↗

Immobilization of functionalized alkyl-poly(ethylene oxide) surfactants on poly(ethylene) surfaces by means of an argon plasma treatment.

Alkyl-poly(ethylene oxide) (PEO) surfactants containing a terminal hydroxyl, sulfate, or carboxylate group were grafted at the surface of poly(ethylene) (PE) samples to improve their blood compatibility. Grafting was achieved by immobilizing PEO surfactants on PE using an argon plasma treatment. The sulfate group containing PEO surfactant was synthesized by sulfating polyoxyethylene(20)stearylether (Brij78; B) with chlorosulfonic acid. A carboxylate-terminated surfactant was synthesized by a substitution reaction of the sodium alkoxide form of B with sodium iodoacetate. XPS analysis of the modified PE samples showed that at short plasma treatment times of up to 5 s the structure of the immobilized surfactants is largely retained. When plasma treatment times longer than 30 s were applied, the PEO chains of the surfactants were degraded. The wettability of the modified PE samples was improved compared to the unmodified PE samples. The wettability of the modified samples did not change when they were stored in air at room temperature for at least 12 weeks.

Alkylation↗