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PubMed1983

Conjugations of acrylonitrile and glycidonitrile with glutathione--a contribution to problems of metabolism of acrylonitrile.

The study of the conjugation of acrylonitrile and glycidonitrile with glutathione has demonstrated the capacity of glutathione of eliminating both acrylonitrile (manifesting mostly cyanide effects) and the primary product of its oxidative turnover, glycidonitrile (mutagenic effect), from acting toxicly. It appears, at the same time, however, that massive doses of acrylonitrile may endanger the biological system by depletion of large quantities of glutathione a schematic chart of the metabolic exchanges of acrylonitrile was suggested demonstrating that a part of the total amount of the excreted thiocyanate in the urine might also be accounted for by the cyanide having been produced by the enzymatically catalyzed conjugation of glycidonitrile with glutathione, with the ensuing secondary breakdown of the intermediary product cyanohydrin.

Acrylonitrile↗
PubMed1978

Gas chromatographic head-space determination of residual acrylonitrile in acrylonitrile-butadiene-styrene resins and migration into a simulated fatty foodstuffs liquid.

Head-space methods are described for the determination of residual acrylonitrile in acrylonitrile-butadiene-styrene resins and in olive oil, which simulates fatty foodstuffs. Dimethylformamide was used as solvent for the resin, with flame ionization detection. The injection of water into the resin dispersion prior to head-space analysis greatly enhances the detection capabilities. The use of a nitrogen-selective detector required dimethyl sulphoxide as the solvent. The determination of acrylonitrile in olive oil was carried out employing both types of detector. The detection sensitivity was much greater with the nitrogen-selective detector.

Acrylonitrile↗
PubMedDate not supplied

Haemoglobin adducts of acrylonitrile and ethylene oxide in acrylonitrile workers, dependent on polymorphisms of the glutathione transferases GSTT1 and GSTM1.

Fifty-nine persons with industrial handling of low levels of acrylonitrile (AN) were studied. As part of a medical surveillance programme an extended haemoglobin adduct monitoring [N-(cyanoethyl)valine, CEV; N-(methyl)valine. MV: N-(hydroxyethyl)valine, HEV] was performed. Moreover, the genetic states of the polymorphic glutathione transferases GSTM1 and GSTT1 were assayed by polymerase chain reaction (PCR). Repetitive analyses of CEV and MV in subsequent years resulted in comparable values (means, 59.8 and 70.3 microg CEV/1 blood; 6.7 and 6.7 microg MV/1 blood). Hence, the industrial AN exposures were well below current official standards. Monitoring the haemoglobin adduct CEV appears as a suitable means of biomonitoring and medical surveillance under such exposure conditions. There was also no apparent correlation between the CEV and HEV or CEV and MV adduct levels. The MV and HEV values observed represented background levels, which apparently are not related to any occupational chemical exposure. There was no consistent effect of the genetic GSTM1 or GSTT1 state on CEV adduct levels induced by acrylonitrile exposure. Therefore, neither GSTM1 nor GSTT1 appears as a major AN metabolizing isoenzyme in humans. The low and physiological background levels of MV were also not influenced by the genetic GSTM1 state, but the MV adduct levels tended to be higher in GSTT1- individuals compared to GSTT1 + persons. With respect to the background levels of HEV adducts observed, there was no major influence of the GSTM1 state, but GST- individuals displayed adduct levels that were about 1/3 higher than those of GSTT1 + individuals. The coincidence with known differences in rates of background sister chromatid exchange between GSTT1- and GSTT1 + persons suggests that the lower ethylene oxide (EO) detoxification rate in GSTT1- persons, indicated by elevated blood protein hydroxyethyl adduct levels, leads to an increased genotoxic effect of the physiological EO background.

Acrylonitrile↗
PubMed1983

Induced tolerance to acrylonitrile toxicity by prior acrylonitrile exposure.

Pretreatment by inhalation with sublethal concentrations of acrylonitrile protects rats from subsequent, normally lethal, ACN exposures. However, inhalation-induced tolerance to ACN does not protect against subsequent poisoning by cyanide. Metabolic liberation of cyanide has been suggested to be responsible for the toxicity of ACN. Protection against ACN toxicity is not provided by pretreatment with compounds which have structural similarity to ACN, i.e. acrylamide or ethylene, nor by cyanide per se. Enzyme induction with Aroclor 1254 also does not protect against ACN toxicity. The latter data suggest that the tolerance resulting from ACN pretreatment is not the result of enzyme induction and the basis for the protective effect of ACN inhalation pretreatment remains unclear.

Acrylonitrile↗
PubMed1978

Gas-solid chromatographic procedures for determining acrylonitrile monomer in acrylonitrile-containing polymers and food simulating solvents.

A gas chromatographic method is described for acrylonitrile monometer (AN), using a nitrogen/phosphorus detector. Procedure for the analysis of AN in 5 food simulants (water, 3% acetic acid, heptane, 50% ethanol, and 8% ethanol) as well as in the polymer matrix are included. The quantitation limit for direct injection of AN/food simulant solution is 0.04 ng AN/microliter. AN-based polymers are dissolved in N,N-dimethylacetamide and injected directly. Residual AN in the polymer can be quantitated at the 0.5 ng/microliter level. Results of migration studies are also presented.

Acrylonitrile↗
PubMed1975

Acrylonitrile biotransformation in rats, mice, and chinese hamsters as influenced by the route of administration and by phenobarbital, SKF 525-A, cysteine, dimercaprol, or thiosulfate.

Female wistar rats, conventional albino mice, and Chinese hamsters were given a single dose of acrylonitrile, 0.5 or 0.75 mM/kg body weight. The elimination in the urine of thiocyanate, which is the main metabolite of acrylonitrile, indicated a decreasing proportion of biotransformation after oral (over 20%), intraperitoneal, or subcutaneous (2 to 5%), and intravenous (1%) administration in rats. Oral administration of acrylonitrile in hamsters and mice was also followed by higher biotransformation than intraperitoneal administration. Pretreatment of rats with phenobarbital, SKF 525 A, cysteine, or dimercaprol did not significantly influence elimination of thiocyanate in the urine after the administration of acrylonitrile, but simultaneous administration of thiosulfate significantly increased the metabolized portion of acrylonitrile given intraperitoneally in rats (almost twice) and mice (more than three times). Acrylonitrile was found to be strongly bound in blood. The study confirmed the marked effect of distribution (first-pass metabolic phenomenon) on the metabolic fate of foreign compounds. The strong acrylonitrile binding and cyanoethylation are apparently responsible for the unusually high influence of the different routes of administration on the metabolic fate of acrylonitrile. Acrylonitrile was more effectively metabolized to thiocyanate in mice than in rats after oral, intraperitoneal, and intravenous administration. A greater response of acrylonitrile to thiocyanate metabolism and a larger decrease in its acute toxicity after thiosulfate in mice than in rats indicate possible differences in the mechanism of acrylonitrile toxicity in these animals. Cyanide apparently plays a minor role in the acrylonitrile toxicity in rats, but may play quite an important one in mice.

Administration, Oral↗
PubMed1984

Subacute and chronic action of acrylonitrile on adrenals and gastrointestinal tract: biochemical, functional and ultrastructural studies in the rat.

A single dose of acrylonitrile can produce fatal adrenal apoplexy within approximately 2 h. Our previous studies also indicate that multiple injections of the chemical cause acute hemorrhagic and occasional nonperforating duodenal ulcers. Other authors have reported increase in gut and lung neoplasia after chronic exposure. The present study was designed to elucidate the subacute and chronic actions of acrylonitrile on the adrenals, stomach and duodenum by correlating biochemical, functional and morphologic investigations, as well as to gain insight into the mechanisms of action of acrylonitrile. Rats were exposed to 0, 0.0001% (1 ppm), 0.002%, 0.01%, 0.05% or 0.2% acrylonitrile in drinking water, or to the same amount of the chemical given through daily gavage, for 7, 21 or 60 days. Acrylonitrile caused a time- and dose-dependent decrease in plasma corticosterone levels; aldosterone was affected only by the 'high' dose and prolonged time of exposure. Young rats were more susceptible than adults to this action of acrylonitrile. The adrenal cortex, especially the zona fasciculata, was atrophic in rats that had ingested the nitrile through drinking water. At 0.05% and 0.2%, it also caused decreased food intake and body weight gain. The adrenals were enlarged with a hyperplastic zona fasciculata after daily doses of a bolus of acrylonitrile. Ingestion of the chemical did not interfere with compensatory enlargement of the adrenal gland following unilateral adrenalectomy. On the other hand, the ACTH-induced elevation of corticosterone plasma concentration was significantly attenuated by acrylonitrile in drinking water. Electron microscopy of the adrenal glands revealed no consistent changes in the steroid-producing cells. We thus postulate that accelerated turnover of circulating corticoids and/or interference with the secretion or action of ACTH may primarily be responsible for the decreased plasma levels of corticosterone and aldosterone in rats that ingest acrylonitrile. The mucosa in the stomach at the junction of the forestomach and glandular region of animals that had ingested acrylonitrile was hyperplastic. The corpus also showed regional mucosal hyperplasia with the appearance of 'cobble-stoning'. These changes were preceded and associated with an elevated concentration of non-protein sulfhydryls mostly in the mucosa of the glandular stomach. A similar, less prominent elevation also occurred in the proximal duodenum. These alterations may resemble the preneoplastic combination of elevated glutathione and focal hyperplasia described in the liver with hepatocarcinogens.(ABSTRACT TRUNCATED AT 400 WORDS)

Acrylonitrile↗
PubMed2000

Species differences in acrylonitrile metabolism and toxicity between experimental animals and humans based on observations in human accidental poisonings.

The high acute toxicity of acrylonitrile may be a result of its intrinsic biological reactivity or of its metabolite cyanide. Intravenous N-acetylcysteine has been recommended for treatment of accidental intoxications in acrylonitrile workers, but such recommendations vary internationally. Acrylonitrile is metabolized in humans and experimental animals via two competing pathways; the glutathione-dependent pathway is considered to represent an avenue of detoxication whilst the oxidative pathway leads to a genotoxic epoxide, cyanoethylene oxide, and to elimination of cyanide. Cases of acute acrylonitrile overexposure or intoxication have occurred within persons having industrial contact with acrylonitrile; the route of exposure was by inhalation and/or by skin contact. The combined observations lead to the conclusion of a much higher impact of the oxidative metabolism of acrylonitrile in humans than in rodents. This is confirmed by differences in the clinical picture of acute life-threatening intoxications in both species, as well as by differential efficacies of antidotes. A combination of N-acetylcysteine with sodium thiosulfate seems an appropriate measure for antidote therapy of acute acrylonitrile intoxications. Clinical observations also highlight the practical importance of human individual susceptibility differences. Furthermore, differential adduct monitoring, assessing protein adducts with different rates of decay, enables the development of more elaborated biological monitoring strategies for the surveillance of workers with potential acrylonitrile contact.

Acrylonitrile↗
PubMed1992

Effect of chronic exposure to acrylonitrile on subjective symptoms.

A cross-sectional study was performed to clarify the relationship between exposure to acrylonitrile (AN) and its effect on subjective symptoms by using a modified Cornell Medical Index (CMI) health questionnaire. The 7 acrylic fiber manufacturing factories surveyed were classified into 3 groups, namely, group L with a mean environmental acrylonitrile concentration of 1.8 ppm, group M with 7.4 ppm, and group H with 14.1 ppm. The total number of workers engaged in acrylic fiber manufacturing processes (acrylonitrile workers) and reference workers analyzed were 504 and 249, respectively. These consisted of 92 acrylonitrile workers and 108 reference workers in group L, 304 and 102 respectively in group M, and 108 and 39 respectively in group H. The mean values for length of exposure to acrylonitrile were 5.6 years in group L, 7.0 years in group M, and 8.6 years in group H. Neurotic status as determined by Fukamachi's criteria and Cornell Medical Index profiles did not show any AN-related differences between AN workers and reference workers in any of the groups. The subjective symptoms with significantly high prevalences in AN workers were "headache", "tongue trouble", "choking lump in throat", "fatigability", "general malaise", "heavy arms", and "heavy sweating". Except for "choking lump in throat" there was no relationship between the prevalence of symptoms and the length or level of exposure to acrylonitrile. These results suggested that long-term exposure to acrylonitrile at levels up to 14.1 ppm did not induce neurotic effects in acrylonitrile workers, but might cause some reversible subjective symptoms.

Acrylonitrile↗
PubMedDate not supplied

Clinical toxicology of acrylonitrile.

Acrylonitrile monomer is used in the production of artificial fibres and resins. It has been used as a fumigant. Acrylonitrile has acute toxic effects for men and animals on over-exposure by inhalation of the vapor, dermal absorption of the liquid and oral intake. Symptoms in men are non-specific and predominantly related to the central nervous system, the respiratory tract, the skin and to the gastrointestinal tract. Severe acrylonitrile intoxication is followed by loss of consciousness, convulsions, respiratory arrest and death. The detailed investigation of a patient with complaints after chronic exposure demonstrates the necessity of objective neurophysiologic studies. Acrylonitrile has carcinogenic properties in animals. It is also embryotoxic and teratogenic. Epidemiological studies in men exposed to acrylonitrile are not convincing. There may be a slight excess of deaths from lung cancers and other malignant tumors. Effects of potential antidotes were studied in animal experiments. Rats were intoxicated with lethal doses of acrylonitrile by different routes of application. The cyanide antidotes 4-dimethylaminophenol plus thiosulfate showed some protective effect only after oral but not after i.p. or inhalational acrylonitrile administration. Of the sulfhydryl compounds cysteine, N-acetyl-cysteine, cysteamine and diethyldithiocarbamate, the two antidotes cysteine and N-acetylcysteine proved to be especially effective. From these experiments a tentative schedule of antidotal therapy for humans accidentally intoxicated with acrylonitrile is inferred, using N-acetylcysteine by analogy with the therapeutic regimen effective in cases of paracetamol poisoning.

Acrylonitrile↗
PubMed1982

Possible role of lipid peroxidation in the actions of acrylonitrile on the adrenals, liver and gastrointestinal tract.

Acrylonitrile-induced adrenal necrosis is associated with the early depletion of adrenal glutathione and elevation of adrenal dopamine. These biochemical events could result in increased susceptibility to free radical-mediated lipid peroxidation which may play a role in the pathogenesis of adrenal injury caused by acrylonitrile. In the studies reported here we found no elevation in malonaldehyde or conjugated diene concentrations of adrenal glands (or of glandular stomach and duodenal mucosa which may be other targets of acrylonitrile action) from rats given acrylonitrile. Conjugated diene concentrations in liver microsomes were significantly elevated (132%) 60 min after administration of carbon tetrachloride or 15 (38%), 30 (58%), and 60 (46%) min after injection of acrylonitrile whereas mitochondrial conjugated diene concentrations were not significantly altered by acrylonitrile. Our results suggest that while lipid peroxidation may not be involved in the pathogenesis of acrylonitrile adrenal injury it may occur in other tissues after acrylonitrile administration.

Acrylonitrile↗
PubMed1993

Modulation of acrylonitrile-induced embryotoxicity in vitro by glutathione depletion.

The effects of glutathione (GSH) depletion on the embryotoxicity of acrylonitrile were assessed in vitro using the rat whole-embryo culture system. Day 10 rat embryos were cultured in rat serum medium for 6 h in the presence of 250 microM L-buthionine-S,R-sulfoximine (BSO), a specific inhibitor of GSH synthesis, to deplete GSH in both embryo and visceral yolk sac. Following pretreatment, conceptuses were cultured for an additional 21 h in the presence of 152, 228, or 304 microM acrylonitrile. At the end of the culture period, conceptuses were assessed for survival, growth and development, malformations, and the protein and glutathione content of embryos and yolk sacs were assayed. Acrylonitrile alone produced concentration-related and statistically significant decreases in yolk sac diameter, crown-rump length, head length and number of somite pairs, as well as in embryonic and yolk sac proteins. The chemical also caused dysmorphogenesis of the brain and of the caudal extremity, and a concentration-related and statistically significant increase in GSH content in the yolk sac. Pretreatment with BSO significantly enhanced the embryotoxic effects of acrylonitrile. The conceptuses displayed further decreases in functional yolk sac circulation, yolk sac diameter, crown-rump and head length, when compared to either acrylonitrile or BSO alone. The incidence of caudal malformations and the severity of brain malformations produced by acrylonitrile were also increased. Marked decreases in embryonic and yolk sac GSH contents were observed after exposure to BSO alone or in combination with acrylonitrile.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Urinary metabolites of [1,2,3-13C]acrylonitrile in rats and mice detected by 13C nuclear magnetic resonance spectroscopy.

Acrylonitrile, a carcinogen in rats, undergoes extensive metabolism via two routes: direct glutathione conjugation or epoxidation. Metabolism to cyanoethylene oxide may mediate the carcinogenic and toxic activity of acrylonitrile. To characterize comprehensively the metabolism in vivo of acrylonitrile, the detection and identification of metabolites in urine of rodents dosed with acrylonitrile have been carried out using NMR spectroscopy. Following administration of [1,2,3-13C]acrylonitrile to male Fisher 344 rats (10 or 30 mg/kg, po) or B6C3F1 mice (10 mg/kg, po), urine samples were collected for 24 h. Carbon-13 NMR spectra were acquired directly on the urine samples after centrifugation and addition of 10-25% D2O. Resonances were assigned to carbons of acrylonitrile metabolites on the basis of chemical shift, proton multiplicity, carbon-carbon coupling, and calculated values of shift, and by comparison with standards. The proton multiplicity of each carbon was determined by heteronuclear 2D J-resolved spectroscopy (HET2DJ), and the carbon-carbon connectivities of resonances were determined using incredible natural abundance double quantum transfer spectroscopy (INADEQUATE). The metabolites identified in rat urine were thiocyanate, N-acetyl-S-(2-cyanoethyl)cysteine, N-acetyl-S-(2-hydroxyethyl)cysteine, N-acetyl-S-(1-cyano-2-hydroxyethyl)cysteine, thiodiglycolic acid, thionyldiacetic acid, and S-(carboxymethyl)cysteine or its N-acetyl derivative. These metabolites were also identified in mouse urine. Metabolites were quantitated by integrating metabolite carbon resonances with respect to that of dioxane added at a known concentration. Thiodiglycolic acid and (carboxymethyl)cysteine (or its N-acetyl derivative) were the major metabolites in the mouse, while N-acetyl-S-(2-cyanoethyl)cysteine and N-acetyl-S-(2-hydroxyethyl)cysteine were the major metabolites in the rat. Metabolites derived from cyanoethylene oxide (CEO) accounted for approximately 60% of the products excreted in rat urine, compared with 80% in the urine from mice. Differences between rat and mouse in the further metabolism of CEO were also observed. The proportion of the dose metabolized via CEO may be an important determinant of the toxicity and carcinogenicity of acrylonitrile.

Acrylonitrile↗
PubMed1984

Acrylonitrile: a suspected human carcinogen.

The literature on carcinogenicity of acrylonitrile (an important intermediate in the chemical industry) is reviewed. The three main conclusions are: (1) Acrylonitrile has genotoxic effects in various tests in microorganisms and in mammal cells. (2) Chronic exposure to acrylonitrile causes tumours in rats. (3) Results of epidemiological studies indicate that acrylonitrile may be a human carcinogen. From this it is clear that acrylonitrile is very probably carcinogenic to humans. Therefore the authors plead for a reduction of acrylonitrile standards to the lowest practicable limit.

Acrylonitrile↗