Time-course studies of the distribution of [1-14C]acrylonitrile in rats after intravenous administration.

Intravenous injection of acrylonitrile (ACN) causes adrenal hemorrhagic necrosis. ACN and its metabolites react with glutathione and bind covalently with macromolecules. Hence the purpose of this investigation was to measure the distribution and covalent binding of radiolabel derived from [1-14C]ACN in order to determine whether binding of ACN or its metabolites may be implicated in the pathogenesis of ACN-induced adrenal injury. Following intravenous injections of ACN, concentrations of total radiolabel were highest in the blood, liver, duodenum, kidneys, and adrenals. Except for blood, there was a time-dependent decrease in total radiolabel in these tissues. Compared with other major organ systems, the levels of covalently bound radiolabel were lower in the adrenal glands. These results do not support a role of covalent binding of ACN or its metabolites in the adrenal toxicity of ACN, but suggest that the initial high concentrations of total radiolabelled compounds derived from ACN could play a role in the action of ACN on the adrenal glands.

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)

Potentiation of duodenal ulcerogenic action of acrylonitrile by PCB or phenobarbital in the rat.

Pretreatment of rats with the polychlorinated biphenyl (PCB) Aroclor 1254 or phenobarbital markedly increased the duodenal ulcerogenic action of acrylonitrile. The extent of forestomach and hepatic lesions in these rats, on the other hand, was not modified. The duodenal ulcers produced by Aroclor 1254 and acrylonitrile morphologically resembled the ulcers induced in other animal models of the human duodenal ulcer disease. The possible mechanisms of this potentiation of acrylonitrile action are discussed.

Role of lipid peroxidation in tissue injury after hepatic ischemia.

Ischemia and anoxia are associated with decreased concentrations of cellular antioxidants. The hypothesis that recirculation of oxygenated blood to previously ischemic tissue may result in enhanced free-radical reactions leading to lipid peroxidation and tissue damage was investigated. Elevated hepatic conjugated diene concentrations were detected 60 min after treatment of rats with carbon tetrachloride, a positive control, but were not found after 90 min ischemia or at 5 or 60 min after reperfusion of ischemic tissue. These findings suggest that lipid peroxidation may not be an early event in ischemia-induced necrosis but do not rule out a role of other free-radical reactions in the pathogenesis of ischemic necrosis.

Structural considerations in the metabolism of nitriles to cyanide in vivo.

In order to investigate structure-activity relationships that influence metabolism of nitriles to CN-, thiocyanate was measured, as an index of CN- release, in urine of rats given equimolar doses of nitriles. Significantly more SCN- was excreted after po than after ip administration of saturated (C2-C5) nitriles, but SCN- excretion was the same after both routes for n-hexanenitrile. Among saturated nitriles, SCN- excretion was maximal for the C3 and C4 compounds, propionitrile, n-butyronitrile, and isobutyronitrile, after both po and ip administration. SCN- excretion was not elevated after administration of the tertiary nitrile trimethylacetonitrile. Administration (po) of the unsaturated nitriles acrylonitrile, crotonitrile, and 3-butenenitrile yielded 37%, 5.6%, and 29% of the dose as SCN-, whereas after ip injection 4.5%, 4.6%, and 18% of the doses were excreted as SCN-, respectively. After iv injection of acrylonitrile, urinary SCN- content was not elevated, whereas 45% of an iv dose of the saturated analog propionitrile was excreted as SCN-. These results suggest that length of the carbon chain, presence of substituents at the alpha-carbon, position of double bonds, and, for some compounds, route of administration, are important factors influencing the release of CN- from nitriles.

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.

Potentiation by triorthotolyl phosphate of acrylate ester-induced alterations in respiration.

The purpose of this study was to determine whether triorthotolyl phosphate (TOTP), an inhibitor of carboxylesterases, would enhance the inhibitory effects of acrylate esters on respiration. Respiratory frequency was measured and the calculated decreases in respiratory frequency were used as an index of respiratory irritancy due to acrylate compounds. Tidal volume, minute ventilation, and rectal temperature were also measured. Dose-dependent decreases in frequency were found in rats inhaling methyl acrylate, ethyl acrylate and acrylic acid. Tidal volume was also reduced in rats exposed to acrylate compounds and, as a result, the percentage change in minute ventilation was greater than the percentage change in frequency or tidal volume alone. Pretreatment with TOTP (125 mg/kg) enhanced the decreases in frequency and minute ventilation caused by acrylate esters but not those resulting from exposure to acrylic acid. Exposure to ethyl acrylate and acrylic acid also resulted in dose-dependent reductions in rectal temperature. TOTP potentiated ethyl acrylate-induced decreases in rectal temperature but not those caused by acrylic acid. The results suggest that inhibition of carboxylesterases can result in enhanced irritant action of acrylate esters on the upper respiratory tract, and provide support for a local role of carboxylesterases in the detoxification of these irritant esters.