Hydroxycobalamin as an antidote to acrylonitrile

doi:10.1016/0041-008X(65)90138-9

Toxicology and Applied Pharmacology

Volume 7, Issue 3, May 1965, Pages 367-372

https://doi.org/10.1016/0041-008X(65)90138-9 Get rights and content

Abstract

Hydroxycobalamin, a derivative of vitamin B₁₂, reduced the immediate toxicity of acrylonitrile in mice. The protection afforded was more obvious if sodium thiosulfate was given additionally, but most of the animals died some hours later. Phenobarbital pretreatment was ineffective. In anesthetized dogs acutely poisoned by intravenous infusion of acrylonitrile solutions, the antidotal effect of the mixture was less evident. The acute toxicity of acrylonitrile was due in part to cyanide and in part to a central action. Hydroxycobalamin is not likely to be of great therapeutic value.

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Cited by (15)

Biological markers of acute acrylonitrile intoxication in rats as a function of dose and time
1997, Fundamental and Applied Toxicology
Three markers of acute acrylonitrile (AN) intoxication, namely, tissue glutathione (GSH), tissue cyanide (CN), and covalent binding to tissue protein, were studied as a function of dose and time. Doses administered and responses expected were 20 mg/kg (LD0), 50 mg/kg (LD10), 80 mg/kg (LD50), and 115 mg/kg (LD90). Liver GSH was the most sensitive marker of AN exposure. At 80 mg/kg AN, virtually complete depletion of liver GSH was observed within 30 min with no recovery through 120 min. Kidney GSH showed a similar, but less intense depletion; while blood and brain GSH were more refractory to AN. Whole blood and brain CN rose progressively during the first 60 min in a dose-dependent fashion. At the lowest dose, CN levels decreased thereafter, whereas, at the three higher doses, CN levels were maintained or continued to increase through 120 min. At the highest dose, blood and brain CN remained at acutely toxic levels through 240 min. Covalent binding increased rapidly in all tissues during the first 30 min at all doses. At the lowest dose, little additional covalent binding was observed beyond 30 min, while at the three higher doses, covalent binding increased, although at a slower rate. The data indicate that these three biologic markers of acute AN intoxication respond dramatically in a time-dependent manner in the toxic dosage range. Furthermore, the data provide evidence that AN toxicity is gated by GSH depletion in liver with the resultant termination of AN detoxification.
Acute acrylonitrile toxicity: Studies on the mechanism of the antidotal effect of d- and l-cysteine and their N-acetyl derivatives in the rat
1990, Toxicology and Applied Pharmacology
Thiol-containing antibotes for acute acrylonitrile (AN) toxicity may exert their action by chemically reacting with AN, by replacing critical sulfhydryl groups cyanoethylated by AN, and by detoxifying cyanide produced from AN metabolism. We have evaluated the ability of the optical isomers of cysteine and N-acetylcysteine to act as antidotes against AN toxicity in order to assess the relative importance of each of these three antidotal mechanisms. The toxicity of AN was determined in male Sprague-Dawley rats and compared to the toxicity determined after treatment with 2 mmol/kg of thiol antidote by computing a protective index (median lethal dose with antidote/median lethal dose without antidote). The protective indices of l-cysteine, d-cysteine, N-acetyl-l-cysteine, and N-acetyl-d-cysteine were 2.03, 1.97, 1.76, and 1.25, respectively. Measurements of urinary mercapturates, derived from the non-oxidative pathway of AN metabolism, indicated that none of the antidotes was able to significantly increase the excretion of these metabolites. Blood cyanide generated from the oxidative metabolism of AN and butyronitrile was also determined. All of the antidotes, except N-acetyl-d-cysteine, lowered blood cyanide levels. A comparison of these results with the predicted relative abilities of the enantiomers to participate in each of the three antidotal mechanisms leads to the conclusion that, under these experimental conditions, the best correlation exists with the cyanide detoxification mechanism.
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Hydroxycobalamin as an antidote to acrylonitrile

Abstract

Acrylonitrile: spectrophotometric determination, acute toxicity and mechanism of action

Arch. Ind. Hyg. Occup. Med.

The assay of acute vapour toxicity and the grading of interpretation of results on 96 chemical compounds

J. Ind. Hyg. Toxicol.

Value of hydroxycobalamin in the treatment of cyanide poisoning

Compt. Rend. Soc. Biol.

Toxicology of acrylonitrile

J. Ind. Hyg. Toxicol.

Characteristics of hydroxycobalamin

Lab. Tec. Farm. Torino

Acrylonitrile, toxicity and mechanism of action

Med. Lavoro