Effects of Long-Term Low-Dose Cyanide Administration to Rats

doi:10.1006/eesa.2002.2189

Ecotoxicology and Environmental Safety

Volume 53, Issue 1, September 2002, Pages 37-41

https://doi.org/10.1006/eesa.2002.2189 Get rights and content

Abstract

Chronic exposure to cyanide has been associated with development of pancreatic diabetes, hypothyroidism, and several neurological diseases in both humans and animals. However, there is a limited number of experimental models for these pathologies. Thus, in the present study 0, 0.15, 0.3, or 0.6 mg KCN/kg body weight/day was administered for 3 months to 26 rats. On the last day, plasma samples were obtained for glucose, cholesterol, and thyroidal hormone measurement, and the pancreas, thyroids, and whole central nervous system were collected for histopathologic study. There were no significant difference in plasma concentrations of the substances measured between groups, and no lesions were found in the pancrease or thyroid. The CNS of experimental animals revealed the presence of spheroids on the ventral horn of the spinal cord, neuron loss in the hippocampus, damaged Purkinje cells, and loss of cerebellar white matter. In conclusion, cyanide administration could promote neuropathological lesions in rats without affecting pancreas or thyroid gland metabolism.

References (41)

O. Dohan et al.
Molecular study of the sodium-iodide symporter (NIS): A new field in thyroidology
Trends Endocrinol. Metab.
(2000)
W.T. Hayes
The 90-dose LD50 and a chronicity factor as measures of toxicity
Toxicol. Appl. Pharmacol.
(1967)
N.P. Okolie et al.
Differential effects of chronic cyanide intoxication on heart, lung and pancreatic tissues
Food Chem. Toxicol.
(2000)
C.F.I. Onwuka et al.
Role of sulphur in cyanide detoxification in ruminants
Small Ruminant Res.
(1992)
H. Sarles
Chronic pancreatitis and diabetes
Bailliers Clin. Endocrinol. Metab.
(1992)
Y. Solberg et al.
The association between cigarette smoking and ocular diseases
Surv. Ophthalmol.
(1998)
T. Teuscher et al.
Absence of diabetes in a rural West African population with a high carbohydrate/cassava diet
Lancet
(1987)
L.G. Adams et al.
Cystitis and ataxia associated with sorghum ingestion by horses
J. Am. Vet. Med. Assoc.
(1969)
A.O. Akanji et al.
The effects of chronic cassava consumption, cyanide intoxication and protein malnutrition on glucose tolerance in growing rats
Br. J. Nutr.
(1993)
R. Assan et al.
Diabetogenic tropical pancreatitis
Diabetes Metab.
(1988)

P. Blanc et al.

Cyanide intoxication among silver-reclaiming workers

J. Am. Med. Assoc.

(1985)

D.W. Boening et al.

A critical review: general toxicity and environmental fate of three aqueous cyanide ions and associated ligands

Water Air Soil Pollut.

(1999)

G.A. Bradley et al.

Neuroaxonal degeneration in sheep grazing sorghum pastures

J. Vet. Diag. Invest.

(1995)

P. Cooles

Diabetes and cassava in Dominica

Trop. Geog. Med.

(1988)

A.G. Freeman

Optic neuropathy and chronic cyanide intoxication: A review

J. R. Soc. Med.

(1988)

E. Gaitan et al.

Antithyroid effects in vivo and in vitro of babassu and mandioca: A staple food in goitre areas of Brazil

Eur. J. Endocrinol.

(1994)

A.A. Geldof et al.

Histopathological changes in rat pancreas after fasting and cassava feeding

In Vivo

(1992)

A. Gutzwiller

The effect of a diet containing cyanogenetic glycosides on the selenium status and the thyroid function of sheep

Anim. Prod.

(1993)

C. Ibebunjo et al.

Comparison of the effects of cassava (Manihot esculenta Crantz), organic cyanide and inorganic cyanide on muscle and bone development in a Nigerian breed of dog

Br. J. Nutr.

(1992)

B.P. Kamalu

The effect of a nutritionally-balanced cassava (Manihot esculenta Crantz) diet on endocrine function using the dog as a model. 1. Pancreas

Br. J. Nutr.

(1991)

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^☆: This study was supported by a grant from FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo).

²: To whom correspondence should be addressed at Research Center for Veterinary Toxicology (CEPTOX), Department of Pathology, School of Veterinary Medicine, University of São Paulo, Av. Orlando Marques de Paiva 87, São Paulo 05508-900, Brazil. E-mail: [email protected].

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Regular ArticleEffects of Long-Term Low-Dose Cyanide Administration to Rats☆

Abstract

Trends Endocrinol. Metab.

Toxicol. Appl. Pharmacol.

Food Chem. Toxicol.

Small Ruminant Res.

Bailliers Clin. Endocrinol. Metab.

Surv. Ophthalmol.

Lancet

Cystitis and ataxia associated with sorghum ingestion by horses

J. Am. Vet. Med. Assoc.

The effects of chronic cassava consumption, cyanide intoxication and protein malnutrition on glucose tolerance in growing rats

Br. J. Nutr.

Diabetogenic tropical pancreatitis

Diabetes Metab.

Cyanide intoxication among silver-reclaiming workers

J. Am. Med. Assoc.

A critical review: general toxicity and environmental fate of three aqueous cyanide ions and associated ligands

Water Air Soil Pollut.

Neuroaxonal degeneration in sheep grazing sorghum pastures

J. Vet. Diag. Invest.

Diabetes and cassava in Dominica

Trop. Geog. Med.

Optic neuropathy and chronic cyanide intoxication: A review

J. R. Soc. Med.

Antithyroid effects in vivo and in vitro of babassu and mandioca: A staple food in goitre areas of Brazil

Eur. J. Endocrinol.

Histopathological changes in rat pancreas after fasting and cassava feeding

In Vivo

The effect of a diet containing cyanogenetic glycosides on the selenium status and the thyroid function of sheep

Anim. Prod.

Comparison of the effects of cassava (Manihot esculenta Crantz), organic cyanide and inorganic cyanide on muscle and bone development in a Nigerian breed of dog

Br. J. Nutr.

The effect of a nutritionally-balanced cassava (Manihot esculenta Crantz) diet on endocrine function using the dog as a model. 1. Pancreas

Br. J. Nutr.

Regular Article
Effects of Long-Term Low-Dose Cyanide Administration to Rats☆