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Several natural compounds reduce tumour cell growth and metastasis by inducing programmed cell death. Cassava (Manihot esculenta Crantz) contains cyanogenic glycosides such as, linamarin and lotaustralin, can be enzymatically cleaved by linamarase to release hydrogen cyanide (HCN), which can have therapeutic benefits against hypertension, asthma, and cancer. We have developed a technology for isolating bio-active principles from cassava leaves.The present study is designed to analyze the cytotoxic effect of cassava cyanide extract (CCE) against human glioblastoma cells (LN229). The treatment of CCE demonstrated a dose dependent toxicity on glioblastoma cells. At higher concentration tested, the CCE (400 μg/mL) was found to be cytotoxic, reducing the cell viability to 14.07 ± 2.15% by negatively influencing the mitochondrial activity, and lysosomal and cytoskeletal integrity. Coomassie's brilliant blue staining confirmed cells' morphological aberration after 24 h of treatment with CCE. Moreover, DCFH-DA assay and Griess reagent showed an increase in ROS but a decrease in RNS production at a concentration of CCE. Flow cytometry analysis revealed that CCE interfered with G0/G1, S, and G2/M stages of the cell cycle of glioblastoma, and Annexin/PI staining indicated a dose-dependent increase in cell death, confirming the toxic nature of CCE on LN229 cells. These findings suggest that cassava cyanide extract has potential as an antineoplastic agent against glioblastoma cells, which is an aggressive and difficult-to-treat type of brain cancer. However, it is important to note that the study was conducted in vitro, and further research is necessary to assess the safety and efficacy of CCE in vivo. Additionally, it is essential to establish the optimal dose and potential side effects before considering its use as a therapeutic agent., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. There is no conflict of interest. No funds received from other sources., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cassava (Manihot esculenta Crantz) is a tropical plant that is used as fresh food, processed food, or raw material for the preparation of flours with high nutritional value. However, cassava contains cyanogenic glycosides, such as linamarin and lotaustralin, that can trigger severe toxic effects and some neurological disorders, including motor impairment, cognitive deterioration, and symptoms that characterize tropical ataxic neuropathy and spastic epidemic paraparesis (Konzo). These alterations that are associated with the consumption of cassava or its derivatives have been reported in both humans and experimental animals. The present review discusses and integrates preclinical and clinical evidence that indicates the toxic and neurological effects of cassava and its derivatives by affecting metabolic processes and the central nervous system. An exhaustive review of the literature was performed using specialized databases that focused on the toxic and neurological effects of the consumption of cassava and its derivatives. We sought to provide structured information that will contribute to understanding the undesirable effects of some foods and preventing health problems in vulnerable populations who consume these vegetables. Cassava contains cyanogenic glycosides that contribute to the development of neurological disorders when they are ingested inappropriately or for prolonged periods of time. Such high consumption can affect neurochemical and neurophysiological processes in particular brain structures and affect peripheral metabolic processes that impact wellness. Although some vegetables have high nutritional value and ameliorate food deficits in vulnerable populations, they can also predispose individuals to the development of neurological diseases.

The consumption by humans of plants with potential to induce neurological disorders is widespread, but overt disease surfaces only when the subject's toxic threshold is exceeded. Excessive intake arising from food dependency in the setting of hunger, chronic undernutrition, vitamin deficiency, inadequate detoxication, or other individual susceptibility, can trigger acute encephalopathy (lychee, ackee fruits), sub-acute spastic paraparesis (grasspea, cassava root/leaves) or ataxic neuropathy (cassava root flour). While these disorders are very rarely encountered in high-income countries, they are not only common among impoverished populations but also often occur as outbreaks that impact a significant proportion of an affected community. Unfamiliarity with the adverse effects of plant toxins has sometimes led to the mistaken attribution of nutritional neurotoxic disease to a neurotropic viral or synthetic pesticidal etiology. The combination of human population growth, food and water insecurity, poverty and, with climate change, increased dependency on environmentally tolerant plants with neurotoxic potential, predictably may result in an increased prevalence of nutritional neurotoxic disorders, especially in certain parts of Africa and Asia., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Cassava leaves are a valuable source of protein but the cyanogenic potential limits their use as food and feed. Four different treatments were investigated to detoxify cassava leaves. Thermal (55 °C for 6 hr), sodium bicarbonate (0.4% NaHCO 3 , 55 °C for 6 hr), enzymatic (0.32% Multifect® GC Extra, 4 hr), and ultrasonic treatments (500 W, 35 kHz, 55 °C, 0.25 hr) reduced the total cyanide (µg HCN equivalents per g fresh leaf or ppm) content by 90%, 93%, 82%, and 84% while the cyanide content reduction in the respective controls was 85%, 90%, 79%, and 84%, respectively. The sodium bicarbonate treatment was found to be the most effective treatment. Therefore, it was further optimized by varying time and temperature. A significant effect on the cyanide content was observed by changing the incubation time while no significant effect of temperature was noticed. Nevertheless, extended incubation time during sodium bicarbonate treatment reduced ascorbic acid content by 7% and 39% when leaves were incubated with sodium bicarbonate for 0.5 hr and 48 hr, respectively. PRACTICAL APPLICATION: Cyanogenic glucosides are the major toxic compound in cassava leaves, which limits their use as food and feed. The methods proposed in this study can be used to detoxify cassava leaves, which are generally considered as an inferior by-product. Hence, detoxified cassava leaves may contribute to fulfil world protein demand in an eco-sustainable way., (© 2019 Institute of Food Technologists®.)

Introduction: Acetone cyanohydrin (ACH) is a toxic substance present in cassava roots (Manihot esculenta Crantz) which results from enzymatic hydrolysis of linamarin. Long-term consumption is associated with 2 neurological disorders: konzo and tropical ataxic neuropathy. Previous studies have evaluated behavioural alterations linked to ACH consumption, but the toxic effects of this substance on physiological processes remain unknown., Method: 32 male Wistar rats were assigned to 4 experimental groups (n=8 per group): a vehicle group (0.3mL saline solution, IP) and 3 ACH groups (PubChem CID: 6406) dosed at 10, 15, and 20mM/24h for 28 days. We evaluated spontaneous motor activity with the open field test and motor coordination with the rotarod and forced swimming tests at 0, 7, 14, 21, and 28 days of treatment. At the end of the assessment period (day 28), blood samples were collected by transcardiac puncture to evaluate kidney and liver function., Results: ACH caused alterations in locomotor activity and promoted both lateral swimming and spinning in the forced swimming test at 21 and 28 days of treatment. Furthermore, it led to an increase in the levels of the parameters of kidney and liver function in a concentration-dependent manner, except for glucose and total bilirubin., Conclusion: Our results suggest that long-term consumption of this toxic compound present in cassava roots may be potentially dangerous for vulnerable subjects., (Copyright © 2017 The Author(s). Publicado por Elsevier España, S.L.U. All rights reserved.)

Epidemics of neurodegenerative diseases putatively caused by food toxins have been reported in the tropics with no clear understanding of their pathogenetic mechanisms. These diseases include the disease named Konzo that has been well documented in sub-Sahara Africa, mostly among children and women of childbearing age. Outbreaks of Konzo have occurred in the Democratic Republic of Congo, Mozambique, Tanzania, Central African Republic, Angola, Cameroun, and most recently in Zambia. The main clinical picture consists of a symmetrical, permanent and irreversible spastic paraparesis (motor neuron disease) with no signs of sensory or genitourinary impairments. Recently, cognitive impairments and neurodevelopmental delays have been reported among school-aged and very young children. The exact pathogenetic mechanisms of the disease remain unknown. Epidemiological studies consistently show an association between outbreaks of the disease and chronic dietary reliance on insufficiently processed cyanogenic cassava (manioc or tapioca). Biochemical and toxicological studies suggest that the metabolites of linamarin (α-Hydroxyisobutyronitrile β-D-glucopyranoside, the main cassava cyanogen), notably cyanide (mitochondrial toxin), thiocyanate (AMPA chaotropic agent), and cyanate (protein carbamoylating agent) may play an important role in the pathogenesis of Konzo. Experimental data suggest that thiol-redox and protein- folding mechanisms may also be perturbed. Factors of susceptibility including genetics, poor nutrition, poverty and dietary cyanogen exposure, or their interactions have been suggested. Serological studies have ruled out the role of retroviruses such as the human lymphotropic viruses HIV-I/II or HTLV-I/II. Because there is no cure for Konzo, prevention of the disease remains of paramount importance. Prospects for cognitive rehabilitation still need to be explored and tested., (Copyright © 2018. Published by Elsevier Inc.)

Since ancient times the increase of size and hardness sometimes presented by the abdominal structure known as the pancreas has attracted attention. Portal was the first to describe the clinical signs of chronic pancreatitis in 1803. In 1815, Fleischman speculated about the potential role of excessive alcohol consumption. Comfort coined the term "chronic relapsing pancreatitis" in 1946 and described hereditary pancreatitis 6 years later. Zuidema defined tropical pancreatitis in 1959 and 2 years later Sarles described another form of pancreatitis to which Yoshida gave the name autoimmune pancreatitis in 1995. Groove pancreatitis was described by Potet in 1970. Obstructive pancreatitis was defined in 1984 and Ammann identified idiopathic pancreatitis 3 years later. This article gives a historical account of the pioneers who developed the knowledge of how to assess the characteristics that allowed the different forms of chronic pancreatitis to be defined., (Copyright © 2018 Elsevier España, S.L.U. All rights reserved.)

Background: Dietary cyanogen exposure from ingesting bitter (toxic) cassava as a main source of food in sub-Saharan Africa is related to neurological impairments in sub-Saharan Africa. We explored possible association with early child neurodevelopmental outcomes., Methods: We undertook a cross-sectional neurodevelopmental assessment of 12-48 month-old children using the Mullen Scale of Early Learning (MSEL) and the Gensini Gavito Scale (GGS). We used the Hopkins Symptoms Checklist-10 (HSCL-10) and Goldberg Depression Anxiety Scale (GDAS) to screen for symptoms of maternal depression-anxiety. We used the cyanogen content in household cassava flour and urinary thiocyanate (SCN) as biomarkers of dietary cyanogen exposure. We employed multivariable generalized linear models (GLM) with Gamma link function to determine predictors of early child neurodevelopmental outcomes., Results: The mean (SD) and median (IQR) of cyanogen content of cassava household flour were above the WHO cut-off points of 10 ppm (52.18 [32·79]) and 50 (30-50) ppm, respectively. Mean (SD) urinary levels of thiocyanate and median (IQR) were respectively 817·81 (474·59) and 688 (344-1032) μmole/l in mothers, and 617·49 (449·48) and 688 (344-688) μmole/l in children reflecting individual high levels as well as a community-wide cyanogenic exposure. The concentration of cyanide in cassava flour was significantly associated with early child neurodevelopment, motor development and cognitive ability as indicated by univariable linear regression (p < 0.05). After adjusting for biological and socioeconomic predictors at multivariable analyses, fine motor proficiency and child neurodevelopment remained the main predictors associated with the concentration of cyanide in cassava flour: coefficients of -0·08 to -.15 (p < 0·01). We also found a significant association between child linear growth, early child neurodevelopment, cognitive ability and motor development at both univariable and multivariable linear regression analyses coefficients of 1.44 to 7.31 (p < 0·01)., Conclusion: Dietary cyanogen exposure is associated with early child neurodevelopment, cognitive abilities and motor development, even in the absence of clinically evident paralysis. There is a need for community-wide interventions for better cassava processing practices for detoxification, improved nutrition, and neuro-rehabilitation, all of which are essential for optimal development in exposed children.

Introduction: Some vegetable foodstuffs contain toxic compounds that, when consumed, favour the development of certain diseases. Cassava (Manihot esculenta Crantz) is an important food source, but it contains cyanogenic glucosides (linamarin and lotaustralin) that have been associated with the development of tropical ataxic neuropathy and konzo. In rats, intraperitoneal administration of acetone cyanohydrin (a metabolite of linamarin) produces neurological disorders and neuronal damage in the hippocampus. However, it is unknown whether hippocampal area CA1 plays a role in neurological disorders associated with acetone cyanohydrin., Method: A total of 32 male Wistar rats 3 months old were assigned to 4 groups (n=8 per group) as follows: vehicle (1μl physiological saline), and 3 groups with acetone cyanohydrin (1μl of 10, 15, and 20mM solution, respectively). The substances were microinjected intrahippocampally every 24hours for 7 consecutive days, and their effects on locomotor activity, rota-rod and swim tests were assessed daily. On the fifth day post-treatment, rats underwent further assessment with behavioural tests to identify or rule out permanent damage induced by acetone cyanohydrin., Results: Microinjection of acetone cyanohydrin 20mM resulted in hyperactivity, motor impairment, and reduced exploration from the third day of treatment. All concentrations of acetone cyanohydrin produced rotational behaviour in the swim test from the first day of microinjection., Conclusion: The hippocampal area CA1 is involved in motor alterations induced by microinjection of acetone cyanohydrin, as has been reported for other cassava compounds., (Copyright © 2015 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

The metabolism of yellow cassava (variety TMS 01/1368) was investigated in male albino rats fed a diet containing yellow cassava for 7 to 28 days. There were significant increases (P < 0.05) in total and free cyanide and thiocyanate in the sera and urine samples of the experimental rats compared with the control, significant increases (P < 0.05) in serum glucose, alanine aminotransaminase, aspartate aminotransaminase, and alkaline phosphatase levels of the experimental rats compared with the control, significant decreases (P < 0.05) in serum albumin of the experimental rats compared with the control, but no significant differences (P > 0.05) in the serum total proteins of the experimental rats compared with the control. The experimental rats treated for 7, 14, 21, or 28 days exhibited body weight decreases of 5.11%, 11.10%, 19.16%, and 24.18%, respectively, whereas the control group showed 9.17% gain in body weight. Total and free cyanide concentrations were detected in the liver, kidney, and heart of most of the rats in both the experimental and control groups, except for free cyanide in the control group that was not detected. Metabolism of the yellow cassava variety in experimental rats was capable of exposing the animals to cyanide, underscoring the need for its proper processing before consumption by humans., (© The Author(s) 2015.)

Over a period of 150 years the Kei Islands have undergone environmental change, from rainforest to dryland savanna woodland. This has been accompanied by a shift in starch staple from sago, tubers, and grain to cassava. We show how this has been an effective ecological adaptation with social ramifications, not least the adoption of bitter cassava as a cultural identity marker. One of the problems of bitter cassava diets where people have become dependent upon them in poor parts of the Old World tropics are the effects of toxicity. We show how through a combination of factors and strategies this has not been a major issue in the Kei Islands, and how through a government-assisted agricultural project, attempts are being made to build upon this successful transition. The viability of present trends are evaluated.

Konzo is a distinct neurological entity with selective upper motor neuron damage, characterized by an abrupt onset of an irreversible, non-progressive, and symmetrical spastic para/tetraparesis. Despite its severity, konzo remains a neglected disease. The disease is associated with high dietary cyanogen consumption from insufficiently processed roots of bitter cassava combined with a protein-deficient diet. Epidemics occur when these conditions coincide at times of severe food shortage. Up to 1993, outbreaks in poor rural areas in Africa contributed to more than 3,700 cases of konzo. The number of affected people is underestimated. From unofficial reports, the number of cases was estimated to be at least 100,000 in 2000, in contrast to the 6,788 cases reported up to 2009 from published papers.

Background and Aim: There have been conflicting reports on the role of cassava ingestion in tropical pancreatitis (TCP). In this study we aimed to estimate cyanogens detoxifying enzyme rhodanese, thiocyanate and sulfur containing amino acids in cassava consumer as well as cassava non-consumer TCP patients and healthy controls and compare the same., Methods: Eighty-six TCP patients and 90 healthy controls were recruited. Serum rhodanese, thiocyanate, plasma amino acids, urinary inorganic sulfate/creatinine were measured., Results: There was significant reduction in serum rhodanese activity in both cassava consumer- and non-consumer TCP patients as compared to controls but no significant difference between cassava consumer- and non-consumer TCP patients was observed. Serum thiocyanate was significantly lower in cassava consumer TCP patients as compared to cassava consumer controls but not significantly different from cassava non-consumer TCP patients. Plasma methionine, cysteine and urinary inorganic sulfate / creatinine ratio was significantly lower in both cassava consumer and non-consumer TCP patients as compared to controls but were comparable among cassava consumers and non-consumers., Conclusions: Significant reduction in rhodanese activity with concomitant decrease in sulfur containing amino acids and antioxidants such as glutathione suggests that TCP patients are at higher risk of defective detoxification of cyanogens. However there was no difference between cassava consumers and non-consumers. Low levels of sulfur amino acids may contribute to the development of pancreatitis.

Toxicity of cassava arises due to the presence of the cyanoglucosides linamarin and lotaustralin which are hydrolysed by endogenous enzyme linamarase to acetonecyanohydrin (ACN) and cyanide (CN) which are toxic. Major research efforts to eliminate/reduce cyanoglucosides have focused on (i) development of acyanogenic cassava varieties by breeding; (ii) controlling its metabolism; and (iii) processing to remove cyanogens. The cyanoglucoside (CNG) content in cassava is genetically controlled and cultivars may be classified as low (<50 μg/g), medium (50-100 μg/g) and high CN (>100 μg CN eq./g) varieties. Molecular techniques for reducing tuber CNG have focused on development of transgenic plants with reduced expression of cyt P 450 in leaves, or increased expression of hydroxynitrilelyase in tuber. For immediate solution, CNG content can be reduced using several processing methods. Traditional methods used for processing include boiling, drying, parboiling and drying, baking, steaming, frying and preparation of flour. These processes result in CN losses ranging from 25% to 98%. The cyanogen level in the final product is influenced both by the tuber CNG and the method of processing. In order to achieve safe levels of 10 μg/g in cassava products, new methods of processing, especially for cassava containing more than 250 μg CN eq./g, remains a challenging problem., (Copyright © 2010. Published by Elsevier Ltd.)

Cassava (Manihot esculenta Crantz) is a major source of dietary energy for humans and domestic animals in many tropical countries. However, consumption of cassava is limited by its characteristic content of cyanogenic glycosides. The present work aimed to evaluate the toxic effects of ingestion of cassava leaves by goats for 30 consecutive days, and to compare the results with the toxic effects of cyanide in goats, which have been described previously. Eight Alpine cross-bred female goats were divided into two equal groups, and were treated with ground frozen cassava leaves at a target dose of 6.0mg hydrogen cyanide (HCN)/kg/day (treated animals), or with ground hay and water only (control group) by gavage for 30 consecutive days. Blood samples were collected on days 0, 7, 15, 21, and 30 for biochemical panel and cyanide determination. At the end of the experiment, fragments of pancreas, thyroid gland, liver, kidney, lungs, heart, spleen, and the whole central nervous system were collected for histopathological examination. Clinical signs were observed in all goats treated with cassava on the first day of the experiment. From the second day the dose of cassava leaves was reduced to 4.5mgHCN/kg/day. No changes were found in the blood chemical panel. A mild increase in the number of resorption vacuoles in the thyroid follicular colloid, slight vacuolation of periportal hepatocytes, and spongiosis of the mesencephalon were found in goats treated with cassava. The pattern of lesions seen in the present goats was similar to what has been described previously in cyanide-dosed goats. Thus, the toxic effects of the ingestion of cassava leaves by goats can be attributed to the action of cyanide released from cyanogenic glycosides, and none of the effects was promoted by these glycosides directly.

Konzo is a neurotoxic motor disease caused by excess consumption of insufficiently processed cassava. Cassava contains the cyanogenic glucoside linamarin, but konzo does not present the known pathological effects of cyanide. We hypothesized that the aglycone of linamarin, acetone cyanohydrin, may be the cause of konzo. This nitrile rapidly decomposes into cyanide and acetone, but the particular exposure and nutrition conditions involved in the emergence of konzo may favor its stabilization and subsequent acute neurotoxicity. A number of preliminary observations were used to design an experiment to test this hypothesis. In the experiment, young female Long-Evans rats were given 10mM acetone cyanohydrin in drinking water for 2 weeks, and then 20mM for 6 weeks. Nutrition deficits associated with konzo were modeled by providing tapioca (cassava starch) as food for the last 3 of these weeks. After this period, rats were fasted for 24h in order to increase endogenous acetone synthesis, and then exposed to 0 (control group) or 50 micromol/kg-h of acetone cyanohydrin for 24h (treated group) through subcutaneous osmotic minipump infusion (n=6/group). Motor activity and gait were evaluated before exposure (pre-test), and 1 and 6 days after exposure. Brains (n=4) were stained for neuronal degeneration by fluoro-jade B. Rats exposed to 50 micromol/kg-h of acetone cyanohydrin showed acute signs of toxicity, but no persistent motor deficits. Two animals showed fluoro-jade staining in discrete thalamic nuclei, including the paraventricular and the ventral reuniens nuclei; one also exhibited labeling of the dorsal endopiriform nucleus. Similar effects were not elicited by equimolar KCN exposure. Therefore, acetone cyanohydrin may cause selective neuronal degeneration in the rat, but the affected areas are not those expected in an animal model of konzo., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

Background: A number of retail shops in Copenhagen sell fresh cassava roots. Cassava roots contain the toxic cyanogenic glucoside linamarin. A survey was made of the shop characteristics, origin of the roots, buyers, shop owner's knowledge of toxicity levels, and actual toxicity levels., Results: Shops selling fresh cassava were shown mostly to be owned by persons originating in the Middle East or Afghanistan, buyers were found to predominantly be of African origin, and sellers' knowledge concerning the potential toxicity was found to be very restricted. Seventy-six per cent of the roots purchased had a total cyanogenic potentials (CNp) above the 50 mg HCN equivalents kg(-1) dry weight (d.w.) proposed as acceptable by an EU working group. Two of 25 roots purchased had CNp higher than 340 mg HCN eq. kg(-1) d.w., Conclusion: The EU has previously made risk assessments concerning cassava and cyanogenic compounds. In the light of the conclusions drawn, the EU needs to make decisions about how to deal with the regulation and control of fresh cassava roots imported to the European food market. Also cassava root products and cassava leaves should be considered., ((c) 2009 Society of Chemical Industry.)

Cassava starch fermentation wastewater is an industrial residue composed mainly of lactic acid bacteria with predominance of the genera Lactobacillus, and organic acids. To evaluate the safety of this residue for possible production of probiotic beverages, acute in mice and sub-chronic (28-day repeated dose) toxicity studies in rats were carried. The administration of a single dose of 5 g/kg/body weight did not produce mortality in mice. Rats treated with water containing 0 (control), 25%, 50%, and 100% of the residue for 28 days, did not present alterations in behaviour or in food and water consumption. There were no treatment-related changes of toxicological significance in the relative weight of the organs neither in the haematological nor in the biochemical parameters. Histopathologic alterations observed in the small intestine did not seem to be associated with the treatment.

Exposure to cyanide from gari, a popular cassava food in West Africa, is implicated in the causation of ataxic polyneuropathy and amblyopia, but this has been questioned because cyanide was not detected in gari in a study. This study was carried out to determine if gari is a source of exposure to cyanide. Gari (150 g) containing cyanohydrin, from which 128 micromol of cyanide ions could be released, was dissolved in 500 ml of cold water for each of the 12 healthy subjects to drink. Concentrations of cyanide in plasma and erythrocytes were determined at baseline and following the meal at 30 min, 1 h, hourly for 4 h and two hourly for 12 h. The mean concentrations of cyanide in the plasma were 6 micromol/l (95% CI 2-10) at baseline, 12 micromol/l (95% CI 6-17) at peak and 6 micromol/l (95% CI 2-10) on return to baseline. The mean amount of cyanide absorbed into the plasma was 13 micromol (S.D. 12), while the transit time of absorbed cyanide was 7.3 h (S.D. 2.1). This study shows that exposure to cyanide follows consumption of gari, but the amount of cyanide absorbed into the plasma from a single meal is small and unlikely to cause acute intoxication. The long transit time of absorbed cyanide in the plasma suggests that frequent intake of gari could cause cyanide to accumulate in the plasma.

Ingestion of cyanogenic plants, such as cassava and sorghum, has been associated with goitre and tropical pancreatic diabetes in both humans and animals. Thus, the objective of the present study was to determine the toxic effects on the thyroid and pancreas in growing goats of prolonged exposure to potassium cyanide (KCN). Thirty-four male goats were divided into five groups dosed with KCN at 0 (control). 0.3, 0.6, 1.2 or 3.0 mg/kg daily for 5 months. Blood samples were obtained in order to determine the glucose, cholesterol, thyroxine (T4), triiodothyronine (T3) and thiocyanate concentrations and for haematological studies; pancreas and thyroid gland were collected for histopathological study. The group receiving the highest dose of cyanide showed lower body weight gains and carcase weights and a decrease in plasma T3 concentrations compared to the control group. Reabsorption vacuoles in follicular colloid and normocytic normochromic anaemia were observed in the experimental animals. Inhibition of peripheral conversion of T4 to T3 is suggested. However, no diabetogenic effects were observed.

Cyanide exposure through cassava consumption has been associated with the development of malnutrition-related diabetes mellitus (MRDM). However, there are few experimental reproductions of this disease. In the present study 42 rats received 0, 9.0 or 12.0 mg KCN/kg bw/d for 15 d, 26 pigs were dosed with 0, 2.0, 4.0 or 6.0 mg KCN/kg for 74 d, and 34 goats received 0, 0.3, 0.6, 1.2 or 3.0 mg KCN/kg for 5 mo. At the end of each experimental period, plasma samples were obtained for glucose and thiocyanate measurement, and the pancreas was collected for histopathologic study. No significant differences in plasma glucose concentrations occurred between groups. The pancreas had no pathology. Chronic cyanide exposure did not promote diabetogenic effects in rats, swine or goats, suggesting that cyanide is not responsible for MRDM in humans.

Cassava (tapioca, manihot) is consumed as a staple food in some developing countries. The intake of cassava has been linked to several diseases including fibrocalculous pancreatic diabetes (tropical calcific pancreatitis). There are few long-term studies on the effect of cassava ingestion on the pancreas in animal models. This article reports on the long-term (up to 1 yr) effects of cassava in the rat model. We found that cassava did not produce diabetes in the rat even after a year of cassava feeding. There were transient changes in serum insulin and lipase levels, but the significance of these findings are not clear. There was no histopathological evidence of either acute or chronic pancreatitis, but there were changes of toxic hepatitis in the liver. In conclusion, chronic cassava ingestion up to a year does not lead to either diabetes or chronic pancreatitis in the rat model.

Neurological disorders have been reported from parts of Africa with protein-deficient populations and attributed to cyanide (CN-) exposure from prolonged dietary use of cassava, a cyanophoric plant. Cyanide is normally metabolized to thiocyanate (SCN-) by the sulfur-dependent enzyme rhodanese. However, in protein-deficient subjects where sulfur amino acids (SAA) are low, CN may conceivably be converted to cyanate (OCN-), which is known to cause neurodegenerative disease in humans and animals. This study investigates the fate of potassium cyanide administered orally to rats maintained for up to 4 weeks on either a balanced diet (BD) or a diet lacking the SAAs, L-cystine and L-methionine. In both groups, there was a time-dependent increase in plasma cyanate, with exponential OCN- increases in SAA-deficient rats. A strongly positive linear relationship between blood CN- and plasma OCN- concentrations was observed in these animals. These data are consistent with the hypothesis that cyanate is an important mediator of chronic cyanide neurotoxicity during protein-calorie deficiency. The potential role of thiocyanate in cassava-associated konzo is discussed in relationship to the etiology of the comparable pattern of motor-system disease (spastic paraparesis) seen in lathyrism.

The root of Cassava, a tropical plant, is consumed in the tropics and has been attributed as the cause for various tropical neuropathies. This study aims to discover the neurotoxic effects of chronic cassava consumption of Indian origin and the effect of malnutrition. The assessment is based on the motor co-ordination and brain neurotransmitters in rats. Cassava consumption reduced the motor co-ordination, but the changes in neurotransmitter levels due to cassava consumption (except for 5HT in corpus striatum) was identical with malnutrition-induced changes, indicating that the toxicity of chronic cassava consumption (of Indian origin) is mainly due to the associated protein calorie malnutrition (PCM).

Processing of cassava roots by the Alur tribe in Uganda includes a stage of solid substrate fermentation in heaps. Changes in cyanogen levels during the process, microflora involved, and protein levels, amino acid patterns and mycotoxin contamination of the final products were studied. Processing was monitored at six rural households and repeated at laboratory site, comparing it to sun-drying. Flour samples from rural households were analysed for residual cyanogens, mutagenicity, cytotoxicity and aflatoxins. Mean (+/- SD) total cyanogen levels in flours collected at rural households were 20.3 (+/- 16.8) mg CN equivalents kg-1 dry weight in 1990 (n = 23) and 65.7 (+/- 56.7) in 1992 (n = 21). Mean (+/- SD) levels of cyanohydrins plus HCN were 9.1 (+/- 8.7) in the 1992 flours. Total cyanogen levels in the village monitored batches were reduced considerably by heap-fermentation from 436.3 (+/- 140.7) to 20.4 (+/- 14.0) mg CN equivalents kg-1 dry weight cassava. Residual cyanogen levels were positively correlated with particle size of the resulting crumbs. Heap-fermentation was significantly more effective in reducing cyanogen levels than sun-drying alone, but did not always result in innocuous levels of of cyanogens. Dominant mycelial growth was from the fungi Neurospora sitophila, Geotrichum candidum and Rhizopus oryzae. No mutagenicity, cytotoxicity nor aflatoxins could be detected in the flours. Protein quantity and quality were not significantly reduced. Cassava gel viscosity pattern was modified to the consumers' preference by this method. As the removal of cyanogens was more efficient and we found no new obvious health risk, heap-fermentation can be regarded as an improvement compared to sun-drying alone in areas where cassava varieties with higher cyanogen levels prevail, but we recommend optimisation of the process for ensuring still safer products.

Female Sprague Dawley rats were fed 5 mg linamarin daily for 10 days. Reduced glutathione (GSH) levels in blood and liver of experimental rats were analysed. The results showed an increase of 45% and 33% glutathione levels in blood and liver respectively in experimental rats. This alteration in glutathione levels could be most likely either due to increased hepatic biosynthesis or as a consequence of decreased peripheral utilization which might be appreciated due to hypothyroidal status induced by linamarin feeding.

Studies were carried out to determine the effects of the toxic principle linamarin, a cyanogenic glucoside, in a diet containing cassava (Manihot esculenta Crantz) in the form of gari fed to growing dogs for 14 weeks. There were three groups of dogs, each comprising six animals. One group was fed on a control diet with rice as the carbohydrate source, the second group was fed on cassava (gari) as the carbohydrate source and which was expected to release 10.8 mg HCN/kg cooked food, the third group was fed on the control diet to which enough NaCN was added at feeding time to release 10.8 mg HCN/kg cooked food in order to monitor the effects of the HCN released from gari. All diets contained 130 g crude protein (N x 6.25)/kg and were supplemented with vitamins and minerals. Each animal was given approximately 100 g diet/kg body weight for the duration of the experiment. The biochemical variables investigated were plasma electrolytes, serum proteins, plasma-free amino acids, plasma enzymes and urine protein, and the histology of some metabolically active tissues, namely liver, kidney, myocardium, testis and adrenal gland, was studied. The gari diet caused an elevated plasma thiocyanate concentration (P < 0.01), elevated 24 h urinary thiocyanate excretion and elevated urinary protein excretion (P < 0.01), lowered serum albumin (P < 0.05), a plasma-free amino acid profile which resembled that found in kwashiorkor, lowered plasma K and Ca (P < 0.05). The rice + cyanide diet caused an elevated plasma thiocyanate (P < 0.01) and a 24 h urinary thiocyanate excretion that was significantly higher (P < 0.01) than that of the dogs fed on gari, but caused a urinary protein excretion that was significantly lower than that of the dogs fed on gari (P < 0.01), lowered serum albumin (P < 0.05), a plasma-free amino acid profile that indicated that the amino acids were not being utilized to the same extent as in the control (rice) group but were accumulating. Neither diet had an effect on plasma gamma-glutamyltransferase (EC 2.3.2.2), alanine aminotransferase (EC 2.6.1.2) or isocitrate dehydrogenase (EC 1.1.1.42) activities, plasma Na, Mg, and P concentrations. The gari diet caused generalized congestion and haemorrhage, periportal vacuolation of the liver, swelling, vacuolation and rupture of the epithelial cells of the proximal convoluted tubules of the kidney, myocardial degeneration and adrenal gland degeneration.(ABSTRACT TRUNCATED AT 400 WORDS)

1. The effects of drying cassava root at different rates on its composition and toxicity to broiler chicks were examined. Unpeeled roots from a high-cyanide cultivar of cassava were chipped and dried at 25 degrees C to a moisture content of below 100 g/kg over 24 h for fast-dried meal (FD) or 72 h for slow-dried meal (SD). The meals were incorporated at 250 and 500 g/kg into semi-synthetic diets which were fed to day-old broiler chicks as mash or pellets in separate experiments. 2. The two drying rates produced meals with similar concentrations of polyphenols, but different concentrations of cyanogens, the latter being 38 and 482 mg total cyanide/kg for SD and FD, respectively. The linamarin, acetonecyanohydrin or total cyanide content measurements of pelleted diets were highly correlated. 3. Growth rates of chicks fed on SD-based diets were significantly higher than those of chicks fed on FD-based diets. Compared with a control diet, weight gain of chicks fed on the 500 g FD/kg diet (containing 258 mg total cyanide/kg) was 77% lower, although performance also appeared to be reduced at 142 mg total cyanide/kg. 4. The ratio of water:food intake of chicks was higher in FD than in SD groups, and this was reflected in the high water content of excreta. There was increased bile excretion, the chloretic effect increasing with the cyanogen content of diet. Pancreas weights were lower in FD than in SD groups in experiment 1 (mash diets), but not in experiment 2 (pelleted diets), while there was a significant interaction between drying method and cassava inclusion rate on liver weight in experiment 2, but not in experiment 1. There were no effects on the mortality rate. 5. Pelleting of diets generated high temperatures, but did not significantly alter the cyanogen concentration or the growth of the chicks. 6. Thus, slower rates of drying cassava roots produce meals with lower cyanogen concentration that are, consequently, less toxic to broiler chicks. Cassava root meal of less than 40 mg total cyanide/kg can be fed to broiler chicks at 500 g/kg without any adverse effects.

Objective: To test the hypothesis that consumption of cassava with liberation of cyanide causes diabetes in malnourished individuals., Research Design and Methods: Glucose tolerance was assessed in two rural communities in Tanzania; in one (Nyambori), the main source of calories was cassava; and in the other (Uswaa), cassava was rarely eaten. Undernutrition was prevalent in both communities. The people of Nyambori were known to have high dietary cyanide exposure for many years from consumption of insufficiently processed cassava. Of the 1435 people in Nyambori greater than or equal to 15 yr old, 1067 (74%) were surveyed, and 1429 of 1472 (97%) eligible subjects in Uswaa were surveyed. All had 75-g oral glucose tolerance tests and measurement of BMI. Plasma and urine thiocyanate and blood cyanide also were measured in some subjects., Results: Mean +/- SD plasma and urine thiocyanate levels in Nyambori were 296 +/- 190 and 497 +/- 457 microM (n = 204), respectively, compared with 30 +/- 37 and 9 +/- 13 microM, respectively, in Uswaa (n = 92) (P less than 0.001 for all differences). The mean blood cyanide level in Nyambori was elevated (1.4 [range 0.1-30.2] microM; n = 91). The prevalence of diabetes in the cassava village (Nyambori) was 0.5% compared with 0.9% in Uswaa (NS). The prevalence of IGT was similar in the two villages in the 15- to 34- and the 34- to 54-yr-old age-groups; but in those greater than or equal to 55 yr old, IGT was higher in Nyambori (17.4 vs 7.2%, P = 0.029). Mean fasting and 2-h blood glucose levels were slightly higher in Nyambori village after adjusting for age, sex, and BMI (4.5 vs. 4.2 and 5.0 vs. 4.4 mM, respectively)., Conclusions: High dietary cyanide exposure was not found to have had a significant effect on the prevalence of diabetes in an undernourished population in Tanzania. Cassava consumption is thus highly unlikely to be a major etiological factor in so-called MRDM, at least in East Africa.

Effects of cassava (Manihot esculenta Crantz)-borne organic cyanide and inorganic cyanide in the form of sodium cyanide on bone and muscle development were investigated in eighteen dogs of Nigerian breed. After 16 weeks of stabilization in the laboratory from the time of purchase when the dogs were fed on the same diet, they were randomly assigned to three experimental groups of six dogs each. The control group was fed on rice while the other two groups were fed on either cassava (gari) or rice plus cyanide. The three diets were made isoenergetic and isonitrogenous by varying the quantity of meat incorporated into them. The results obtained after 14 weeks of feeding the respective diets indicated that there was retardation of muscle development in the gari-fed dogs. This may have resulted from gluconeogenesis from muscle protein associated with suppression of production of insulin by the pancreas in this group. The results indicated also that the effects of inorganic dietary cyanides on muscle development were different. Both forms of dietary cyanides, however, had no adverse effect on bone development.

Histopathological changes in rat pancreas were induced by cyclic periods of experimental malnutrition or by cassava (manioc) feeding for 11 weeks. Decline of body weight was correlated with decrease in testicular fat pad weight as a measure of body fat stores. A marked decrease in pancreatic weight in the cassava-fed group was correlated with shrinkage of acinar structures and degenerative features in exocrine pancreas. In the malnutrition group vacuolisation and loss of tissue architecture were observed in some parts of the organ. No signs of ductal obstruction as a tentative cause of pancreatic pathology after malnutrition could be detected. Loss of islets tissue was occasionally seen in degenerative areas. It is concluded that histopathological changes in exocrine pancreas result from malnutrition and cassava feeding differentially and precede ultimate degenerative processes of pancreas endocrine tissue. Tropical malnutrition type diabetes and low protein related diabetes may in their etiology be different entities, but may coincide in practice and aggravate each other to yield severe and irreversible morbidity.

Grated cassava to which tap water was added at levels of 25%, 50% and 75% (v/w) was held at 30 degrees C, 40 degrees C or 50 degrees C and examined over a 6 h period for cyanide content, pH and titratable acidity (TTA). During the come-up time, i.e. the time between addition of water and attainment of desired holding temperature (between 14 and 47 min), reductions in bound cyanide of ca 54-85% occurred, depending on the level of added water and holding temperature. The corresponding losses for the control samples, to which no water was added, were ca 25-33%. The biggest reduction in the bound cyanide of > 99% (from 89.0 to 0.6 ppm) occurred in grated cassava with 75% added water held at 50 degrees C. There was little or no change in pH during the period of study. The reduction of processing time for certain cassava products based on separation into detoxication and flavour development/fermentation stages is discussed.

Different cassava products were found to contain mutagenic activities in the Ames test. This paper describes how the flavonol quercetin is released during the cooking of fresh cassava leaves, following a process very similar to culinary habits. The hydrolysis of the glucoside(s) and the release of free quercetin has been followed by the monitoring of mutagenic activities with a simultaneous isolation and purification by thin-layer chromatography. The fluorodensitometric method applied revealed that fresh leaves contained about 1300 mg quercetin per kg wet weight, of which 800 mg were released during a normal cooking process.