Regarding toxins in food, the compounds that call for discussions in further detail are the cya-nogenic glycosides, but also the MAM glycosides, ptaquiloside, the saponins, the favism agents (vicine and convicine), and the glucosinolates.
Although discussions concerning a toxicity of intact cyanogenic glycosides may be found, the literature at present concludes that known intoxication syndromes, whether acute or chronic, are mainly due to HCN that is formed from the compounds.235,236
A plant containing cyanogenic glycosides may or may not contain enzymes that catalyze their breakdown (i.e., hydrolases [(3-glycosi-dases] and cyanohydrin lyases). These are stored separately from the glycosides.211 When a tissue containing both cyanogenic glycosides and these enzymes is crushed, enzyme(s) and substrate(s) are brought together and hydrolysis and further lysis (i.e., cyanogenesis) starts. Thus, the intake of raw or processed cyanogenic material normally will mean an intake of a mixture of the genuine glycoside(s) and accompanying hydrolysis products. Tissues that only contain the glycosides (and not the enzymes) will only give rise to exposure to the genuine glycoside(s).
Although cyanogenic glycosides may undergo acid hydrolysis,3083 the conditions in the stomach of a nonruminant, together with the very short residence time, will let the main fraction pass to the intestine. In the intestine, the glycosides will be absorbed, as shown for linamarin in a number of animal species and in humans, >9.37,110,208 an(j for pmnasin and amygdalin in different animal species,44,220'221,235 or it will be hydrolyzed by microorganisms.28,44,210 In humans, Carlson et al,43 very recently found that approximately 25% of linamarin ingested in a stiff porridge prepared from cassava flour was absorbed and excreted unchanged in the urine, whereas a little less than 50% was converted to cyanohydrin or cyanide and absorbed as such. The rest could not be accounted for. Most or all of the absorbed glycosides will be excreted in the urine, as shown for both linamarin and amygdalin in animals and humans.7,37,110,173 HCN as well as cyanohydrins will give rise to cyanide exposure through absorption and nonenzymatic lyses of the cyanohydrins.
Whereas the absorbed glycosides will be excreted unchanged in the urine, the HCN will be totally or partly metabolized, the main metabolite being the goitrogenic compound, thiocyan-ate. The rate of this conversion will depend on the nutritional status of the individual. Current knowledge concerning the known biomarkers for cyanide exposure (acute and long term) and their use in clinical and experimental toxicology was reviewed by Rosling.231 The detoxification processes (metabolization) and methods for the estimation of the sulphane sulphur pools available for this were reviewed by Westley.281 Acute human intoxications have been described as a result of the intake of cassava products and almonds, whereas sorghum and cyanogenic acacia leaves and pods have caused veterinary intoxications.
Acute intoxications in humans caused by the intake of insufficiently processed cassava meals have been reported from nearly all parts of the cassava consuming area, although it must be emphasized that the published reports are very scarce in relation to the extensive use of cassava as human food.5,76,78,172 The symptoms of acute intoxication include vomiting, nausea, headache, dizziness, difficulty with vision, and collapse.172
Evidence has accumulated that cyanide exposure from the diet is a causative factor in konzo,115,269 and may aggravate iodine deficiency disorders.60 The influence, if any, on the development of special types of diabetes remains a matter of discussion.3,263 Symptoms and diagnosis of konzo have been described by Rosling & Tylleskar.232
Based on the knowledge available concerning the toxicity of cyanide and cyanogenic glycosides, the Joint World Health Organization (WHO)/Food and Agricultural Organization (FAO) Expert Commitee on Food Additives and Contaminants (JECFA) tried to estimate a safe level for the intake of cyanogenic glycosides by humans. The committee concluded that "because of lack of quantitative toxicological and epidemiological information, a safe level of intake of cyanogenic glycosides could not be estimated." However, the committee also concluded that "a level of up to 10 mg HCN/kg of product is not associated with acute toxicity."253'?332' Thus, no authority has yet felt confident to set scientifically based safe levels for the intake of one or more of the known cyanogenic glycosides (or their products of degradation), that is, levels that take the risk(s) for the development of chronic intoxications into consideration. In acknowledgement of this, the "International Workshop on Cassava Safety," held in Ibadan, Nigeria in 1994, concentrated on making recommendations concerning steps to be taken in research; in breeding programs; and in information to extension workers in the agricultural, food, and nutrition sectors.10
Long before humans knew the identity of cyanide, they did know that bitter cassava is a good starch crop, but that it must be detoxified before consumption.67,69 Today, we know that this is because of its content of the cyanogenic gluco-sides, linamarin and lotaustralin. Overviews of the occurrence of cyanogenic glycosides in plants used for human or animal consumption are provided in Conn51 and Jones.129 Some of the important species of plants have been subjected to selection/breeding for a low total cyanogenic potential (TCP). Examples of the constituents and the TCP of economically important crops are provided in the following sections, together with some remarks concerning their importance as food or feed commodities.
Phaseolus lunatus (Seeds) and Other Beans. Seeds from several species of legumes are used for human consumption, many of which contain toxic and antinutritional substances. Thus, seeds from, for example, P. lunatus, P. aureus, Cajanus cajan, Canavalia gladiata, and Vigna unguiculata have been examined due to concerns about the possibility for cyanide intoxications.63192 All of these species are known to be cyanogenic in one or more tissues.242 P. lunatus contains linamarin as its main cyanogenic constituent; the cyanogens have not been identified in the other species.242 Only P. lunatus has been subjected to investigations concerning the variation in the cyanogenic potential.21 However, several of the other species certainly may contain toxic amounts of cyanogens in the seeds.192
Prunus Species (Seeds). Peach, plum, cherry, apricot, and almond (family Amygdalaceae sensu Dahlgren ) are all drupes (stone fruits) of great importance to man. Cyanogenic glycosides typical for Amygdalaceae are phenylalanine derived.182 Thus, the ripe seeds of P. persica (peach), P. domestica (plum), P. avium/cerasus (cherry), P. dulcis (P. amygdalus) (almond), and P. armeniaca (apricot) all contain amygdalin as the major cyanogenic constituent. The total cyanogenic potential per gram dry weight of whole fruit rises during the early development, and the relative composition of cyanogens changes from 100% prunasin in the beginning to nearly 100% of amygdalin in the ripe seed.90 170 189 Amygdalin and different Prunus seeds have, in spite of their ineffectivity, been commercially promoted for years as medicines to treat different cancers.108
• Almond—This tree is very widely cultivated around the Mediterranean. The naming of the species and its varieties/cultivars has changed through time.99 The tree comes in two varieties, var. dulcis and var. amara, of which var. amara contains high concentrations of amygdalin in its ripe seeds (also denoted "bitter almonds").39 50 " The seeds are used in confectionary and bakery.99 They contain approximately 50% of lipids, the oil being used in cosmetics and dermatology.39" Bitter almonds (but also, e.g., apricot seeds) are also used to produce an essential (volatile) oil called "oil of almonds." This competes with synthetic benzaldehyde as a source of flavor.39 Only few references exist concerning the content of cyanogenic glycosides in almonds.50-90 Conn50 found bitter almond seeds to release 290 mg of HCN/100 g of seed. According to Sturm,260 commercial sweet almonds from California in general contain less bitter seeds (approximately 1%) than the 2-3% that is normally found in the Mediterranean ones.
• Apricot—Apricots have considerable economic importance for several countries such as Italy, the production of which was approximately 200,000 tons in 1988.259 Different products are marketed from apricots, including fresh, dried, and canned fruits; nectar; jam; and distilled liqueur.176 The number of varieties and hybrids of apricots are numerous.174 Thus, Audergon et al.14 tested more than 400 varieties as part of a physicochemical characterization program. Several marketed products of apricots require destoning,55 leaving the stones as a byproduct from which oil can be extracted. The use of the seed/presscake is, however, restricted by the toxicity.266 Depending on the variety and type of apricot, the apricot stone is relatively small, representing 6-8% of the fruit weight, even if it can sometimes reach 10%.176 To the best knowledge of the present author, no investigations have been published concerning the variation in content of amygdalin in seeds of different cultivars. However, as part of investigations concerning the microbial degradation of cyanogens in such seeds, Tuncel et al. 266 267 analyzed two batches of bitter and one of sweet Turkish apricot seeds, obtained on the commercial market. The bitter ones were found to contain approximately 52 and 92 |imol/g d.w., respectively; the sweet ones contained approximately 2.5 |J.mol/g.
• Peach—Much of the same that has been said for apricot can be said for peach. Seeds from P. persica Batsch (peach) also contain amygdalin as their major cyanogenic constituent.193 Kupchella & Syty141 analyzed the total cyanogenic potential of the seeds from an undefined cultivar and found it to correspond to a content of amygdalin of approximately 2.45% w/w.
Linum usitatissimum (Seeds = Linseed/Flax-seed). Flax is grown for two main purposes, fibers and seeds. Different cultivars are used for the two products. Whole seeds are used as a laxative due to the swelling seed coat polysaccharides.200 Both full-fat flaxseed flour and defatted meal from the oil extraction are on the commercial market, the latter in two qualities, with 30% and 40% protein, respectively.198 Flax is one of the major industrial oilseeds traded in world markets. Global production for crop year 1994-1995 was 2.44 million metric tons, with Canada contributing a major share. Flaxseed oil is used for a multitude of purposes, the oil being priced up to four times that of the whole seed.198 The extraction cake (linseed meal) is traditionally used for fodder purposes. Recently, research into the refinement of flax products has accelarated. Thus, two patents have been issued for the use of flaxseed polysaccharide (gum) for cosmetic and medical preparations,13196 and an optimization of protein extraction from defatted flaxseed meal has been presented.199
Until 1980, linamarin was thought to be the main cyanogen in linseed. However, looking for the factor(s) in linseed meal responsible for its protective effect against selenium toxicity, Smith et al.2S] isolated two new cyanogenic glycosides (linustatin and neolinustatin). A later TLC-based investigation concerning the concentrations of different cyanogenic glycosides in a linseed sample gave the following (imol/g: linustatin+neolinustatin 4.6, linamarin 0.46, and lotaustralin 0.36,32 pointing to linustatin and neolinustatin as the major cyanogenic constituents. This was further confirmed by a high performance liquid chromatography (HPLC) analysis of 48 samples, which on the other hand only found traces of linamarin and lotaustralin.240 However, a recent investigation showed quite some variation between 10 cultivars. Two contained no linamarin, whereas in the cultivar Vimy, 7.8% of the weight of the total cyanogenic glycosides were linamarin.201 This is close to the findings of Brimer et al.32 for an unspecified sample. Frehner et al.90 analyzed both the cyanogenic potential and the relative cyanogen composition during fruit development—one cultivar. As in Prunus seeds, the monoglucosides predominated at anthesis, shifting toward diglycosides during maturation. Rosling230 found the cyanogenic potential of a nonspecified number of commercially sold linseed in Sweden to range from 4 mmol/kg to 12 mmol/kg (112336 mg kg-1 HCN). The acute lethal dose is less than 2 mmol in 24 hours in sick and malnourished patients.270
Manihot esculenta (Roots and Leaves). The genus Manihot (Euphorbiaceae) incorporates more than 200 species, all originating in tropical America, from where several have been spread to other continents. Thus, M. esculenta Crantz (cassava) is today grown as a major source of starch in tropical Africa, India, Indochina, Indonesia, and Polynesia.184 As early as 1605, Clusius reported that cassava could be toxic to man. The two cyanogenic glucosides, linamarin and lotaustralin, are responsible for this.70 183 The cyanogenic potential (CNp) of several cassava germplasm collections has been investigated. Thus, Aalbersberg & Limalevu1 analyzed 28 cultivars grown in Fiji, and found a variation from approximately 15 mg to 120 mg HCN equivalents/kg f.w. Dufour67 69 looked at 14 cultivars of the Tukanoan Indians in northwest Amazonia and found very high levels (310-561 mg HCN eq./kg f.w.) in Kii (toxic cultivars) and 171 mg HCN eq./kg f.w. in the only Makasera
(nontoxic/safe cultivar) grown. The Tukanoan Indians clearly expressed that they preferred toxic varieties as the main staple (70% of calorie intake) component of their diet. In this connection, it should be noted that the so-called "safe" (Makasera) cultivar had a higher CNp than the 100 ppm (f.w.) that was proposed as the upper limit by Koch6769 based on acute toxicity. Finally, Bokanga24 examined 1,768 different cassava collections and found that the content of the central pith of the root varied from approximately 1 mg to more than 530 mg HCN equivalent/ kgd.w. The peel surrounding the pith has a much greater content, as have the leaves.24 No acyanogenic cassava was found. While discussing the cyanogenic potential in this precise way, it should be born in mind that variations of up to 100% may be recorded between roots of the same plant.24 It has also been shown that age, agricultural practices,73 and environment may have a strong influence on its cyanogenic potential.24 26
The leaves of M. esculenta also serve as food and feed.25 The cyanogenic potential of leaves from the same plant is less variable than that of the roots,24 and is usually 5 to 20 times higher on a fresh weight basis.25 The high content in the leaves normally does not present a problem for their use in food, given the methods generally used in their preparation.25 In contrast, the roots of many cultivars, if not properly processed, have actually caused both acute and chronic intoxications worldwide. However, it should be emphasized again that the cassava root (even highly cyanogenic types) is a very valuable and irreplaceable crop. To ensure its safe use in every community under all conditions, the effectiveness of the different processing techniques (under rural as well as industrialized conditions) needs to be verified and the knowledge spread.10
Sorghum Species (Leaves and Seeds). Seedlings of S. bicolor (Poaceae) and other Sorghum species synthesize the cyanogenic glucoside dhurrin that is localized in the ariel shoots of the plant.101 Thus, three-day-old etiolated seedlings of S. vulgare (i.e., the name for any cultivated grain sorghum) was found to contain up to 15 (j.moles/g.4 The content in mature leaves is much lower. The concentration depends on species, subspecies, and race/cultivar, and is also influenced by ecological factors.65 Although most intoxications are seen in cattle browsing a newly sprouted field, forage may not be totally safe.65,282 Grain sorghums constitute an important part of human nutrition in several semi-arid areas of the world.6188 Generally, the grains are considered completely safe for human consumption,88136 although the digestibility and biological value are not always high as a result of the occurrence of quite high concentrations of phytate and polyphenols in several cultivated types.88 120 Especially in Sudan, sorghum is irreplaceable, being the traditional stable food.64 Although sorghum seeds in general are safe, germinated seeds are not. In certain African countries, germinated sorghum seeds are used traditionally for the production of malt,88 which in turn is used for the brewing of alcoholic beverages64 and for the production of the baked products called Hulu-mur.64 According to FAO,88 the traditional methods of preparation of these products remove the dhurrin effectively; however, it is stressed that the existence of these products must not be seen as an indication of sprouted sorghums being safe—they are not.88
A metabolic fate and mechanism of toxicity, including the same alkylating end product as with dimethylnitrosamine, has been proposed for the MAM that is released from the MAM glycosides.209 Thus, cycasin has been shown to be toxic to a number of animals, causing hepatic lesions and demyelination with axonal swelling in the spinal cord.22,246 Cow's milk may be a vector of transmission of plant toxins. Thus, Mickelsen et al.m showed that MAM can pass into the milk of lactating rats, causing tumors in the offspring. The seeds of several Cycas spp. are traditionally eaten in Australia22 and on certain islands.150-254 A special neurological syndrome occurring on the island of Guam, and termed Guam ALS-PDC, has been hypothesized to be due to the intake of seeds of C. circinalis,150>254 In 1987, Spencer et al.254 pro posed that the causative factor of this syndrome was the neuroexcitotoxic amino acid (J-N-methylamino-L-alanine (BMAA). However, a number of subsequent investigations doubted this, as reviewed by Stone258 in an article on the gradual disappearance of this disease. Thus, it may never be known whether the MAM glycosides could have a role in this disease, though it remains a possibility given the spinal cord lesions reported in goats as a result of chronic intake of cycasin.246
The carcinogenicity of ptaquiloside demonstrated in feeding experiments with rats, mice, hamsters, guinea pigs, and cattle, among others, is alarming because the young shoots of bracken fern are highly regarded as a tasty dish in Japan.111 Hence, this intake of bracken has been linked to high incidences of stomach cancer in Japan,111 and in Costa Rica among people who have been exposed to milk that was produced in bracken-infested grasslands.6 The theory has been supported by the finding of a high tumor incidence in rats and mice that were fed milk from cows that had been fed with dietary complements of bracken, and by the subsequent demonstration of ptaquiloside in bovine milk.6
Food and feed containing saponins include soybean, guar, quinoa, balanites fruits, and others. Besides the membranolytic action of many saponins, certain of these compounds exert special effects due to the structure of their agly-cone.286 Such effects include (1) lowering of blood cholesterol;144 (2) reversible sodium retention and potassium loss leading to hypertension, water retention, and electrolyte imbalance (e.g., glycyrrhizinic acid found in licorice root, the roots and stolons from Glycyrrhiza glabra, and for products to which licorice root extract, or glycyrrhizinic acid, has been added);100'133,239,256 and (3) crystal formation in the liver and biliary system, which may inhibit the excretion of phylloerythrin (from chlorophyll degradation), causing a subsequent photosensitation as seen in "Geeldikkop" (a Tribulus terristris intoxication).131 A number of saponins are bitter. The occurrence of bitter saponins in palmyrah (Borassus flabellifer L) fruit pulp thus reduces the use of juices based on this fruit.74 Likewise, seeds of Chenopodium spp. used for human consumption (C. quinoa [quinoa], C. pallidicaule [canihua], and C. berlandieri ssp. nuttaliae [Safford] Wilson and Heiser [huauzontle]) contain bitter saponins,95 107 226 most of which are concentrated in the outer layers of the grain.40 41-223
Favism is characterized by anemia, jaundice, and hemoglobinuria, and may develop in subjects with glucose-6-phosphate dehydrogenase (G6PD) deficiency as a consequence of faba bean intake. Favism has also been reported in breast-fed infants whose mothers had eaten faba beans, and in newborn infants.54 More than 300 variants of G6PD are known.273 In addition, an association between the genotype of ACP, (human red cell acid phosphatase) and favism has been shown, and a possible biochemical mechanism has been proposed.27 Most cases of G6PD deficiency described in the past were from Italy and other countries around the Mediterranean, that is, patients with the common Mediterranean B-form of G6PD, rather than the common African A (-) form.273 However, recent investigations have shown that subjects with variants that result in a relatively mild G6PD deficiency may also develop favism.93181 Preventive measures and treatments have been described elsewhere.102 162 188
The most prominent toxic manifestation of glucosinolates in humans is the occurrence of goiter.214 In animal experiments, this and other effects were generally more pronounced when myrosinases were included in the diet.252 The effects seen were related to differences in the side chains and to chirality.252 The fact that there are several mechanisms behind the toxic and antinutritional effects has also been very re cently stressed by the results of the most detailed studies on the degradation products of various glucosinolates.23 These authors presented an overview of the different degradation products formed from glucosinolates, which also include, for example, oligomers. From the degradation of glucobrassicin (an indole glucosinolate), indolyl-3-methanol is formed in considerable amounts, but it disappears very quickly, giving rise to, among others, appreciable amounts of thiocyanate ion. No organic isothiocyanates and thiocyanates are formed. In contrast, the degradation of various aliphatic glucosinolates results in the formation of nitriles as well as isothiocyanates and thiocyanates.23 Toxic effects of glucosinolates in B. oleracea have been reviewed by Stoewsand257 and those of crambe (Crambe abyssinica) meal fed to broiler chicks by Kloss et al.137 The mechanism behind the observed decrease in cancer risk for people on diets with a high content of cruciferous vegetables has been investigated by Wallig et al,274
VARIATION IN TOXIN CONCENTRATION AMONG VARIETIES AND CULTIVARS: THE INFLUENCE OF TRADITIONAL DOMESTICATION AND MODERN BREEDING
Several toxic glycosides (including various saponins and cyanogenic glycosides, etc.) are known to be bitter tasting in addition to toxic. Hence, the term "bitter," as opposed to "sweet," has been used traditionally to designate naturally occurring or selected groups within a plant species that contain high amounts of the toxic (and bitter) substance. Depending on the view of the botanical author, the groups in question may be divided on the level of variety, form, or cultivar. Examples of plant species for which the division bitter/sweet has been used are P. dulcis and other Prunus spp. (containing amygdalin), as well as M. esculenta (cassava, containing linamarin), and in quinoa.139 In most such cases, a correlation between the toxicity (content of glycoside) and the degree of bitterness of the plant part has been established. However, it is only seldom that a proper investigation concerning the degree to which this correlation holds has been performed. Thus, a positive correlation, but with exceptions, was found in a number of smaller studies on cassava roots.247 Hence, King & Bradbury135 took up the challenge of investigating in more detail the bitter-tasting substances in cassava parenchyma and cortex. Linamarin was found to be the sole contributer to bitterness present in the parenchyma; a new structure (isopropyl-P-D-apiofuranosyl-( l-6)-p-D-glucopyranoside) contributing in the cortex of some cultivars. This is in agreement with a very recent study from Malawi, 234 which compared the content of cyanogenic glucosides in the cortex of 492 cassava roots with their taste as estimated by a taste panel. The correlation had an r2 = 0.96 when looking at the cultivar level.
It is well documented, at least for a number of cyanogenic plant species, that the concentration of both the glycosides and the enzymes degrading them can show a discrete variation (polymorphism) as well as a continous one. The polymorphism is genetically based, whereas the continous variations observed may be both genetically and environmentally influenced.24-26 116~ 119,130,159,186 The genetic polymorphism (discrete variation, chemical races) with respect to the occurrence of both cyanogenic constituents and hydrolytic enzymes makes it difficult to define what is meant by a "cyanogenic species." Furthermore, it should be noted that the cyanohydrin lyase, which cleaves the cyanohydrins formed after the hydrolysis of the glycoside(s), may be expressed in certain organs and not in others. Thus, White et al.m recently showed that this enzyme, although present in the leaves, is not expressed in the roots of cassava. This observation explains why very high intermediate concentrations of cyanohydrins are formed during the processing of cassava roots. The environmental influences mentioned above may furthermore mean that certain plants will be found positive at some times of the year and negative at others.
Increased use of more highly cyanogenic cultivars of cassava among small farmers has been reported from several places. Thus, Dufour reported on a clear preference for Kii (toxic variet ies) for most purposes by the Tukanoan Indians,6769 whereas Aalbersberg & Limalevu1 stated that planting of the toxic (bitter) cultivars increased in New Guinea. Also, Onabolu et al.197 found that the three most commonly grown cultivars in Ososa (a semi-urban farming community approximately 80 km east of Lagos, Nigeria), where cassava has been the main staple for decades, were all stated to be poisonous and to need processing. However, this was not regarded as a disadvantage. Farmers' reasons for preferentially growing cassava cultivars providing bitter roots were studied in Malawi.48 In many traditional agricultural communities, the farmers (often the women) judge the "safeness" of the roots by chewing a small piece. According to Dufour,67 69 the Tukanoan Indians appear to be able to distinguish accurately less from more poisonous cultivars by the taste. Very recent studies from Malawi prove such a procedure to exist, and to be very effective (Chiwona-Karltun, personal communication, October 2000).
Several of the species within the family Cucurbitaceae, which are used as human food, naturally contain cucurbitacins in amounts that are unacceptable to the market. However, intense domestication and breeding have resulted in cultivars low in bitter compounds.126127 Breeding programs for curcurbits are constantly aware of the bitterness.84
Great variations (0-13000 |ig/g) may also be found in the content of ptaquiloside in bracken fern as a result of both ecological and genetic variation, a tendency for higher contents being reported when originating in relatively colder climates.249 In addition, P. esculentum contains the cyanogenic glucoside, prunasin, the concentration of which similarly has been related to climatic conditions.153
Also, quinoa cultivars vary concerning the quantitative content of saponins, and the tradition has, as for other crops, been working with so-called sweet and bitter varieties.139
For V. faba, it should be mentioned that, although Duc et al.66 gave the first report of a gene that codes for nearly a zero content of vicine and convicine, present-day cultivars contain approximately 7 and 2.5 mg g"1 respectively.276
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