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1265. The oblique toxicity test
272
NATURAL PRODUCTS
Tamimie, H. S. & Pscheidt, G. R. (1966). Effect of feeding high levels of L-phenylalanine to day-old chicks and its relationship to sex and breed. Comp. Biochem. Physiol. 17, 1159. Phenylketonuria is a hereditary disorder associated with mental deficiency and an inability to metabolize phenylalanine (I) to tyrosine. Certain aspects of this disease have been reproduced in various animal species by administering excess I in the diet. Toxic effects due to excess I have been described in rats (Cited in F.C.T. 1966, 4, 528) but avian studies have hitherto been neglected. On feeding diets supplemented with 5 % I to day-old and l-month-old chicks for 4 wk, Tamimie & Pscheidt (first paper, cited above) observed weight loss, greatly depressed feed efficiency, abnormalities of the toe and hock joints, poor motor co-ordination, discoloration of the shanks and face, enlarged crops, rough feathers and a reduced blood haemoglobin level. Organ weights were also reduced, the spleen being affected most and, as is usual under adverse dietary conditions, the brain least. When the birds were transferred at 4 wk from the 5 % I diet to a basic diet a dramatic recovery ensued and within 4 wk all the above adverse effects were reversed except for the reduced spleen weight. The latter finding suggests that the blood-forming apparatus may be particularly sensitive to excess dietary I, particularly since there was a reduced red cell count in the blood of the older chicks. In a further study on day-old chicks by Tamimie & Pscheidt (second paper, cited above) it was shown not only that these deleterious effects were directly related to the concentration of I in the diet (pronounced at the 8 ~o dietary level and minimal at the 2 and 4 % levels) but also that sex and strain differences exist in the susceptibility to the toxic effects of I. It was concluded that a dietary level of at least 5 % of I is required before gross physical effects are apparent in growing chicks.
1264. You can't keep healthy on starch Warshauer, S. E. (1966). Starch-eater's anemia. Sth. reed. J., Nashville 59, 538. Corn starch may be all very well for rats living on a low protein diet (Cited in F.C.T. 1966, 4, 445), but it seems to be a source of trouble in the Deep South, where Negro women quite often make a habit of eating starch to the exclusion of essential dietary elements. Although I lb of corn starch (produced in lumps for the convenience of the launderer, and not intended as an energy-producing fuel) yields 1590 calories and is 86% sheer carbohydrate, it contains negligible amounts of essential factors such as iron. A case is reported of a Negro woman who developed a severe hypochromic anaemia after subsisting on a diet largely composed of launderer's starch, of which she ate several Ib daily. The condition was rapidly corrected by the administration of iron. Another Negro woman who had a compulsive starch-eating habit presented a similar picture. The anaemia in such women develops as a result of menstrual iron loss without adequate replacement, and it is commonly associated with obesity. 1265. The oblique toxicity test Crawford, D. L., Sinnhuber, R. O., Stout, F. M., Oldfield, J. E. & Kaufmes, J. (1965). Acute toxicity of malonaldehyde. Toxic. appl. Pharmac. 7, 826. The instability and reactivity of malonaldehyde (I), which is one of the decomposition products of many oxidized lipid materials, preclude its being tested directly for toxicity. Use was therefore made of its ethoxy derivative, 1,1,3,3-tetraethoxypropane (II) and the enolic salt, sodium fl-oxyacrolein (III), which would be degraded to yield I in the gastro-intestiHal tract. When single oral doses of II were given by stomach tube to rats, inconsistencies arose from the different degrees of dilution. They were attributed to different hydrolysis rates in
NATURAL PRODUCTS
273
the alimentary tract whereby ethanol and I were formed. Contrary to general experience, more concentrated doses resulted in lower toxicity. Lethal doses caused severe convulsive seizures leading to respiratory failure and death, usually within 2 hr. The LDso of I based on the use of II was 527 mg/kg, which probably represented also the toxicity of ethanol and other possible hydrolysis products. With III, the anomalous dilution, factor did not arise and the toxic effects were slower to develop. The LDs0 of I using Ill was 632 mg/kg. Hence of the two compounds tested, III afforded a more accurate assessment of the toxicity of I. Compared with other aldehydes, I is more toxic than formaldehyde (LDso 800 mg/kg) and glyoxal (LDso 2020 mg/kg). 1266. Tetrodotoxin from oriental fish
Tsuda, K. (1966). Llber Tetrodotoxin, Giftstoff der Bowlfische. Naturwissenschaften 53, 171. Puffer fish (various species of Fugu) have been consumed in Japan and China for hundreds of years and cases of poisoning due to this delicacy have been known for a very long time. The first systematic pharmacological study of the poisonous constituent of these fish was apparently reported in 1884, although the toxin, later named tetrodotoxin (I), was not isolated in crystalline form until 1950. Its structure has appeared previously in this Journal (Cited in F.C.T. 1965, 3, 611). Over 200 cases of poisoning from this type of fish occurred in Japan in 1959, and 56 ~o of these cases were fatal. Strict marketing control, however, is reducing the incidence yearly• I is found mainly in the internal organs of the fish, especially the ovaries, liver and gut, and the content varies with the season, being highest in winter. It has been shown to be identical with tarichatoxin, isolated from the California salamander. The LDso of purified I administered to mice by intravenous or subcutaneous injection is only 8-10 ~g/kg, and it appears to be lethal to all animals except the fish and salamanders in which it occurs. In man, the first symptoms of poisoning, parasthesia and motor paralysis, appear 0.5--4 hr after ingestion, and within 6--8 hr death is likely to ensue from paralysis of the respiratory centre and muscles. I acts selectively on the cell membranes in muscle tissue to block the entry of sodium ions through the membrane, a fact which has made it a useful tool in the study of muscle physiology. [The acute toxicity of tetrodotoxin in the mouse is thus of the same order as that of saxitoxin (Cited in F.C.T. 1964, 2, 629), a highly toxic substance found in shellfish. This also induces muscle paralysis by blocking the transport of sodium ions across the cell membrane (ibid 1966, 4, 358.] 1267. Fungal toxins responsible for deaths?
Becroft, D. M. O. (1966). Syndrome of encephalopathy and fatty degeneration of viscera in New Zealand children. Br. med. 3". il, 135. An unusual syndrome of acute cerebral damage and severe fatty degeneration of the liver has been reported in young children from such widely separated countries as Australia, United Kingdom, South Africa and Czechoslovakia. A description is given of the clinical and pathological features of nine fatal cases of the disease reported in Auckland since 1959 and of two cases in which the patients survived the acute illness with residual cerebral damage. The cause of the disease is at present unknown• Only one case has been traced to viral infection. Fungal toxins are implicated by the nature of the liver damage, and it is suggested that in any future cases an examination should be made for hepatotoxins of fungal origin, which may be present in apparently innocuous foods.
NATURAL PRODUCTS
Tamimie, H. S. & Pscheidt, G. R. (1966). Effect of feeding high levels of L-phenylalanine to day-old chicks and its relationship to sex and breed. Comp. Biochem. Physiol. 17, 1159. Phenylketonuria is a hereditary disorder associated with mental deficiency and an inability to metabolize phenylalanine (I) to tyrosine. Certain aspects of this disease have been reproduced in various animal species by administering excess I in the diet. Toxic effects due to excess I have been described in rats (Cited in F.C.T. 1966, 4, 528) but avian studies have hitherto been neglected. On feeding diets supplemented with 5 % I to day-old and l-month-old chicks for 4 wk, Tamimie & Pscheidt (first paper, cited above) observed weight loss, greatly depressed feed efficiency, abnormalities of the toe and hock joints, poor motor co-ordination, discoloration of the shanks and face, enlarged crops, rough feathers and a reduced blood haemoglobin level. Organ weights were also reduced, the spleen being affected most and, as is usual under adverse dietary conditions, the brain least. When the birds were transferred at 4 wk from the 5 % I diet to a basic diet a dramatic recovery ensued and within 4 wk all the above adverse effects were reversed except for the reduced spleen weight. The latter finding suggests that the blood-forming apparatus may be particularly sensitive to excess dietary I, particularly since there was a reduced red cell count in the blood of the older chicks. In a further study on day-old chicks by Tamimie & Pscheidt (second paper, cited above) it was shown not only that these deleterious effects were directly related to the concentration of I in the diet (pronounced at the 8 ~o dietary level and minimal at the 2 and 4 % levels) but also that sex and strain differences exist in the susceptibility to the toxic effects of I. It was concluded that a dietary level of at least 5 % of I is required before gross physical effects are apparent in growing chicks.
1264. You can't keep healthy on starch Warshauer, S. E. (1966). Starch-eater's anemia. Sth. reed. J., Nashville 59, 538. Corn starch may be all very well for rats living on a low protein diet (Cited in F.C.T. 1966, 4, 445), but it seems to be a source of trouble in the Deep South, where Negro women quite often make a habit of eating starch to the exclusion of essential dietary elements. Although I lb of corn starch (produced in lumps for the convenience of the launderer, and not intended as an energy-producing fuel) yields 1590 calories and is 86% sheer carbohydrate, it contains negligible amounts of essential factors such as iron. A case is reported of a Negro woman who developed a severe hypochromic anaemia after subsisting on a diet largely composed of launderer's starch, of which she ate several Ib daily. The condition was rapidly corrected by the administration of iron. Another Negro woman who had a compulsive starch-eating habit presented a similar picture. The anaemia in such women develops as a result of menstrual iron loss without adequate replacement, and it is commonly associated with obesity. 1265. The oblique toxicity test Crawford, D. L., Sinnhuber, R. O., Stout, F. M., Oldfield, J. E. & Kaufmes, J. (1965). Acute toxicity of malonaldehyde. Toxic. appl. Pharmac. 7, 826. The instability and reactivity of malonaldehyde (I), which is one of the decomposition products of many oxidized lipid materials, preclude its being tested directly for toxicity. Use was therefore made of its ethoxy derivative, 1,1,3,3-tetraethoxypropane (II) and the enolic salt, sodium fl-oxyacrolein (III), which would be degraded to yield I in the gastro-intestiHal tract. When single oral doses of II were given by stomach tube to rats, inconsistencies arose from the different degrees of dilution. They were attributed to different hydrolysis rates in
NATURAL PRODUCTS
273
the alimentary tract whereby ethanol and I were formed. Contrary to general experience, more concentrated doses resulted in lower toxicity. Lethal doses caused severe convulsive seizures leading to respiratory failure and death, usually within 2 hr. The LDso of I based on the use of II was 527 mg/kg, which probably represented also the toxicity of ethanol and other possible hydrolysis products. With III, the anomalous dilution, factor did not arise and the toxic effects were slower to develop. The LDs0 of I using Ill was 632 mg/kg. Hence of the two compounds tested, III afforded a more accurate assessment of the toxicity of I. Compared with other aldehydes, I is more toxic than formaldehyde (LDso 800 mg/kg) and glyoxal (LDso 2020 mg/kg). 1266. Tetrodotoxin from oriental fish
Tsuda, K. (1966). Llber Tetrodotoxin, Giftstoff der Bowlfische. Naturwissenschaften 53, 171. Puffer fish (various species of Fugu) have been consumed in Japan and China for hundreds of years and cases of poisoning due to this delicacy have been known for a very long time. The first systematic pharmacological study of the poisonous constituent of these fish was apparently reported in 1884, although the toxin, later named tetrodotoxin (I), was not isolated in crystalline form until 1950. Its structure has appeared previously in this Journal (Cited in F.C.T. 1965, 3, 611). Over 200 cases of poisoning from this type of fish occurred in Japan in 1959, and 56 ~o of these cases were fatal. Strict marketing control, however, is reducing the incidence yearly• I is found mainly in the internal organs of the fish, especially the ovaries, liver and gut, and the content varies with the season, being highest in winter. It has been shown to be identical with tarichatoxin, isolated from the California salamander. The LDso of purified I administered to mice by intravenous or subcutaneous injection is only 8-10 ~g/kg, and it appears to be lethal to all animals except the fish and salamanders in which it occurs. In man, the first symptoms of poisoning, parasthesia and motor paralysis, appear 0.5--4 hr after ingestion, and within 6--8 hr death is likely to ensue from paralysis of the respiratory centre and muscles. I acts selectively on the cell membranes in muscle tissue to block the entry of sodium ions through the membrane, a fact which has made it a useful tool in the study of muscle physiology. [The acute toxicity of tetrodotoxin in the mouse is thus of the same order as that of saxitoxin (Cited in F.C.T. 1964, 2, 629), a highly toxic substance found in shellfish. This also induces muscle paralysis by blocking the transport of sodium ions across the cell membrane (ibid 1966, 4, 358.] 1267. Fungal toxins responsible for deaths?
Becroft, D. M. O. (1966). Syndrome of encephalopathy and fatty degeneration of viscera in New Zealand children. Br. med. 3". il, 135. An unusual syndrome of acute cerebral damage and severe fatty degeneration of the liver has been reported in young children from such widely separated countries as Australia, United Kingdom, South Africa and Czechoslovakia. A description is given of the clinical and pathological features of nine fatal cases of the disease reported in Auckland since 1959 and of two cases in which the patients survived the acute illness with residual cerebral damage. The cause of the disease is at present unknown• Only one case has been traced to viral infection. Fungal toxins are implicated by the nature of the liver damage, and it is suggested that in any future cases an examination should be made for hepatotoxins of fungal origin, which may be present in apparently innocuous foods.