124 Articles of general interest

(f) Percutaneous migration of vinyl chloride. (g) Levels of vinyl chloride in food; estimated daily intake in children and adults. (h) Interaction of vinyl chloride with food and drink components. (i) Levels of vinyl chloride in PVC products (sheets, film). (j) Levels of vinyl chloride in potable water and PVC tubing.

The vinyl chloride problem should be capable of solution without recourse to total abol- ition of PVC manufacture and usage, but it was recognized that the latter policy might be adopted in some countries as a matter of expediency. Should this occur, there would be considerable risk to other plastics materials. It is obviously desirable that the co-oper- ation of all interested parties be attained to facilitate and expedite the resolution of this problem.

THE WINDING MONOSODIUM GLUTAMATE TRAIL

The treatment of newborn rats with monosodium glutamate (MSG) in intragastric doses of 1.25, 2.5 or 5 g/kg/day for 5-day periods has been shown to induce behavioural defects, particularly in discrimination aptitude, and to reduce spontaneous motor activity, most strikingly in animals that had received the higher doses (Cited in F.C.T. 1973, 11,686). Sub- sequently, Johnston (Bioehem. Pharmac. 1973, 22, 137) reported that convulsions were pro- duced by ip injection of neutral aqueous solutions of MSG, aspartate, methylaspartate, homocysteate,/%N-oxalyl-L-c~,/~-diaminopropionate or ibotenate into 10-day-old rats in doses up to 20 mmols/kg body weight. L-Aspartate and D- and L-glutamate proved convul- sant only at the highest test dose of 20 mmols/kg and after about 30 minutes, whereas the other amino acids were considerably more potent in this respect. The convulsant activities of these compounds in neonatal rats were roughly in line with their relative abilities to excite feline central neurones, which suggested that the same basic mechanism was in- volved in the two effects. Several of these amino acids, in addition to MSG, are known to produce neuronal damage in the hypothalamus of infant mice after sc injection.

A paper by Olney et al. (New Engl. J. Med. 1973, 289, 391) indicates that glutamic, aspar- tic and cysteic acids present in casein hydrolysates intended for iv therapy may pose a hazard. Parenteral feeding of such solutions to surgical and paediatric patients, including premature infants, is apparently increasing. Olney et al. (loc. cit.) gave casein hydrolysates sc to 10-day-old mice in a single dose of 20-100 ml/kg and found that these, like an injec- tion of a fibrin hydrolysate in a dose of 80-100 ml/kg, induced acute degeneration of neurons in the developing hypothalamus. The combined concentrations of acidic amino acids were 2460/~mols/100 ml in the casein hydrolysate and 1130 #mols/100 ml in the fibrin hydrolysate. The hypothalamic lesions appeared to be identical with those induced by oral or parenteral treatment with glutamic, aspartic or cysteic acid, and control injec- tions with an amino acid mixture free of these three compounds caused no hypothalamic damage. On the other hand, Arthur et al. (Proc. Soc. exp. Biol. Med. 1973, 144, 34) found that, in weanling mice, daily sc injections of 1 g MSG/kg or 0'92 g monosodium aspartate/ kg for up to 21 days had no significant effect upon the activities of glutamic dehydrogenase or glutamic-oxalacetic and glutamic-pyruvic transaminases in brain or liver. The same doses given to newborn mice, however, caused a two- or three-fold increase in the activity of these enzymes in both brain and liver. Evidently weanling mice are able to metabolize relatively large quantities of these amino acids, although newborn mice cannot.

Articles of general interest 125

We have seen that, in mice, only glial cells and not neurones are damaged by oral administration of MSG, and that in monkeys, whose central nervous system is fully my- elinated at birth, even large doses of MSG fail to have any such effect (Cited in F.C.T. 1972, 10, 585). Chi-Pang Wen et al. (Am. J. elin. Nutr. 1973, 26, 803) studied the effects of dietary supplements of MSG on infant squirrel monkeys, weanling rats and suckling mice. Feed- ing 4"8-16"7~o MSG to the monkeys for 9 weeks failed to induce hypothalamic or retinal lesions. These authors also detected no adverse effect when they fed a diet containing 9-1~o MSG to infant cynomolgus and bushbaby monkeys for 1 year. Weanling rats fed 20 or 40~o MSG for 5 weeks showed some depression of growth, which was attributed to the excessive sodium intake rather than to glutamate as such. Infant mice given 2, 6 or 9 g MSG/kg on days 6-10 of life had developed no hypothalamic lesions when killed on day 11. In a similar experiment not terminated at day 11, about one-third of the treated mice died within 30 days, apparently from the effect of the high-sodium diet and/or the high osmolarity of the MSG solution. The ultimate survivors failed to become obese or hyperactive within 1 year. This study thus supports the view that considerable amounts of MSG appear to be harmless when ingested as part of an otherwise normal diet.

Some data regarding the absorption and distribution of MSG, when given alone or in conjunction with an infant food formula, have been given by Stegink et al. (J. Nutr. 1973, 103, 1138). In fasted 3-day-old pigs given 0.01, 0"1 or 1"0 g MSG/kg by gavage, plasma glu- tamate levels reached a maximum 15-30 minutes after administration of MSG given alone in solution, or 90-120 minutes after administration in infant food. The maximum level ulti- mately reached was not affected by the vehicle. Plasma amino acid levels did not differ significantly between pigs given 0.01 g MSG/kg and the controls, but 0'1 g/kg produced slight increases in plasma glutamate and aspartate at times when absorption of MSG was at its maximum. With 1.0 g MSG/kg, there were marked increases in plasma glutamate, aspartate and alanine. With the two lower levels of MSG (the only two studied in this con- nexion), there were no significant changes in free amir/o acid concentrations in brain, muscle or cerebrospinal fluid. The considerable metabolism of glutamate in the liver was confirmed by the demonstration that levels of glutamate in portal blood were five times higher than those in peripheral blood, even in control animals.

Further studies of MSG metabolism in newborn pigs by Stegink et al. (ibid 1973, 103, 1146) followed the distribution of radioactivity after administration of U-~4C-labelled MSG in a dose of 1 g/kg by gavage. Radioactivity promptly appeared in plasma glutamate, arginine, aspartate, glutamine, alanine, ornithine, citrulline, urea and two ninhydrin-nega- tire metabolites, subsequently found to be glucose and lactate. Glucose, glutamate and lac- tate between them accounted for 65-80~o of the total activity. Very small amounts of radioactivity appeared in pyruvate and ~-ketoglutarate, but there was no significant amount in plasma succinate, pyrrolidone carboxylate, malate, citrate or oxalacetate. Moreover, it appeared that no labelled glutamate or aspartate entered the cerebrospinal fluid, although substantial quantities of labelled glutamine, glucose, lactate and urea were detected here.

It appears from this latest collection of studies that while there is still little evidence to suggest that oral administration of MSG, even in considerable amounts, might give rise to lesions of the central nervous system, there may be a case for looking further into the question of parenteral nutrients destined for injection into premature infants. In consider- ing the work on such preparations, however, it is important to bear in mind that myelina- tion, which is thought to contribute to the blood-brain barrier, occurs at a much earlier

126 Articles of general interest

stage of development in man than in mice (Cited in F.C.T. 1972, 10, 585), so that results obtained in newborn mice must be interpreted with caution.

[P. Cooper--BIBRA]

ALCOHOL MUSCLES IN

Alcoholic cardiomyopathy

The question of the effects of alcohol on the heart sprang into prominence some 7 years ago in connexion with several outbreaks of fatal heart disease among heavy beer drinkers. This particular syndrome was associated with a combination of factors, including the con- sumption of beer to which cobalt had been added to improve the foaming properties (Cited in F.C,T. 1972~ 10, 99), and was characterized by certain features not found in other types of cardiomyopathy, such as that induced by high alcohol consumption alone.

Though less spectacular, the latter type ofcardiomyopathy is no less important. Review- ing the problem of alcoholism in Australia, where excessive drinking is held to be respon- sible for 3~,o of all deaths, Laurie (Med. J. Aust. 1971, 1, 1224) suggested that cardiomyo- pathy due to a very high intake of alcohol was probably an underestimated factor in mor- bidity, since it could easily go undetected in autopsies following sudden death. Alcoholic cardiomyopathy is a common, though not invariable, complication of heavy or prolonged drinking and, according to Laurie (loc. cir.), this is attributable in most cases to a direct toxic action on the myocardium, nutritional deficiency and cobalt toxicity being involved only in relatively rare and special cases. In some instances, ethanol produces a microscopi- cally visible fibrosis affecting the left and sometimes also the right ventricle, and the myo- cardium becomes oedematous and vacuolated, with fatty degeneration and an increase in interstitial tissue (Laurie, Ioc. cit.).

The cause of alcoholic cardiomyopathy is disputed. Burch & Giles (Am. J. Med. 1971, 50, 141) believe that it is produced by chronic damage to the myocardium brought about by important changes in metabolism. Electron microscopy of affected myocardial tissue has revealed marked mitochondrial swelling with fragmentation of the cristae, swelling of the sarcoplasmic reticulum and disruption of myofibrils. Increased numbers of lysosomes and granules oflipofuscin and other pigments are distributed throughout the myocardium, and histochemical studies have demonstrated deposits of lipids, particularly triglycerides, within the myocardial fibres together with severe enzyme depletion. While such toxic changes follow chronic alcohol abuse in the absence of nutritional deficiencies (Burch & Giles, loc. cit.), they constitute a non-specific response which is found in various other dis- eases. In its early stages alcoholic cardiomyopathy is reversible, but when advanced it can only be treated by prolonged bed rest in conjunction with conventional therapy for con- gestive heart failure.

Shanoff (Can. reed. Ass. J. 1972, 106, 55), who considered that relatively few heavy chronic drinkers developed cardiomyopathy, suggested that this lesion was explicable on the grounds of an individual susceptibility. The disease process starts with severe damage to heart muscle produced by high ethanol concentrations, and this is followed by marked heart dilatation and an increase in wall tension, which the ventricles are unable to over- come. Thus, according to Shanoff(loc. cit.), it is the inadequacy of the usual compensatory mechanism of hypertrophy that leads to progressive and intractable ventricular failure in such individuals, most of them middle-aged men who have been drinking heavily for years.