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1825. Mainly on coumarin
FLAVOURINGS, SOLVENTS AND SWEETENERS
681
males with thyroiditis. Histologically, the glands showed invasion of lymphocytes, plasma cells and occasional haemosiderin-containing macrophages into the interstitium and later into the basement membrane of the acini. Hyperplastic epithelial acinar cells eventually obscured many of the lumina. In addition, four males and one female without thyroiditis had cysts, with flattened epithelial lining cells and sloughed cells in the lumina. Histological changes were also found in the pituitaries, adrenals, lymph nodes, spleen, the portal areas of the liver and the distal convoluted tubules of the kidney. The mechanism of the effect of I on the thyroid is still obscure. It has been suggested that I may compete with thyroxine for serum protein binding sites. The thyroxine would then inhibit the secretion of thyroid-stimulating hormone (TSH) and result in decreased functioning of the thyroid gland (Shimoda et al. Endocrinology 1962, 71, 414; Yamada, ibid 1960, 67, 204). On the other hand, Christie (J. Anat. 1964, 98, 377) suggested that I increased the secretion of TSH and inhibited the release of thyroglobulin from the thyroid gland.
FLAVOURINGS, SOLVENTS AND SWEETENERS 1825. Mainly on coumarin Bar, F. & Griepentrog, F. (1967). Die Situation in der gesundheitlichen Beurteilung der Aromatisierungsmittel fiir Lebensmittel. Medizin Erniihr. 8, 244. Shilling, W. H., Crampton, R. F. & Longland, R. C. (1969). Metabolism of coumarin in man. Nature, Lond. 221,664. Coumarin (I) is known to cause liver damage at high levels in rats (Cited in F.C.T. 1969, 7, 261). The occurrence of bile-duct carcinoma in this species following treatment with I has been reported by Bar & Griepentrog (first paper cited above), who fed I, allyl caproate (II), ethyl methylphenyl glycidate (III), methyl heptine carbonate (IV), 7-undecalactone, 9'nonalactone, resorcinol dimethyl ether, hydroxycitronellal or piperonal to groups of rats at dietary levels of 1000 or 5000 ppm for 2 yr. Appearance, behaviour and weight gain were observed and the liver, kidneys, adrenals, heart, spleen, pancreas and brain from animals dying during the experiment or killed after 2 yr were examined histologically. Of the rats surviving a diet containing 5000 ppm I for 18 months or more, 11/12 males and 1/12 females developed bile-duct carcinomas. Extra-hepatic metastasis was only slight, but considerable enlargement and destruction of the liver parenchyma occurred. Some bile-duct proliferation and benign bile-duct adenomas were also observed. In the case of rats receiving 5000 ppm II, multiple bile-duct adenomas and proliferation of the small bile ducts occurred in 5/25 animals surviving a minimum of 18 months, while another animal developed an adenoma after less than 9 months. Several rats receiving III developed paresis of the hind extremities with corresponding degeneration of the sciatic nerves. Further work is in progress on both II and III, as the small numbers of animals used prevented an accurate evaluation of results. IV caused only growth retardation at the 5000 ppm level, while the other compounds tested had no adverse effects at the levels given. The second paper cited above reports a metabolic study in four men and four women volunteers given a single oral dose of 200 mg I. Urine was collected on the day preceding and on the two days following treatment. In the day 1 urine, 68-92 70 of the I administered was excreted as 7-hydroxycoumarin (V) and 1-6 70 as o-hydroxyphenylacetic acid (VI). No significant quantities of either compound could be detected in the control or day 2 urines. This indicated that, in man, I is rapidly absorbed by the gut and any enterohepatic circulation of
682
FLAVOURINGS, SOLVENTS AND SWEETENERS
I or its metabolites is unlikely. These results emphasize the weakness of animal toxicity data alone as a basis for human assessment. It has been shown (Kaighen & Williams, J. mednl pharm. Chem. 1961, 3, 25) that rats excrete less than 1 ~o of a dose of I as V and about 2 0 ~ as VI in the urine, while a further 40 ~o is eliminated as unidentified compounds in the faeces. Inhibition of glucose 6-phosphatase in human and rat liver, an indication of toxic damage, has been produced by VI but not by I or V (Feuer et al. Fd Cosmet. Toxicol. 1966, 4, 157). The hepatotoxicity of I in rats can therefore be attributed to the major metabolite of I in that species and has little relevance to the safety of I for use as a flavouring in human foods, since the metabolic route terminating in VI is a very minor one for man. [Hagan et al. (Fd Cosmet. Toxicol. 1967, 5, 141), found that a dietary level of 5000 ppm I in rats caused focal proliferation of bile ducts of atypical appearance with associated fibrosis. The photographs published by B~r & Griepentrog (cited above) are consistent with this diagnosis and do not appear to support a theory of malignant growth. The written description, too, contains no clear indication as to why a diagnosis of carcinoma was made.] 1826. MSG hits the brain
Olney, J. W. (1969). Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science, N . Y . 164, 719. Monosodium glutamate (MSG) has been shown to be the culprit in the 'Chinese restaurant syndrome', but few studies have been conducted on the basic mechanisms involved (Cited in F.C.T. 1969, 7, 384). Prompted by the observations that MSG administered parenterally to neonatal mice produced retinal lesions (Lucas & Newhouse, A.M.A. Archs Ophthal. 1957, 58, 193) and obesity (Cohen, Am. J. Anat. 1967, 120, 319), Olney (cited above) has studied the effects of MSG on the developing brain. When mice, 2-9 days old, were given one subcutaneous injection of 0.5-4 g MSG/kg, intracellular oedema and neuronal necrosis developed within a few hours in several regions of the brain, including the hypothalamus. Acute brain lesions were also found in adult mice given 5-7 g/kg subcutaneously and in newborn rats given unspecified doses of MSG. Mice given MSG subcutaneously (also in unspecified doses) on each of days 1-10 after birth were smaller than the untreated controls at the termination of treatment, but by day 45 their weight had surpassed that of the controls, although their food consumption remained lower throughout. The weight gain was proportionately greater in females than in males. Despite excessive weight, adults in the test group were on average 10 ~o shorter than the controls and their general condition was poor. At 5-9 months the females were sterile, but treated males mated normally and produced normal offspring. The uteri were found to be poorly developed when the treated animals were autopsied at 9 months and there were about double the normal number of atretic follicles in the ovaries. Autopsy also revealed massive accumulations of adipose tissue and fatty changes in the liver. In the pituitary, an overall reduction in mass and in the number of cells was apparent in the anterior lobe. Indications of a mild adrenocortical hypertrophy are undergoing further study. Other mice given 3 g MSG/kg in a single subcutaneous injection 2 days after birth were about 17 g heavier than litter-mate controls at 9 months. Together, these findings suggest a complex endocrine disturbance resulting from neonatal disruption of neuronal development in the neuroendocrine regulatory centres of the brain. Since acute degenerative changes were not found in neonatal pituitary glands, the small size of these glands in adults may indicate an interference with the effect of the hypothalamus on their development. As the primate placenta maintains a level of glutamic acid in the foetal
681
males with thyroiditis. Histologically, the glands showed invasion of lymphocytes, plasma cells and occasional haemosiderin-containing macrophages into the interstitium and later into the basement membrane of the acini. Hyperplastic epithelial acinar cells eventually obscured many of the lumina. In addition, four males and one female without thyroiditis had cysts, with flattened epithelial lining cells and sloughed cells in the lumina. Histological changes were also found in the pituitaries, adrenals, lymph nodes, spleen, the portal areas of the liver and the distal convoluted tubules of the kidney. The mechanism of the effect of I on the thyroid is still obscure. It has been suggested that I may compete with thyroxine for serum protein binding sites. The thyroxine would then inhibit the secretion of thyroid-stimulating hormone (TSH) and result in decreased functioning of the thyroid gland (Shimoda et al. Endocrinology 1962, 71, 414; Yamada, ibid 1960, 67, 204). On the other hand, Christie (J. Anat. 1964, 98, 377) suggested that I increased the secretion of TSH and inhibited the release of thyroglobulin from the thyroid gland.
FLAVOURINGS, SOLVENTS AND SWEETENERS 1825. Mainly on coumarin Bar, F. & Griepentrog, F. (1967). Die Situation in der gesundheitlichen Beurteilung der Aromatisierungsmittel fiir Lebensmittel. Medizin Erniihr. 8, 244. Shilling, W. H., Crampton, R. F. & Longland, R. C. (1969). Metabolism of coumarin in man. Nature, Lond. 221,664. Coumarin (I) is known to cause liver damage at high levels in rats (Cited in F.C.T. 1969, 7, 261). The occurrence of bile-duct carcinoma in this species following treatment with I has been reported by Bar & Griepentrog (first paper cited above), who fed I, allyl caproate (II), ethyl methylphenyl glycidate (III), methyl heptine carbonate (IV), 7-undecalactone, 9'nonalactone, resorcinol dimethyl ether, hydroxycitronellal or piperonal to groups of rats at dietary levels of 1000 or 5000 ppm for 2 yr. Appearance, behaviour and weight gain were observed and the liver, kidneys, adrenals, heart, spleen, pancreas and brain from animals dying during the experiment or killed after 2 yr were examined histologically. Of the rats surviving a diet containing 5000 ppm I for 18 months or more, 11/12 males and 1/12 females developed bile-duct carcinomas. Extra-hepatic metastasis was only slight, but considerable enlargement and destruction of the liver parenchyma occurred. Some bile-duct proliferation and benign bile-duct adenomas were also observed. In the case of rats receiving 5000 ppm II, multiple bile-duct adenomas and proliferation of the small bile ducts occurred in 5/25 animals surviving a minimum of 18 months, while another animal developed an adenoma after less than 9 months. Several rats receiving III developed paresis of the hind extremities with corresponding degeneration of the sciatic nerves. Further work is in progress on both II and III, as the small numbers of animals used prevented an accurate evaluation of results. IV caused only growth retardation at the 5000 ppm level, while the other compounds tested had no adverse effects at the levels given. The second paper cited above reports a metabolic study in four men and four women volunteers given a single oral dose of 200 mg I. Urine was collected on the day preceding and on the two days following treatment. In the day 1 urine, 68-92 70 of the I administered was excreted as 7-hydroxycoumarin (V) and 1-6 70 as o-hydroxyphenylacetic acid (VI). No significant quantities of either compound could be detected in the control or day 2 urines. This indicated that, in man, I is rapidly absorbed by the gut and any enterohepatic circulation of
682
FLAVOURINGS, SOLVENTS AND SWEETENERS
I or its metabolites is unlikely. These results emphasize the weakness of animal toxicity data alone as a basis for human assessment. It has been shown (Kaighen & Williams, J. mednl pharm. Chem. 1961, 3, 25) that rats excrete less than 1 ~o of a dose of I as V and about 2 0 ~ as VI in the urine, while a further 40 ~o is eliminated as unidentified compounds in the faeces. Inhibition of glucose 6-phosphatase in human and rat liver, an indication of toxic damage, has been produced by VI but not by I or V (Feuer et al. Fd Cosmet. Toxicol. 1966, 4, 157). The hepatotoxicity of I in rats can therefore be attributed to the major metabolite of I in that species and has little relevance to the safety of I for use as a flavouring in human foods, since the metabolic route terminating in VI is a very minor one for man. [Hagan et al. (Fd Cosmet. Toxicol. 1967, 5, 141), found that a dietary level of 5000 ppm I in rats caused focal proliferation of bile ducts of atypical appearance with associated fibrosis. The photographs published by B~r & Griepentrog (cited above) are consistent with this diagnosis and do not appear to support a theory of malignant growth. The written description, too, contains no clear indication as to why a diagnosis of carcinoma was made.] 1826. MSG hits the brain
Olney, J. W. (1969). Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science, N . Y . 164, 719. Monosodium glutamate (MSG) has been shown to be the culprit in the 'Chinese restaurant syndrome', but few studies have been conducted on the basic mechanisms involved (Cited in F.C.T. 1969, 7, 384). Prompted by the observations that MSG administered parenterally to neonatal mice produced retinal lesions (Lucas & Newhouse, A.M.A. Archs Ophthal. 1957, 58, 193) and obesity (Cohen, Am. J. Anat. 1967, 120, 319), Olney (cited above) has studied the effects of MSG on the developing brain. When mice, 2-9 days old, were given one subcutaneous injection of 0.5-4 g MSG/kg, intracellular oedema and neuronal necrosis developed within a few hours in several regions of the brain, including the hypothalamus. Acute brain lesions were also found in adult mice given 5-7 g/kg subcutaneously and in newborn rats given unspecified doses of MSG. Mice given MSG subcutaneously (also in unspecified doses) on each of days 1-10 after birth were smaller than the untreated controls at the termination of treatment, but by day 45 their weight had surpassed that of the controls, although their food consumption remained lower throughout. The weight gain was proportionately greater in females than in males. Despite excessive weight, adults in the test group were on average 10 ~o shorter than the controls and their general condition was poor. At 5-9 months the females were sterile, but treated males mated normally and produced normal offspring. The uteri were found to be poorly developed when the treated animals were autopsied at 9 months and there were about double the normal number of atretic follicles in the ovaries. Autopsy also revealed massive accumulations of adipose tissue and fatty changes in the liver. In the pituitary, an overall reduction in mass and in the number of cells was apparent in the anterior lobe. Indications of a mild adrenocortical hypertrophy are undergoing further study. Other mice given 3 g MSG/kg in a single subcutaneous injection 2 days after birth were about 17 g heavier than litter-mate controls at 9 months. Together, these findings suggest a complex endocrine disturbance resulting from neonatal disruption of neuronal development in the neuroendocrine regulatory centres of the brain. Since acute degenerative changes were not found in neonatal pituitary glands, the small size of these glands in adults may indicate an interference with the effect of the hypothalamus on their development. As the primate placenta maintains a level of glutamic acid in the foetal