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2786. Effect of diet on nitrite-induced methaemoglobinaemia
142
Emulsifiersand stabilizers,Preservatives
Studies in pregnant mice (Cited in F.C.T. 1967, 5, 723) and rats (Grote & Gunther, Arzneimittel-Forsch. 1971, 21, 2016) yielded no evidence that coumarin administered orally either alone or combined with rutin had any teratogenic potential. Support for these negative findings has now been obtained in a third species treated by a different route. White New Zealand rabbits were given a daily iv injection of coumarin or the coumarin-rutin combination "equivalent to 10 or 100 times the therapeutic dose" on days 6-18 of gestation. Control groups were given the dosage vehicle (10% 1,2-propylene glycol) or remained untreated. Body weight and food and water intake by the pregnant rabbits was unaffected by the treatment. The rabbits were killed on day 29 of gestation and the test and control groups showed no differences in the numbers of resorptions and dead foetuses or in foetal or placental weights. The incidence of malformations was not increased by any of the treatments, being 3.7 and 1"1% in the untreated and vehicle-treated controls, respectively, 4-0 and 4.6% in the groups given the lower doses of the two test materials and 1.1 and 1-6% in those given the higher doses. Earlier work in these animals had established a spontaneous malformation rate of 3.4%.
EMULSIFIERS AND STABILIZERS 2785. Delayed hypersensitivity reaction to carrageenan Mizushima, Y. & Noda, M. (1973). Induction of delayed hypersensitivity by carrageenan. Experientia 29, 605. Carrageenan is known to interfere with various aspects of the immune response and, in this connexion, the importance of its cytotoxic effect on macrophages has been demonstrated (Cited in F.C.T. 1973, 11, 1141). Carrageenan has also been shown to elicit a delayed hypersensitivity reaction in guinea-pigs (Mizushima & Noda, cited above). Male guinea-pigs weighing 300-500 g were sensitized by intradermal injection of 0-0251.5 mg carrageenan suspended in saline. Some 2-3 wk later, 0.05 ml of a 0.5-0.05% carrageenan suspension was injected into the skin on the opposite side of the back. A weak skin reaction developed 5 hr after this challenge injection both in the sensitized animals and, to the same degree, in non-sensitized controls. The following day, however, the sensitized animals showed an intensive erythema frequently associated with a pale central area, bleeding and induration and persisting for more than 72 hr. Granulomas consisting mainly of lymphoid cells and scattered giant cells were demonstrated at 48 and 72 hr, and systemic passive transfer studies using peritoneal exudate cells from carrageenan-sensitized guineapigs showed the reaction to be a typical delayed-type hypersensitivity.
PRESERVATIVES 2786. Effect of diet on nitrite-induced methaemoglobinaemia Stoewsand, G. S., Anderson, J. L. & Lee, C. Y. (1973). Nitrite-induced methaemoglobinemia in guinea pigs: Influence of diets containing beets with varying amounts of nitrate, and the effect of ascorbic acid, and methionine. J. Nutr. 103, 419.
Agriculturalchemicals
143
Nitrites have come under a cloud recently because of their ability to produce nitrosamines by reaction with secondary amines (Cited in F.C.T. 12, 156). A longer-established hazard is the methaemoglobinaemia induced by high levels of nitrites, which may be formed from nitrates by bacterial action during food storage or in the alimentary tract (ibid 1967, 5, 425). Vitamin A supplementation may alleviate the toxic effects of nitrites (ibid 1969, 7, 543) and some protection against methaemoglobinaemia may also be afforded by methionine (Mortensen, Archs Biochem. Biophys. 1953, 46, 241) and ascorbic acid (Kociba & Sleight, Toxic. appl. Pharmac. 1970, 16, 424), although some workers have reported negative results with the latter compound (Bolyai et al. ibid 1972, 21, 176; Kilgore et al. Am. J. clin. Nutr. 1964, 14, 52). Stoewsand et al. (cited above) maintained young, male guinea-pigs on beet-supplemented diets containing either 242 or 1998 ppm nitrate-nitrogen, the higher level being the result of application of an ammonium nitrate fertilizer to the growing beets. Other guineapigs were fed a purified diet coiltaining 148 or 1798 ppm nitrate-nitrogen. The nitritenitrogen content of all four diets was in the 1.7-4"0 ppm range. After 2.5 4 wk, the blood levels of methaemoglobin in the four groups did not differ significantly, all falling in the range of 1.(L1.8~o of the total haemoglobin. However, methaemoglobin levels were significantly increased by the oral administration of 7-6 or 15.0 mg nitrite/kg body weight. The effect of the lower nitrite dose was more severe in animals receiving a high-nitrate diet~ and with the higher dose of nitrite animals on the low-nitrate beet diet were much less severely affect, d than the other three groups (having a mean methaemoglobin level of 27% compared with 44~46%). With a nitrite dose as high as 22"8 mg/kg, the methaemoglobin levels of all four groups were approximately 60%, but mortality was lower in the group fed the low-nitrate beet diet than in the other groups. These findings suggested that nitrate could greatly exacerbate the effects of nitrite and that some factor present in the beet diet could give some degree of protection against nitrite toxicity. In a second experiment, guinea-pigs were fed an isolated soya-bean protein diet supplemented with 0, 0"02 or 1.0% ascorbic acid and/or 0 or 1-0% methionine. The methaemoglobinaemia induced by a dose of 7.6 mg nitrite/kg was less severe in the animals given ascorbic acid at the 1.0% than at the 0"02% level and an additional 50% reduction was obtained when the diet contained 1% levels of both ascorbic acid and methionine. Increasing the level of each additive to 2%, however, brought about no further reduction in the nitriteinduced methaemoglobinaemia.
AGRICULTURAL CHEM ICALS
2787. Ironing out carbaryl discrepancies Weil, C. S., Woodside, M. D., Bernard, J. B., Condra, N. I., King, J. M. & Carpenter, C. P. (1973). Comparative effect of carbaryl on rat reproduction and guinea-pig teratology when fed either in the diet or by stomach intubation. Toxic. appl. Pharmac. 26, 621. Recent publications have brought to light the relative rarity of studies comparing the effects resulting from dietary and garage administration of a given test material. One such study has been carried out on carbaryl (N-methyl-l-naphthylcarbamate) by the authors named above. Discrepancies have been noted in the results of different studies on the effect of this insecticide on animal reproduction and in assessments of its teratogenic potential I-.('.T. I ] , ' l
J
Emulsifiersand stabilizers,Preservatives
Studies in pregnant mice (Cited in F.C.T. 1967, 5, 723) and rats (Grote & Gunther, Arzneimittel-Forsch. 1971, 21, 2016) yielded no evidence that coumarin administered orally either alone or combined with rutin had any teratogenic potential. Support for these negative findings has now been obtained in a third species treated by a different route. White New Zealand rabbits were given a daily iv injection of coumarin or the coumarin-rutin combination "equivalent to 10 or 100 times the therapeutic dose" on days 6-18 of gestation. Control groups were given the dosage vehicle (10% 1,2-propylene glycol) or remained untreated. Body weight and food and water intake by the pregnant rabbits was unaffected by the treatment. The rabbits were killed on day 29 of gestation and the test and control groups showed no differences in the numbers of resorptions and dead foetuses or in foetal or placental weights. The incidence of malformations was not increased by any of the treatments, being 3.7 and 1"1% in the untreated and vehicle-treated controls, respectively, 4-0 and 4.6% in the groups given the lower doses of the two test materials and 1.1 and 1-6% in those given the higher doses. Earlier work in these animals had established a spontaneous malformation rate of 3.4%.
EMULSIFIERS AND STABILIZERS 2785. Delayed hypersensitivity reaction to carrageenan Mizushima, Y. & Noda, M. (1973). Induction of delayed hypersensitivity by carrageenan. Experientia 29, 605. Carrageenan is known to interfere with various aspects of the immune response and, in this connexion, the importance of its cytotoxic effect on macrophages has been demonstrated (Cited in F.C.T. 1973, 11, 1141). Carrageenan has also been shown to elicit a delayed hypersensitivity reaction in guinea-pigs (Mizushima & Noda, cited above). Male guinea-pigs weighing 300-500 g were sensitized by intradermal injection of 0-0251.5 mg carrageenan suspended in saline. Some 2-3 wk later, 0.05 ml of a 0.5-0.05% carrageenan suspension was injected into the skin on the opposite side of the back. A weak skin reaction developed 5 hr after this challenge injection both in the sensitized animals and, to the same degree, in non-sensitized controls. The following day, however, the sensitized animals showed an intensive erythema frequently associated with a pale central area, bleeding and induration and persisting for more than 72 hr. Granulomas consisting mainly of lymphoid cells and scattered giant cells were demonstrated at 48 and 72 hr, and systemic passive transfer studies using peritoneal exudate cells from carrageenan-sensitized guineapigs showed the reaction to be a typical delayed-type hypersensitivity.
PRESERVATIVES 2786. Effect of diet on nitrite-induced methaemoglobinaemia Stoewsand, G. S., Anderson, J. L. & Lee, C. Y. (1973). Nitrite-induced methaemoglobinemia in guinea pigs: Influence of diets containing beets with varying amounts of nitrate, and the effect of ascorbic acid, and methionine. J. Nutr. 103, 419.
Agriculturalchemicals
143
Nitrites have come under a cloud recently because of their ability to produce nitrosamines by reaction with secondary amines (Cited in F.C.T. 12, 156). A longer-established hazard is the methaemoglobinaemia induced by high levels of nitrites, which may be formed from nitrates by bacterial action during food storage or in the alimentary tract (ibid 1967, 5, 425). Vitamin A supplementation may alleviate the toxic effects of nitrites (ibid 1969, 7, 543) and some protection against methaemoglobinaemia may also be afforded by methionine (Mortensen, Archs Biochem. Biophys. 1953, 46, 241) and ascorbic acid (Kociba & Sleight, Toxic. appl. Pharmac. 1970, 16, 424), although some workers have reported negative results with the latter compound (Bolyai et al. ibid 1972, 21, 176; Kilgore et al. Am. J. clin. Nutr. 1964, 14, 52). Stoewsand et al. (cited above) maintained young, male guinea-pigs on beet-supplemented diets containing either 242 or 1998 ppm nitrate-nitrogen, the higher level being the result of application of an ammonium nitrate fertilizer to the growing beets. Other guineapigs were fed a purified diet coiltaining 148 or 1798 ppm nitrate-nitrogen. The nitritenitrogen content of all four diets was in the 1.7-4"0 ppm range. After 2.5 4 wk, the blood levels of methaemoglobin in the four groups did not differ significantly, all falling in the range of 1.(L1.8~o of the total haemoglobin. However, methaemoglobin levels were significantly increased by the oral administration of 7-6 or 15.0 mg nitrite/kg body weight. The effect of the lower nitrite dose was more severe in animals receiving a high-nitrate diet~ and with the higher dose of nitrite animals on the low-nitrate beet diet were much less severely affect, d than the other three groups (having a mean methaemoglobin level of 27% compared with 44~46%). With a nitrite dose as high as 22"8 mg/kg, the methaemoglobin levels of all four groups were approximately 60%, but mortality was lower in the group fed the low-nitrate beet diet than in the other groups. These findings suggested that nitrate could greatly exacerbate the effects of nitrite and that some factor present in the beet diet could give some degree of protection against nitrite toxicity. In a second experiment, guinea-pigs were fed an isolated soya-bean protein diet supplemented with 0, 0"02 or 1.0% ascorbic acid and/or 0 or 1-0% methionine. The methaemoglobinaemia induced by a dose of 7.6 mg nitrite/kg was less severe in the animals given ascorbic acid at the 1.0% than at the 0"02% level and an additional 50% reduction was obtained when the diet contained 1% levels of both ascorbic acid and methionine. Increasing the level of each additive to 2%, however, brought about no further reduction in the nitriteinduced methaemoglobinaemia.
AGRICULTURAL CHEM ICALS
2787. Ironing out carbaryl discrepancies Weil, C. S., Woodside, M. D., Bernard, J. B., Condra, N. I., King, J. M. & Carpenter, C. P. (1973). Comparative effect of carbaryl on rat reproduction and guinea-pig teratology when fed either in the diet or by stomach intubation. Toxic. appl. Pharmac. 26, 621. Recent publications have brought to light the relative rarity of studies comparing the effects resulting from dietary and garage administration of a given test material. One such study has been carried out on carbaryl (N-methyl-l-naphthylcarbamate) by the authors named above. Discrepancies have been noted in the results of different studies on the effect of this insecticide on animal reproduction and in assessments of its teratogenic potential I-.('.T. I ] , ' l
J