NTP toxicology and carcinogenesiss studies of citral (microencapsulated) (CAS No. 5392-40-5) in F344/N rats and B6C3F1 mice (feed studies).
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Citral is used primarily as lemon flavoring in foods, beverages, and candies. It is also used as a lemon fragrance in detergents, perfumes, and other toiletries. Citral was nominated by the National Cancer Institute for study because of its widespread use in foods, beverages, cosmetics, and other consumer products and its structure as a representative beta-substituted vinyl aldehyde. Male and female F344/N rats and B6C3F1 mice were exposed to microencapsulated citral (greater than 96% pure) in feed for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, mouse bone marrow cells, and mouse peripheral blood erythrocytes. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing starch microcapsules with a load of 31.3% citral. The concentration of citral in the diet was 3,900, 7,800, 15,600, or 31,300 ppm microencapsulated citral (equivalent to average daily doses of approximately 345, 820, 1,785, and 1,585 mg citral/kg body weight to males and 335, 675, 1,330, and 2,125 mg/kg to females) for 14 weeks. Additional groups of 10 male and 10 female rats received untreated feed (untreated controls) or feed containing placebo microcapsules (vehicle controls). In the second week of the study, all rats in the 31,300 ppm groups were killed moribund. Mean body weights of exposed males and females that survived to the end of the study were generally significantly less than those of the vehicle controls. Feed consumption by 15,600 and 31,300 ppm males and females was less than that by the vehicle controls during the first week of the study. Males and females in the 31,300 ppm groups exhibited listlessness, hunched posture, absent or slow paw reflex, and dull eyes. Exposure of rats to citral may have been associated with forestomach epithelial hyperplasia and hyperkeratosis, bone marrow atrophy and hemorrhage, and nephrotoxicity. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were fed diets containing 3,900, 7,800, 15,600, or 31,300 ppm microencapsulated citral (equivalent to average daily doses of approximately 745, 1,840, 3,915, and 8,110 mg/kg to males and 790, 1,820, 3,870, and 7,550 mg/kg to females) for 14 weeks. Additional groups of 10 male and 10 female mice received untreated feed (untreated controls) or feed containing placebo microcapsules (vehicle controls). In the second week of the study, four males in the 31,300 ppm group were killed moribund. Mean body weights of all exposed groups of males and females were significantly less than those of the vehicle controls. Feed consumption by females exposed to 7,800 ppm or greater was less than that by the vehicle controls during the first week of the study. By the end of the study, feed consumption by all exposed groups was greater than that by the vehicle controls. Mice in the 15,600 and 31,300 ppm groups were generally thin and lethargic; a few males in the 7,800 ppm group were also thin. The incidences of ovarian atrophy were significantly increased in females exposed to 15,600 or 31,300 ppm. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were fed diets containing 1,000, 2,000, or 4,000 ppm microencapsulated citral for 2 years. Additional groups of 50 male and 50 female rats received untreated feed (untreated controls) or feed containing placebo microcapsules (vehicle controls). Dietary concentrations of 1,000, 2,000, and 4,000 ppm delivered average daily doses of approximately 50, 100, and 210 mg/kg to males and females. Survival of all exposed groups of males was significantly greater than that of the vehicle control group. Mean body weights of rats exposed to 4,000 ppm were generally less than those of the vehicle controls from week 49 (males) or 25 (females) to the end of the study. Feed consumption by exposed groups was similar to that by the vehicle controls. No neoplasms or nonneoplastic lesions were attributed to exposure to citral. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F1 mice were fed diets containing 500, 1,000, or 2,000 ppm microencapsulated citral for 2 years. Additional groups of 50 male and 50 female mice received untreated feed (untreated controls) or feed containing placebo microcapsules (vehicle controls). Dietary concentrations of 500, 1,000, and 2,000 ppm delivered average daily doses of approximately 60, 120, and 260 mg/kg to males and females. Survival of exposed males and females was similar to that of the vehicle control groups. Mean body weights of mice exposed to 1,000 or 2,000 ppm were generally less than those of the vehicle controls throughout the study, and mean body weights of 500 ppm females were less from week 30 to the end of the study. Feed consumption by the exposed groups was similar to that by the vehicle controls. The incidences of malignant lymphoma occurred with a positive trend in female mice, and the incidence in 2,000 ppm females was significantly greater than that in the vehicle control group. Tissues most commonly affected by malignant lymphoma were the spleen, mesenteric lymph node, thymus, and, to a lesser extent, the ovary. GENETIC TOXICOLOGY: Citral was not mutagenic in S. typhimurium strain TA98, TA100, TA1535, or TA1537 with or without induced rat or hamster liver S9 enzymes. In cytogenetic tests with cultured Chinese hamster ovary cells, citral induced sister chromatid exchanges with and without S9, but chromosomal aberrations were not significantly increased after exposure to citral, with or without S9. Negative results were obtained in an in vivo bone marrow micronucleus test in male B6C3F1 mice treated by intraperitoneal injection with 250 to 750 mg/kg daily for 3 days. Likewise, no increases in the frequencies of micronucleated erythrocytes were observed in peripheral blood samples collected from male and female mice within 24 hours of the final exposure in the 14-week study. In conclusion, citral gave negative results in in vitro and in vivo tests for genotoxicity, with the exception of the in vitro mammalian cell test for sister chromatid exchange induction CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of citral in male or female F344/N rats exposed to 1,000, 2,000, or 4,000 ppm. There was no evidence of carcinogenic activity of citral in male B6C3F1 mice exposed to 500, 1,000, or 2,000 ppm. There was equivocal evidence of carcinogenic activity in female B6C3F1 mice based on increased incidences of malignant lymphoma. (+info)
Tumoricidal activity of lauryl gallate towards chemically induced skin tumours in mice.
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Lauryl gallate (antioxidant food additive E-312) prevents the formation of dimethylbenzanthracene-induced skin tumours in mice, and kills, selectively, tumoral cells on established tumours. This results in total remission, after topical application of the compound on the tumoral mass, without affecting the surrounding tissue. (+info)
Antimicrobial growth promoters used in animal feed: effects of less well known antibiotics on gram-positive bacteria.
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There are not many data available on antibiotics used solely in animals and almost exclusively for growth promotion. These products include bambermycin, avilamycin, efrotomycin, and the ionophore antibiotics (monensin, salinomycin, narasin, and lasalocid). Information is also scarce for bacitracin used only marginally in human and veterinary medicine and for streptogramin antibiotics. The mechanisms of action of and resistance mechanisms against these antibiotics are described. Special emphasis is given to the prevalence of resistance among gram-positive bacteria isolated from animals and humans. Since no susceptibility breakpoints are available for most of the antibiotics discussed, an alternative approach to the interpretation of MICs is presented. Also, some pharmacokinetic data and information on the influence of these products on the intestinal flora are presented. (+info)
Improved net protein balance, lean mass, and gene expression changes with oxandrolone treatment in the severely burned.
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OBJECTIVE: To determine the effects of the anabolic agent oxandrolone on muscle protein and gene expression in severely burned children. SUMMARY BACKGROUND DATA: The authors previously showed that oxandrolone increased net muscle protein synthesis in emaciated burned patients receiving delayed treatment for severe burns. They hypothesized that similar effects would be seen in those treated early after burn. METHODS: Thirty-two severely burned children were enrolled in a prospective randomized trial. Subjects underwent studies to assess leg protein net balance 5 days after the first excision and grafting procedure. Immediately after these studies, treatment with placebo (n = 18) or 0.1 mg/kg oxandrolone (n = 14) twice a day was started. One week after this, another net balance study was performed in each subject. Body weights and total body potassium counting were used to determine body compositional changes. Muscle biopsies were taken 1 week after treatment in oxandrolone subjects to examine gene expression changes with gene array (12,600 genes). RESULTS: Protein net balance did not change in the placebo group, while oxandrolone-treated subjects had a significant improvement. Body weights and fat free mass significantly decreased in the placebo group, while no changes were found in the oxandrolone-treated subjects. Expression changes were seen in 14 genes in the oxandrolone group compared to placebo. Some of these included myosin light chain (+2.7-fold change), tubulin (+2.3), calmodulin (-2.3), and protein phosphatase I inhibitor (-2.8). CONCLUSIONS: Oxandrolone improves protein net balance and lean mass in the severely burned. These changes are associated with increased gene expression for functional muscle proteins. (+info)
Effects of carrageenans on the binding, phagocytotic, and killing abilities of macrophages to salmonella.
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The effects of carrageenans (CGNs) on the host defense mechanisms of macrophages against Salmonella infection were examined in vitro by using macrophage-like J774.1 cells. Iota-CGN reduced the Salmonella-binding and phagocytotic activities of J774.1 cells, but it increased the killing activity of the cells. Kappa-CGN increased the binding activity, but reduced the killing ability. CGNs would affect the host defense mechanisms by modulating the macrophage functions. (+info)
Estimation of inorganic food additive (nitrite, nitrate and sulfur dioxide), antioxidant (BHA and BHT), processing agent (propylene glycol) and sweetener (sodium saccharin) concentrations in foods and their daily intake based on official inspection results in Japan in fiscal year 1998.
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The mean concentration and daily intake of inorganic food additives (nitrite, nitrate, and sulfur dioxide), antioxidants (BHA and BHT), a processing agent (propylene glycol), and a sweetener (sodium saccharin) were estimated based on the results of an analysis of 34,489 food samples obtained in official inspections by 106 local governments in Japan in fiscal year 1998. The ratios of mean concentrations of these seven food additives to each allowable limit were 20.0%, 53.9%, 15.5%, 6.2%, 0.4%, 18.5%, and 5.7%, respectively. The daily intakes of these food additives estimated from their concentrations in foods and the daily consumption of foods were 0.205, 0.532, 4.31, 0.119, 0.109, 77.5, and 7.27 mg per person, respectively. These amounts were 6.8%, 0.3%, 12.3%, 0.5%, 0.7%, 6.2%, and 2.6% of the acceptable daily intake (ADI), respectively, when body weight was assumed to be 50 kg. No remarkable differences in the daily intakes of these seven food additives or the ratios to the ADI were observed compared with the results based on the official inspections in fiscal years 1994 and 1996. (+info)
Neuroendocrine alterations impair enamel mineralization, tooth eruption and saliva in rats.
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Neonatal administration of monosodium glutamate (MSG) in rats causes definite neuroendocrine disturbances which lead to alterations in many organ systems. The possibility that MSG could affect tooth and salivary gland physiology was examined in this paper. Male and female pups were injected subcutaneously with MSG (4 mg/g BW) once a day at the 2nd, 4th, 6th, 8th and 10th day after birth. Control animals were injected with saline, following the same schedule. Lower incisor eruption was determined between the 4th and the 10th postnatal days, and the eruption rate was measured between the 43rd and the 67th days of age. Pilocarpine-stimulated salivary flow was measured at 3 months of age; protein and amylase contents were thereby determined. The animals treated with MSG showed significant reductions in the salivary flow (males, -27%; females, -40%) and in the weight of submandibular glands (about -12%). Body weight reduction was only about 7% for males, and did not vary in females. Saliva of MSG-treated rats had increased concentrations of total proteins and amylase activity. The eruption of lower incisors occurred earlier in MSG-treated rats than in the control group, but on the other hand the eruption rate was significantly slowed down. The incisor microhardness was found to be lower than that of control rats. Our results show that neonatal MSG treatment causes well-defined oral disturbances in adulthood in rats, including salivary flow reduction, which coexisted with unaltered protein synthesis, and disturbances of dental mineralization and eruption. These data support the view that some MSG-sensitive hypothalamic nuclei have an important modulatory effect on the factors which determine caries susceptibility. (+info)
Effect of ingredients use in condensed and frozen dairy products on thermal resistance of potentially pathogenic staphylococci.
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A cell suspension of Staphylococcus aureus (196E) was injected into raw skim milk which contained different concentrations of sugar, serum solids, fat, stabilizers, and emulsifiers. The ingredient samples were exposed for the desired length of time in a constant-temperature water bath (60 C). Standard plate counts were made, and the number of surviving organisms was determined. Regression coefficients for each ingredient concentration were calculated and plotted against the per cent ingredient concentration to give an indication of protective action. Analyses of variance were conducted on bacterial counts to test the protective action of each ingredient. A comparison of the number of survivors in different sugar concentrations showed that with up to 14% sugar all the organisms were killed within 30 min. In sugar concentrations above 14%, the number of survivors increased regularly with each increase in sugar concentration up to 57%, which was the maximum used. In concentrations of serum solids above 9%, some organisms survived 35 min of heat treatment. Butter fat, stabilizer, and emulsifier did not offer any protective action in the concentrations observed. (+info)