Printer friendly formatBasic Research on Food Dyes & Flavorings
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Note that, while there are many studies on food colorings, there are very few on the 5000+ flavorings in food. This is due to the success of their manufacturers in convincing the U.S. Food & Drug Administration that "a little bit can't hurt" (see Kroes 2000, Kroes 2002 and Kroes 2005 below).
In reverse date order:
Lau 2006 Synergistic Interactions Between Commonly Used Food Additives in a Developmental Neurotoxicity Test. Salih 2005 Risk assessment of combined photogenotoxic effects of sunlight and food additives. Tanaka 2005 Reproductive and neurobehavioural toxicity study of tartrazine administered to mice in the diet. Kroes 2005 The threshold of toxicological concern concept in risk management. FDA 2003 Reports of blue discoloration and death in patients receiving enteral feedings tinted with the dye, FD&C Blue No. 1. Kroes 2002 Threshold of toxicological concern (TTC) in food safety assessment. Sasaki 2002 The comet assay with 8 mouse organs: results with 39 currently used food additives. Avison 2001 Infusion of volatile flavor compounds into low-density polyethylene. Flood 2001 Safety evaluation of lipase produced from Candida rugosa: summary of toxicological data. George 2001 Evaluation of the developmental toxicity of isoeugenol in Sprague-Dawley (CD) rats. Granville 2001 Blue colon at autopsy. Munro 2001 Comparison of estimated daily per capita intakes of flavouring substances with no-observed-effect levels from animal studies. Tanaka 2001 Reproductive and neurobehavioural toxicity study of erythrosine administered to mice in the diet. Tsuda 2001 DNA damage induced by red food dyes orally administered to pregnant and male mice. Ashida 2000 Synergistic effects of food colors on the toxicity of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) in primary cultured rat hepatocytes. Boutilier 2000 Green colon: an unusual appearance at autopsy. Kroes 2000 Threshold of toxicological concern for chemical substances present in the diet: a practical tool for assessing the need for toxicity testing. Maloney 2000 Systemic Absorption of Food Dye in Patients with Sepsis. World Health Org 2000 Evaluation of certain food additives. Fifty-first report of the Joint FAO/WHO Expert Committee on Food Additives. Zillich 2000 Skin discoloration with blue food coloring. DeLattre 1999 Factors contributing to adverse soft tissue reactions due to the use of tartar control toothpastes: report of a case and literature review. Lancaster 1999 Determination of benzidine in the food colours tartrazine and sunset yellow FCF, by reduction and derivatization followed by high-performance liquid chromatography. Huang 1998 Study of skin rashes after antibiotic use in young children. Koutsogeorgopoulou 1998 Immunological aspects of the common food colorants, amaranth and tartrazine. MMWR 1998 Lead poisoning associated with imported candy and powdered food coloring--California and Michigan. Munro 1998 Principles for the safety evaluation of flavouring substances. Paumgartten 1998 Study of the effects of beta-myrcene on rat fertility and general reproductive performance. Taylor 1998 Flavorings and colorings. Taylor 1998 The role of flavoring substances in food allergy and intolerance. Yagyu 1998 Smell and taste of chewing gum affect frequency domain EEG source localizations. Abdel 1997 A study on the reproductive toxicity of erythrosine in male mice. Aboel-Zahab 1997 Physiological effects of some synthetic food colouring additives on rats. Aoshima 1997 Modulation of GABA receptors expressed in Xenopus oocytes by 13-L-hydroxylinoleic acid and food additives. Dees 1997 Estrogenic and DNA-damaging activity of Red No. 3 in human breast cancer cells. Pediatrics 1997 Inactive" ingredients in pharmaceutical products: update (subject review). American Academy of Pediatrics Committee on Drugs. Yagyu 1997 Chewing-gum flavor affects measures of global complexity of multichannel EEG. Araujo 1996 Study of the embryofoetotoxicity of alpha-terpinene in the rat. Bhatia 1996 Allergy to tartrazine in alprazolam. Kumar 1996 Sweeteners, dyes, and other excipients in vitamin and mineral preparations. Rao 1996 Progressive effects of malachite green at varying concentrations on the development of N-nitrosodiethylamine induced hepatic preneoplastic lesions in rats. Reyes 1996 Effect of organic synthetic food colours on mitochondrial respiration. Tanaka 1996 Reproductive and neurobehavioral effects of Sunset yellow FCF administered to mice in the diet. Corder 1995 Aspirin, salicylate, sulfite and tartrazine induced bronchoconstriction. Safe doses and case definition in epidemiological studies. Nogueira 1995 Study on the embryofeto-toxicity of citral in the rat. Kawane 1994 Aspirin-induced asthma and artificial flavors. Lowry 1994 Leukocytoclastic vasculitis caused by drug additives. Sweeney 1994 Evidence for direct-acting oxidative genotoxicity by reduction products of azo dyes. Bamforth 1993 Common food additives are potent inhibitors of human liver 17 alpha-ethinyloestradiol and dopamine sulphotransferases. Delgado 1993 Peri- and postnatal developmental toxicity of beta-myrcene in the rat. Kumar 1993 The mystery ingredients: sweeteners, flavorings, dyes, and preservatives in analgesic/antipyretic, antihistamine/decongestant, cough and cold, antidiarrheal, and liquid theophylline preparations. Prival 1993 Determination of combined benzidine in FD & C yellow no. 5 (tartrazine), using a highly sensitive analytical method. Tanaka 1993 Reproductive and neurobehavioral effects of amaranth administered to mice in drinking water. Wuthrich 1993 Adverse reactions to food additives. Chung 1992 The reduction of azo dyes by the intestinal microflora. Tanaka 1992 Effects of amaranth on F1 generation mice. el-Saadany 1991 Biochemical effect of chocolate colouring and flavouring like substances on thyroid function and protein biosynthesis. Kumar 1991 Sweeteners, flavorings, and dyes in antibiotic preparations. Dipalma 1990 Tartrazine sensitivity. Rosenkranz 1990 Structural basis of the mutagenicity of 1-amino-2-naphthol-based azo dyes. D'Souza 1987 Aspirin, indomethacin, and tartrazine increase carotid-sinus-nerve activity and arterial blood pressure in guinea pigs. Howrie 1985 Candy flavoring as a source of salicylate poisoning. Levitan 1984 Brain uptake of a food dye, erythrosin B, prevented by plasma protein binding. Smith 1984 Effect of erythrosin B on hyperpolarizing responses to catecholamines in amphibian sympathetic ganglia. Chung 1983 The significance of azo-reduction in the mutagenesis and carcinogenesis of azo dyes. Vorhees 1983 Developmental toxicity and psychotoxicity of FD and C red dye No. 40 (allura red AC) in rats. Hedman 1981 Effects of tartrazine of different contractile stimuli in guinea pig tracheal muscle. Augustine 1980 Neurotransmitter Release from a Vertebrate Neuromuscular Synapse Affected by a Food Dye. Gallagher 1980 Inhibition of platelet aggregation by tartrazine and a pyrazolone analogue in normal and allergic individuals. Ceserani 1978 Tartrazine and prostaglandin-system. Chung 1978 Reduction of azo dyes by intestinal anaerobes. Lafferman 1979 Erythrosin B inhibits dopamine transport in rat caudate synaptosomes. Logan 1979 Erythrosin B Inhibition of Neurotransmitter Accumulation by Rat Brain Homogenate. Ershoff 1977 Effects of diet on growth and survival of rats fed toxic levels of tartrazine (FD & C Yellow No. 5) and sunset yellow FCF (FD & C Yellow No. 6). Levitan 1977 Food, drug, and cosmetic dyes: Biological effects related to lipid solubility.
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- A study on the reproductive toxicity of erythrosine in male mice. Abdel Aziz AH, Shouman SA, Attia AS, Saad SF, Pharmacol Res 1997 May;35(5):457-62
"... The potential adverse effects of erythrosine (ER, FD & C Red No. 3) on the spermatogenesis process were investigated in adult mice. ... sperm count as well as the percentage of motile sperms were significantly inhibited by about 50% and 57% respectively. Moreover, ER was shown to disrupt the normal morphology of the sperm head. ...it increased the incidence of sperms with abnormal head by about 57% and 65% respectively. The induced increase in sperm abnormalities could enhance the spermatogenic dysfunction and germ cell mutagenicity. These findings indicate that ER in the used doses has a potential toxic effect on spermatogenesis in mice and in turn, it may affect its testicular function and reproductive performance."- Physiological effects of some synthetic food colouring additives on rats. Aboel-Zahab H, et al., Boll Chim Farm 1997 Nov;136(10):615-27
" Three different synthetic chocolate colourant agents (A, B and C) were administered to healthy adult male albino rats for 30 and 60 day periods to evaluate their effects ... Ingestion of colourant C (brown HT and indigocarmine) significantly decreased rat body weight, serum cholesterol and HDL-cholesterol fraction, while, T4 hormone, liver RNA content, liver enzymes (S. GOT, S. GPT and alkaline phosphatase), total protein and globulin fractions were significantly elevated. Significant increases were observed in serum total lipids, cholesterol, triglycerides, total protein, globulin and serum transaminases in rats whose diets were supplemented with chocolate colours A and B (sunset yellow, tartrazine, carmoisine and brilliant blue in varying concentrations). ... haemoglobin concentrations and red blood cell counts were significantly decreased in the rats who were administered food additives A and B. ... Congested blood vessels and areas of haemorrhage in both liver and renal sections were revealed in those rats who were given colourants B and C. ..."- Modulation of GABA receptors expressed in Xenopus oocytes by 13-L-hydroxylinoleic acid and food additives. Aoshima H, Tenpaku Y, Biosci Biotechnol Biochem 1997 Dec;61(12):2051-7
"...Then effects of various kinds of food additives on GABA receptors were also examined; perfumes such as alcohols or esters potentiated the responses strongly, while hexylamine, nicotinamide, or caffeine inhibited the responses, mainly in a competitive manner, and vanillin inhibited the responses noncompetitively. These results suggest the possibility that ... intake of much of some food additives, modulates the neural transmission in the brain, ... and changes the frame of the human mind, as alcohol or tobacco does."- Study of the embryofoetotoxicity of alpha-terpinene in the rat. Araujo IB, Souza CA, De-Carvalho RR, Kuriyama SN, Rodrigues RP, Vollmer RS, Alves EN, Paumgartten FJ. Food and Chemical Toxicology 1996 May;34(5):477-82
" alpha-Terpinene (1-isopropyl-4-methyl-1,3-cyclohexadiene) (TER) is a monoterpene found in the essential oils of a large variety of useful plants. Despite the widespread use of plants and essential oils containing TER in folk medicine potions and cosmetics, and as a flavouring food additive, toxicity studies of this monoterpene are scarce. . . . A decrease in foetal body weight (in the unborn rat) and an increase in foetal kidney weights were noted at 250 mg TER/kg body weight. Signs of delayed ossification (poorly ossified and not ossified bones as well as irregular spongy bones) and a higher incidence of minor skeletal malformations were observed at doses of 60 mg/kg body weight or more. These findings indicate that the no-observed-adverse-effect level for TER-induced embryofoetotoxicity can be set at 30 mg/kg body weight by the oral route. "- Synergistic effects of food colors on the toxicity of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) in primary cultured rat hepatocytes. Ashida H, Hashimoto T, Tsuji S, Kanazawa K, Danno G., Journal of Nutritional Science and Vitaminology. (Tokyo) 2000 Jun;46(3):130-6
" ... the in vitro treated food-color mixture itself showed cytotoxicity: ... The food-color mixture enhanced cytotoxicity of Trp-P-1 obviously. We then investigated the effects of in vivo-dosed food additives or food colors on Trp-P-1-caused toxicity. Hepatocytes were isolated and cultured from rats fed a diet containing a mixture of food additives or a mixture of food colors with half the amount of their respective acceptable daily intake for 4 wk. Trp-P-1 was administered to the hepatocytes at various concentrations for 12 h. ... These results suggest that the daily intake of artificial food colors may impair hepatic functions such as gluconeogenesis and ureogenesis, when dietary carcinogens are exposed to the liver cells. "- Neurotransmitter Release from a Vertebrate Neuromuscular Synapse Affected by a Food Dye, G.Augustine, H.Levitan, Science Magazine, March 28, 1980, Vol. 207, pp. 1489-90
"...FD&C No.3 ... produced an irreversible, dose-dependent increase in neurotransmitter release ... These results suggest that erythrosine might prove a useful pharmacological tool for studying the process of transmitter release, but that its use as a food additive should be re-examined."- Infusion of volatile flavor compounds into low-density polyethylene. Avison SJ, Gray DA, Davidson GM, Taylor AJ. J Agric Food Chem 2001 Jan;49(1):270-5
" . . . To study the feasibility of infusing flavors into matrixes as a potential flavoring mechanism, a wide range of volatile flavor compounds was infused into a well-defined synthetic polymer (low-density polyethylene) using supercritical carbon dioxide. . . . Forty-five volatiles were infused, from which a model was developed to predict infusion as a function of certain physicochemical properties. "Polyethylene is plastic. Hmmmm.
- Common food additives are potent inhibitors of human liver 17 alpha-ethinyloestradiol and dopamine sulphotransferases. Bamforth KJ, Jones AL, Roberts RC, Coughtrie MW, Biochem Pharmacol 1993 Nov 17;46(10):1713-20
"... dopamine sulphotransferase (ST) activity was inhibited strongly by (+/-)-catechin, (+)-catechin, octyl gallate, tartrazine [Yellow #5] and vanillin. Sulphation of the xenobiotic steroid 17 alpha-ethinyloestradiol (EE2) was inhibited by vanillin, erythrosin B and octyl gallate [anti-oxidant used in margarine]. ... Vanillin was found to inhibit 50% of liver EE2 ST activity ..."- Allergy to tartrazine in alprazolam. Bhatia MS, Indian J Med Sci 1996 Aug;50(8):285-6
"Allergy to tartrazine-containing psychotropic medication (especially antidepressants) had been reported. 20 patients of apparent allergy to tartrazine-containing alprazolam brands in 480 patients exposed to the dye are described. Rechallenge with non tartrazine-containing alprazolam brands did not produce the similar allergic reactions."- Green colon: an unusual appearance at autopsy. Boutilier RG, Murray SK, Walley VM. Arch Pathol Lab Med. 2000 Sep;124(9):1397-8.
No abstract- Tartrazine and prostaglandin-system. Ceserani R, Colombo M, Robuschi M, Bianco S., Prostaglandins Med 1978 Dec;1(6):499-505
" Tartrazine, a dye largely employed for colouring foods, drinks, drugs and cosmetics, induces in some aspirin-sensitive subjects a bronchoconstriction similar to that caused by aspirin and other nonsteroidal anti-inflammatory drugs. . . . Preliminary experiments on aspirin asthmatic patients treated or not with tartrazine are discussed. "- The significance of azo-reduction in the mutagenesis and carcinogenesis of azo dyes. Chung KT. Mutation Research 1983 Apr;114(3):269-81
" Azo dyes are widely used . . . The extent of such use is related to the degree of industrialization. Since intestinal cancer is more common in highly industrialized countries, a possible connection may exist between the increase in the number of cancer cases and the use of azo dyes. Azo dyes can be reduced to aromatic amines by the intestinal microflora. The mutagenicity of a number of azo dyes is reviewed in this paper. . . "- The reduction of azo dyes by the intestinal microflora. Chung KT, Stevens SE Jr, Cerniglia CE. Critical Reviews in Microbiology. 1992;18(3):175-90
" Azo dyes . . . are metabolized to aromatic amines by intestinal microorganisms. Reductive enzymes in the liver can also catalyze the reductive cleavage of the azo linkage to produce aromatic amines. However, evidence indicates that the intestinal microbial azoreductase may be more important than the liver enzymes in azo reduction. In this article, we examine the significance of the capacity of intestinal bacteria to reduce azo dyes and the conditions of azo reduction. . . . The azoreductase activity in a variety of intestinal preparations was affected by various dietary factors such as cellulose, proteins, fibers, antibiotics, or supplementation with live cultures of lactobacilli."TOP
- Reduction of azo dyes by intestinal anaerobes. Chung KT, Fulk GE, Egan M. Applied and Environmental Microbiology, 1978 Mar;35(3):558-62
" Reduction of seven azo dyes (amaranth, Ponceau SX, Allura Red, Sunset Yellow, tartrazine, Orange II, and methyl orange) was carried out by cell suspensions of predominant intestinal anaerobes. . . ."
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Full Text - Aspirin, salicylate, sulfite and tartrazine induced bronchoconstriction. Safe doses and case definition in epidemiological studies. Corder EH, Buckley CE 3rd, J Clin Epidemiol 1995 Oct;48(10):1269-75
Allergic-like reactions to chemical components of foods and medicines may be common. ... A 15% decrease in the amount of air expired in one second was defined a positive response. ... Doses to which the most sensitive (5%) and practically all (95%) susceptible persons might respectively respond are: metabisulfite 4.6 mg, 255.8 mg; tartrazine 3.4 mg, 885.6 mg; aspirin 0.8 mg, 332.3 mg; and salicylate 2.6 mg, 89.9 mg. Doses within these ranges can be used in epidemiological studies."- Aspirin, indomethacin, and tartrazine increase carotid-sinus-nerve activity and arterial blood pressure in guinea pigs.D'Souza SJ, Biggs DF, Pharmacology 1987;34(2-3):96-103
" Acetylsalicylic acid (ASA...), indomethacin (IND...), and tartrazine (TZ...), given intravenously induced dose-dependent increases in carotid-sinus nerve (CSN) activity, accompanied by increases in mean arterial blood pressure . . . These findings indicate that ASA, IND, and TZ act directly on carotid baroreceptors to increase their activity. "- Estrogenic and DNA-damaging activity of Red No. 3 in human breast cancer cells. Dees C, Askari M, Garrett S, Gehrs K, Henley D, Ardies CM, Environ Health Perspect 1997 Apr;105 Suppl 3:625-32
"Exposure to pesticides, dyes, and pollutants that mimic the growth promoting effects of estrogen may cause breast cancer. ...Red No. 3 increased binding of the ER from MCF-7 cells to the estrogen-responsive element. Consumption of Red No. 3, which has estrogenlike growth stimulatory properties and may be genotoxic, could be a significant risk factor in human breast carcinogenesis."- Factors contributing to adverse soft tissue reactions due to the use of tartar control toothpastes: report of a case and literature review. DeLattre VF., Journal of periodontology 1999 Jul;70(7):803-7
" Tetrasodium and/or tetrapotassium pyrophosphate (Ppi) is the anticalculus component of most tartar control dentifrices on the market today. . . . While pyrophosphates have been approved as additives in dentifrices, these compounds along with the increased concentrations of flavorings and detergents and their higher intraoral alkalinity are strongly implicated as the causative factor in certain hypersensitivity reactions. "- Peri- and postnatal developmental toxicity of beta-myrcene in the rat. Delgado IF, Nogueira AC, Souza CA, Costa AM, Figueiredo LH, Mattos AP, Chahoud I, Paumgartten FJ. Food and Chemical Toxicology 1993 Sep;31(9):623-8
" . . .Despite the importance of human exposure to MYR, its toxicological profile has not been comprehensively studied. The aim of this study was to provide data on the peri- and postnatal developmental toxicity of this terpene. . . . No adverse effects on the offspring were seen with the lowest dose tested, but 0.5 g/kg (500 mg/kg) and higher doses decreased birth weight, increased perinatal mortality (death at or after birth) and delayed the day of appearance of landmarks of postnatal development. Moreover, fertility was impaired in female offspring exposed to the two highest doses of MYR. From the data presented in this paper the no-observed-adverse-effect level for peri- and postnatal developmental toxicity could be set at 0.25 g (250 mg/kg) beta-myrcene/kg body weight. "No neurological or neurotoxicity testing.
Myrcene is a synthetic flavoring agent used in beverages, ice cream, candy and baked goods, according to Ruth Winter's Consumer's Dictionary of Food Additives.- Tartrazine sensitivity, Dipalma JR, Am Fam Physician 1990 Nov;42(5):1347-50
"Tartrazine (FD & C Yellow No. 5) is an approved azo dye present in many drugs and food products. ... Tartrazine sensitivity is most frequently manifested by urticaria and asthma... The mechanism of sensitivity is obscure and has been called pseudoallergic. Management consists mainly of avoidance of drugs and food products that contain tartrazine."- Biochemical effect of chocolate colouring and flavouring like substances on thyroid function and protein biosynthesis. el-Saadany SS, Nahrung 1991;35(4):335-43
"Synthetic chocolate colourant, flavourant and the mixture of both were administered to healthy adult male albino rats to evaluate their effect on the nucleic acids metabolism,... total serum protein, thyroid hormones (T4 and T3) and nuclease enzymes, ... in brain, liver, and kidneys. Also, the activity of the fundamental enzymes ... (G-6-PD and 6-PGD), as well as total lipids and cholesterol contents in the same organs were studied. Ingestion of the studied food additives significantly increased serum protein, RNA and T4 hormone, while, DNA and T3 hormone were insignificantly elevated. In connection with this, the hydrolytic enzymes of nucleic acids... were stimulated by all studied food additives and in all mentioned organs. The activity of G-6-PD and 6-PGD ... increased. The highest increase was noticed in rats fed on diets supplemented with the mixture of both colourant and flavourant followed by colourant then flavourant, respectively."- Effects of diet on growth and survival of rats fed toxic levels of tartrazine (FD & C Yellow No. 5) and sunset yellow FCF (FD & C Yellow No. 6). Ershoff BH., The Journal of nutrition. 1977 May;107(5):822-8
" Tests were conducted on the effects of diet on the response of immature male rats to massive doses of tartrazine (FD&C Yellow No.5) and Sunset Yellow FCF (FD&C Yellow No. 6). When incorporated at a 5% level in a stock diet, tartrazine and Sunset Yellow FCF had no grossly observable toxic effects. When fed with a purified diet, however, both tartrazine and Sunset Yellow FCF at 5% level in the diet resulted in a marked retardation in growth, an unthrifty appearance of the fur and death of 50% or more of the rats within an experimental period of 14 days. . . . "- FDA Public Health Advisory: Reports of blue discoloration and death in patients receiving enteral feedings tinted with the dye, FD&C Blue No. 1
"Dear Health Care Professional:
The Food and Drug Administration (FDA) would like you to be aware of several reports of toxicity, including death, temporally associated with the use of FD&C Blue No. 1 (Blue 1) in enteral feeding solutions. . . in vitro evidence that Blue 1 can be a mitochondrial toxin lends plausibility to the idea ... "See full report by clicking on the title above.
- Safety evaluation of lipase produced from Candida rugosa: summary of toxicological data. Flood MT, Kondo M. Regulatory toxicology and pharmacology 2001 Apr;33(2):157-64
" The toxicity of lipase AY, an enzyme preparation used in lipid hydrolysis to produce flavors, was evaluated in a series of studies. A 13-week dietary toxicity study in Sprague-Dawley (Crj:CD) rats was conducted in which animals received lipase AY in the feed at concentrations of 0, 625, 1250, or 2500 mg/kg body wt. No adverse treatment-related effects were observed. . . .Finally, the particular strain of Candida rugosa, the yeast strain used to prepare lipase AY, has been shown to be nonpathogenic upon a single injection into the tail vein of rats of viable spores . . . The results of these studies demonstrate that the enzyme preparation may be considered safe to workers and consumers when employed in the production of flavors from fats."- Inhibition of platelet aggregation by tartrazine and a pyrazolone analogue in normal and allergic individuals. Gallagher JS, Splansky GL, Bernstein IL, Clin Allergy 1980 Nov;10(6):683-90
"The effect of tartrazine (T) (yellow dye No. 5) and one of its metabolites an aminopyrazolone analogue (...SCHP) upon collagen-induced platelet aggregation (C-PA) was investigated ... The mean inhibitory concentrations of SCHP were similar to aspirin in both atopic and normal individuals. ... this in vitro system may be a useful method of assessing non-immune mechanisms involved in reactions to tartrazine."- Evaluation of the developmental toxicity of isoeugenol in Sprague-Dawley (CD) rats George JD, Price CJ, Marr MC, Myers CB, Jahnke GD. Toxicological Sciences 2001 Mar;60(1):112-20
" Isoeugenol, used as a perfumery and flavoring agent, was evaluated for developmental toxicity. . . . Clinical signs associated with isoeugenol exposure included dose-related evidence of sedation and aversion to treatment (rooting behavior) in all isoeugenol groups, as well as an increased incidence of piloerection (raised hair) . . . Maternal body weight, weight gain, and gestational weight gain . . . were reduced at all doses in a dose-related manner. . . . liver weight was increased at all three dose levels. . . At 1000 mg/kg/day, average fetal body weight/litter was decreased by 7% (male) or 9% (female). . . . In summary, the maternal toxicity lowest observed adverse effect level (LOAEL) was 250 mg/kg/day (lowest amount used) based primarily on reduced body weight and gestational weight gain . . . The developmental toxicity LOAEL was 1000 mg/kg/day based on intrauterine growth retardation and mildly delayed skeletal ossification. . . "- Blue colon at autopsy. Granville LA, Finch C., Arch Pathol Lab Med. 2001 May;125(5):599.
Comment on Boutilier 2000, Green colon: an unusual appearance at autopsy.
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Full Text with full page picture - Effects of tartrazine of different contractile stimuli in guinea pig tracheal muscle. Hedman SE, Andersson RG, Acta Pharmacol Toxicol (Copenh) 1981 Feb;48(2):101-7
" Tracheal smooth muscle obtained from ovalbumin-sensitized guinea pigs contracted with micromolar concentrations of tartrazine and indomethacin. . . .We suggest that SRS-A plays an important role in the immediate hypersensitivity reactions of tartrazine and indomethacin in guinea pig trachea. "- Candy flavoring as a source of salicylate poisoning. Howrie DL, Moriarty R, Breit R. Pediatrics 1985 May;75(5):869-71
" Methyl salicylate (oil of wintergreen) in the form of candy flavoring was ingested by a 21-month-old male infant who subsequently developed vomiting, lethargy (extreme tiredness), and hyperpnea (abnormally fast or deep breathing). . . Hazards associated with salicylate use in this form include lack of parental awareness of the substance's toxic potential, the attractiveness of the candy-like odor, and the availability of the liquid in non-child-resistant packaging containing potentially lethal quantities. "- Study of skin rashes after antibiotic use in young children. Huang SW, Borum PR, Clin Pediatr (Phila) 1998 Oct;37(10):601-7
After having a rash upon antibiotic use, 62 children were given dye-free antibiotics at the next infection. "... Of the 62 patients who received dye-free suspensions, only eight developed a mild skin rash, which was managed successfully. ..."- Aspirin-induced asthma and artificial flavors. Kawane H. Chest 1994 Aug;106(2):654-5
No abstract- Immunological aspects of the common food colorants, amaranth and tartrazine. Koutsogeorgopoulou L, Maravelias C, Methenitou G, Koutselinis A, Vet Hum Toxicol 1998 Feb;40(1):1-4
"We describe ... the cytotoxic and immunosuppressive effects of food colorants such as amaranth [Red #2] and tartrazine [Yellow #5].... The results showed clear immunosuppressive effects from the 2 substances tested, although the concentrations chosen for this study proved to be non-cytotoxic..."- Threshold of toxicological concern for chemical substances present in the diet: a practical tool for assessing the need for toxicity testing. Kroes R, Galli C, Munro I, Schilter B, Tran L, Walker R, Wurtzen G, Food Chem Toxicol 2000 Feb-Mar;38(2-3):255-312
" The de minimis concept acknowledges a human exposure threshold value for chemicals below which there is no significant risk to human health. It is the underlying principle for the US Food and Drug Administration (FDA) regulation on substances used in food-contact articles. Further to this, the principle of Threshold of Toxicological Concern (TTC) has been developed and is now used by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in their evaluations. Establishing an accepted TTC would benefit consumers, industry and regulators, since it would preclude extensive toxicity evaluations when human intakes are below such threshold,. . . The allergenicity endpoint was not analysed as such. It was addressed in a separate section because this issue is not relevant to the overall population but rather to subsets of susceptible individuals, and allergic risks are usually controlled by other means (i.e. labelling) than the Threshold of Toxicological Concern approach. "Note: "de minimis" means "a little bit can't hurt you." While it is clear that lack of testing chemicals added to your food and environment would benefit industry and regulators, they fail utterly to show how it would benefit consumer health.
- Threshold of toxicological concern (TTC) in food safety assessment. Kroes R, Kozianowski G. Toxicol Lett 2002 Feb 28;127(1-3):43-6
" ... The concept that exposure thresholds can be identified for individual chemicals in the diet is already widely embodied in practice of many regulatory bodies in setting acceptable daily intakes (ADIs) for chemicals whose toxicological profile is known. However, the TTC concept goes further than this in proposing that a de minimis value can be identified for many chemicals, including those of unknown toxicity, taking the chemical structure into consideration. This concept forms the scientific basis of the US Food and Drug Administration (FDA) '1995 Threshold of Regulation' for indirect food additives. The TTC principle has also been adopted by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in its evaluations of flavouring substances. The establishment of a more widely accepted TTC would benefit consumers, industry and regulators. .. An International Life Sciences Institute (ILSI)-Europe expert group has examined this TTC principle, which was based on general toxicity endpoints (including carcinogenicity), for its applicability in food safety evaluation. ... "Note:
- The term "de minimis" means "a little bit can't hurt."
- ILSI, a food industry group that used to be called the Nutrition Foundation, is composed of companies that make food additives, pesticides, snack foods, etc.
- How this approach would benefit regulators and industry is clear. How it would benefit consumers' health is questionable.
- The threshold of toxicological concern concept in risk assessment. Kroes R, Kleiner J, Renwick A., Toxicological Sciences. 2005 Aug;86(2):226-30. Epub 2005 Apr 13
"... The concept proposes that a low level of exposure with a negligible risk can be identified for many chemicals, including those of unknown toxicity, based on knowledge of their chemical structures. ... "
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Full Text - Sweeteners, dyes, and other excipients in vitamin and mineral preparations. Kumar A, Aitas AT, Hunter AG, Beaman DC, Clin Pediatr (Phila) 1996 Sep;35(9):443-50
"Multivitamins and mineral preparations are widely used for infants and children. All of these preparations contain a variety of excipients ("inert ingredients"). ...The information about sweeteners, dyes, and other excipients (flavorings, preservatives, stabilizers, and fillers) for 41 chewable/liquid multivitamin and mineral preparations was obtained and tabulated. ... The FD&C yellow #6 (sunset yellow) was the most common dye, present in 46% (19/41) of the preparations followed by FD&C Red #40 in 29% (12/41). ... The mandatory listing of all excipients is the only way to assure that physicians and consumers will be fully informed about the hidden ingredients."- The mystery ingredients: sweeteners, flavorings, dyes, and preservatives in analgesic/antipyretic, antihistamine/decongestant, cough and cold, antidiarrheal, and liquid theophylline preparations. Kumar A, Rawlings RD, Beaman DC. Pediatrics 1993 May;91(5):927-33
" ...Pharmaceutical preparations may contain a variety of excipients ("inert ingredients"). . . Information about the excipients in a particular preparation is not readily available. . . Information about excipients in 102 chewable and liquid preparations was compiled. An average preparation contained two sweeteners. Saccharin and sucrose were the most common sweeteners found. . . For 36 of the 102 preparations, type of flavoring was not specified. In the remaining preparations, cherry was the most common flavoring, followed by vanilla and lemon. Twenty-one different dyes and coloring agents were used. Red dye No. 40 was the most common (42/102), followed by yellow No. 6 (27/102). Of the eight preservatives used, sodium benzoate and methylparabens were present in 42 and 27 of the preparations, respectively. . . The tables should be helpful to physicians in selecting preparations containing different excipients when an adverse reaction occurs. The mandatory labeling of excipients in all pharmaceutical preparations is the only way that physicians and patients can be fully informed. "- Sweeteners, flavorings, and dyes in antibiotic preparations. Kumar A, Weatherly MR, Beaman DC. Pediatrics 1991 Mar;87(3):352-60
" Even though a variety of adverse effects caused by sweeteners, flavorings, and dyes in susceptible individuals have been reported, there is no good single reference with information about these substances in pediatric antimicrobials. Data on sweeteners, flavorings, and dyes in 91 antimicrobial preparations were collected. Sucrose was present in 74 (85%) of 87 preparations, followed by saccharin in 30 (34%) preparations. Mannitol, lactose, and sorbitol were each present in 7 preparations. None of the preparations were free of sweeteners. Thirty-four (37%) of 91 preparations did not specify the flavoring content. While cherry was the most common flavoring used, there were 25 other flavorings. Thirteen different dyes and coloring agents were used in these antimicrobials. Red dye no. 40 was present in 45% of preparations. . . . "- Erythrosin B inhibits dopamine transport in rat caudate synaptosomes. Lafferman JA, Silbergeld EK.
" Erythrosin B is a member of a class of fluorescein dyes that are suggested to elicit hyperkinesis when ingested by susceptible children. We found that erythrosin B inhibits dopamine uptake . . . Erythrosin B also decreased nonsaturable binding of dopamine to the synaptosome membrane. The inhibitory action of erythrosin B on dopamine uptake is consistent with the hypothesis that erythrosin B can act as a central excitatory agent able to induce hyperkinetic behavior. "- Determination of benzidine in the food colours tartrazine and sunset yellow FCF, by reduction and derivatization followed by high-performance liquid chromatography. Lancaster FE, Lawrence JF, Food Addit Contam 1999 Sep;16(9):381-90
" Free and bound benzidine, a non-sulphonated aromatic amine (NSAA), were determined in the food colours tartrazine and sunset yellow FCF. . . . Levels of total benzidine . .. ranged from < 5 to 270 ng/g. Total aniline was also determined (0.2-188 micrograms/g). . . ."NOTE: The Code of Federal Regulations, Title 21, Revised April 1, 2002, specifies that Tartrazine may contain "Benzidine, not more than 1 part per billion." That is 1 ng/g
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- Synergistic Interactions Between Commonly Used Food Additives in a Developmental Neurotoxicity Test. Lau K, McLean WG, Williams DP, Howard CV., Toxicol Sci. 2006 Mar;90(1):178-87, 2005 Dec 13; [Epub ahead of print]
" Exposure to non-nutritional food additives during the critical development window has been implicated in the induction and severity of behavioural disorders such as attention deficit hyperactivity disorder (ADHD). . . We therefore examined the neurotoxic effects of four common food additives in combinations of two (Brilliant Blue and L-glutamic acid, Quinoline Yellow and aspartame) to assess potential interactions. . . Neurotoxicity was measured as an inhibition of neurite outgrowth. . . . Theoretical exposure to additives was calculated based on analysis of content in foodstuff, and estimated percentage absorption from the gut. Inhibition of neurite outgrowth was found at concentrations of additives theoretically achievable in plasma by ingestion of a typical snack and drink. . . both combinations had a straightforward additive effect on cytotoxicity. These data have implications for the cellular effects of common chemical entities ingested individually and in combination. "Full text of study
TOP- Brain uptake of a food dye, erythrosin B, prevented by plasma protein binding. Levitan H, Ziylan Z, Smith QR, Takasato Y, Rapoport SI, Brain Res 1984 Nov 19;322(1):131-4
"... Thus, significant brain uptake of intravascular dye is normally prevented by its binding to plasma protein (greater than 99% bound) and by the blood-brain barrier impermeability to the dye-protein complex. Sensitivity to food dyes such as erythrosin B in some individuals may reflect altered plasma protein binding capacity, which can vary with age and disease."EXPLANATION OF PROTEIN-BINDING:
Quoted from Drugs and Human Behavior, Second Ed., Palfai & Jankiewicz, 1997 (p.55)"Many drugs attach themselves to the large protein globules in the blood, particularly to albumin, the predominant protein. These bound drugs are then trapped in the capillaries unable to act, because the capillary pores, wide as they are, are still smaller than the protein globules. Such a drug is in the position of a person chained to an elephant, trying to climb out a porthole. Ninety percent of the antipsychotic drug chlorpromazine (Thorazine) and 99 percent of the tranquilizer diazepam (Valium) binds with proteins... Bound and unbound portions of a drug in the bloodstream balance in a type of equilibrium ... Different drugs protein-bind to different extents, but the ratio of bound to unbound molecules for a particular drug is a constant. Chlorpromazine ions will always be found in the blood 90 percent bound to 10 percent free. As the free 10 percent diffuses out of circulation, bound molecules free themselves to maintain the proportion. Hence, chlorpromazine escapes from the blood slowly, at a low, steady level, as the body works on the small portion of the drug available at any given moment. ... One method of overcoming the impediments posed by protein-binding ... is to administer an initial dose of the drug large enough to saturate the binding site and then give more to provide a satisfactory effect as well. Another technique is to administer a second drug that exhibits more of an affinity for the tissue than the first. This second drug unseats the molecules of the first drug and replaces them in the tissue [blood]. The first drug is then freed for action. This mechanism can cause poisoning if a drug is accidentally bumped from its binding site, and blood concentrations suddenly soar to toxic levels."
- Food, drug, and cosmetic dyes: Biological effects related to lipid solubility. Levitan H (1977).Proceedings of the National Academy of Sciences, U.S.A., 74, 2914-2918.
"The synthetic coloring agents increased the resting membrane potential and conductance of the neurons in a dose-dependent manner by increasing the potassium permeability of the membrane relative to that of other ions."- Erythrosin B Inhibition of Neurotransmitter Accumulation by Rat Brain Homogenate., Logan WJ, Swanson JM (1979). Science, 206, 363-364.
"A mixture of seven food dyes inhibited the accumulation of eight neurotransmitters or neurotransmitter precursors by rat brain homogenate."- Leukocytoclastic vasculitis caused by drug additives. Lowry MD, Hudson CF, Callen JP, J Am Acad Dermatol 1994 May;30(5 Pt 2):854-5
"Chronic cutaneous small vessel (leukocytoclastic) vasculitis (LCV) is a process believed to be related to the presence of circulating immune complexes. ... We report a patient with chronic cutaneous LCV in whom the presumed cause was an excipient (a dye) used in the capsule form of lithium carbonate. Furthermore, ingestion of foods containing dyes results in a disease flare in our patient."- Systemic Absorption of Food Dye in Patients with Sepsis Maloney JP, Halbower AC, Fouty BF, Fagan KA, Balasubramaniam V, Pike AW, Fennessey PV, Moss M, N Engl J Med 2000 Oct 5;343(14):1047-8
" Autopsies of both patients revealed green or blue discoloration of the skin and internal organs, without gastrointestinal perforation. . . it is unlikely that oral-intake limits established by the Food and Drug Administration (FDA) for blue dye no. 1 (12 mg per kilogram of body weight per day) were exceeded. . . . FD&C blue dye no. 1 was approved by the FDA for use in food . . . However, these experiments were performed in healthy animals. . . . Blue dye no. 1, . . . reduces oxygen consumption by a factor of eight in mitochondrial preparations in vitro. . . . Although both patients had serious underlying illnesses, their condition was improving before they received the dye and turned color. . . .We encourage judicious use of this food dye in patients with sepsis or other illnesses associated with increased gastrointestinal permeability. "- Lead poisoning associated with imported candy and powdered food coloring--California and Michigan. MMWR Morb Mortal Wkly Rep. 1998 Dec 11;47(48):1041-3.
" Although the most common source of pediatric lead poisoning is dust within the home that contains deteriorated lead-based paint from walls and windowsills, other less common sources (1-3) can result in excess exposure among children . . . This report describes two cases of pediatric lead poisoning associated with eating imported candy and food stuffs and underscores the importance of thorough history-taking to identify unusual sources of lead exposure. "We wonder why this does not underscore the importance of getting the lead out of artificial food colorings?
- Principles for the safety evaluation of flavouring substances. Munro IC, Shubik P, Hall R. Food and chemical toxicology 1998 Jun;36(6):529-40
" This paper reviews efforts by various organizations to develop principles and procedures for the safety evaluation of flavouring substances. . . . . "- Comparison of estimated daily per capita intakes of flavouring substances with no-observed-effect levels from animal studies. Munro IC, Kennepohl E. Food and chemical toxicology 2001 Apr;39(4):331-54
" A study was conducted to determine the margins of safety between no-observed-effect levels (NOELs) and daily per capita intake of flavouring substances . . . . 98% of flavouring substances have margins of safety greater than 1000, illustrating that even if intake was underestimated by several fold, in almost every case, a wide margin of safety would still exist."But did they test for neurotoxicity or cognitive effects?
- Study on the embryofeto-toxicity of citral in the rat. Nogueira AC, Carvalho RR, Souza CA, Chahoud I, Paumgartten FJ. Toxicology 1995 Feb 6;96(2):105-13
" Citral . . . found in the essential oils of a large variety of useful plants, is used as a scenting agent in household products, as a fragrance in cosmetics, and as a food flavouring additive. . . .Citral (60; 125; 250; 500 and 1000 mg/kg) in corn oil was given orally to Wistar rats from day 6 to 15 of pregnancy. . . . A transient decrease in weight gain from days 6 to 11 of gestation at the lowest doses, and a reduction in body weight minus uterine weight at term at the highest doses, indicated that citral was maternally toxic over the dose range tested. A slight but statistically significant increase in the ratio of resorptions per implantations was observed with 60 and 125 mg/kg body weight. . . . Signs of fetal growth retardation and a higher incidence of minor skeletal abnormalities were found in doses higher than 60 mg/kg. . . . an increase in fetal spleen weight was observed in doses higher than 125 mg/kg. Therefore, data presented in this paper indicate that the no-observed adverse effect level for embryofeto-toxicity is lower than 60 mg citral/kg body weight p.o. "Translation: Their lowest dose was too high. But how many mg/kg is used as a food additive? Note that no cognitive or neurological toxicity testing was done.
- Study of the effects of beta-myrcene on rat fertility and general reproductive performance. Paumgartten FJ, De-Carvalho RR, Souza CA, Madi K, Chahoud I. Brazilian journal of medical and biological research 1998 Jul;31(7):955-65
" beta-Myrcene (MYR) is a monoterpene found in the oils of a variety of aromatic plants including lemongrass, verbena, hop, bay, and others. MYR and essential oils containing this terpenoid compound are used in cosmetics, household products, and as flavoring food additives. . . Except for an increase in liver and kidney weights, no other sign of toxicity was noted in male and female rats exposed to MYR. . . . No adverse effect of MYR on postnatal weight gain was noted but days of appearance of primary coat, incisor eruption and eye opening were slightly delayed in the exposed offspring. . . .. "Note: Neurological testing was not done.
- Inactive" ingredients in pharmaceutical products: update (subject review). American Academy of Pediatrics Committee on Drugs. Pediatrics 1997 Feb;99(2):268-78
"Because of an increasing number of reports of adverse reactions associated with pharmaceutical excipients, in 1985 the Committee on Drugs issued a position statement recommending that the Food and Drug Administration mandate labeling of over-the-counter and prescription formulations to include a qualitative list of inactive ingredients. However, labeling of inactive ingredients remains voluntary. ... The original statement, therefore, has been updated and its information expanded.
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Full Text - Determination of combined benzidine in FD & C yellow no. 5 (tartrazine), using a highly sensitive analytical method.
Prival MJ, Peiperl MD, Bell SJ, Food Chem Toxicol 1993 Oct;31(10):751-8" 53 samples of FD & C Yellow No. 5 (tartrazine; Colour Index No. 19140) were examined for combined benzidine. . . . The limit of quantitation for benzidine in FD & C Yellow No. 5 by this method is 5 ng/g. 25 samples of FD & C Yellow No. 5 were found to contain 7-83 ng/g of combined benzidine that was released by dithionite reduction. . . ."- Progressive effects of malachite green at varying concentrations on the development of N-nitrosodiethylamine induced hepatic preneoplastic lesions in rats. Rao KV, Fernandes CL, Tumori 1996 May-Jun;82(3):280-6
"Malachite green (MG) is a triarylmethane textile dye which is banned for use as a food colour. However, despite the ban it is used unscrupulously as a food colouring agent. It is also used extensively for dyeing silk, wool, jute, leather, cotton and also as a laboratory reagent,... MG tested at all the three concentrations and PB were found to enhance liver carcinogenesis to a significant extent ..."- Effect of organic synthetic food colours on mitochondrial respiration. Reyes FG, Valim MF, Vercesi AE. Food Additives and Contaminants. 1996 Jan;13(1):5-11
" ... The compounds tested were: Erythrosine, Ponceau 4R, Allura Red, Sunset yellow, Tartrazine, Amaranth, Brilliant Blue, Blue, Fast Red E, Orange GGN and Scarlet GN. All food colours tested inhibited mitochondrial respiration ...This inhibition varied largely, e.g. from 100% to 16% for Erythrosine and Tartrazine respectively, ...This effect was dose related .... "- Structural basis of the mutagenicity of 1-amino-2-naphthol-based azo dyes. Rosenkranz HS, Klopman G. Mutagenesis 1990 Mar;5(2):137-46
" A structure-activity study of 1-amino-2-naphthol derived azo dyes using CASE, the Computer Automated Structure Evaluation system, revealed that for optimal mutagenicity, reduction of the azo bond was required. . .it has long been known that sulfonation of azo dyes resulted in decreased carcinogenicity . . . Unexpectedly, CASE indicates that one of the aromatic amines obtained upon azo reduction of FD and C Red no. 40 is predicted to be mutagenic (making mutations or changes in DNA) "- Risk assessment of combined photogenotoxic effects of sunlight and food additives. Salih FM, Sci Total Environ. 2005 Jun 24
" The presence of flavored colorants (peach and raspberry), flavors (caramel, citric acid and vanilla) and food preservatives (sodium nitrite, sodium nitrate, sodium benzoate, benzoic acid, potassium sorbate and sodium chloride) in Escherichia coli suspension during exposure to sunlight did not change the extent of cell survival. No effect . . . in the dark. However, when the relevant additive was present in cell suspension during sunlight exposure the number of induced mutations was increased to varying extents over that seen with sunlight alone. . . . The impact of this investigation reflects the significance of combination of sunlight and chemical food additives as potential risk, which requires special attention and necessitates further investigations to evaluate the risk. ".
- The comet assay with 8 mouse organs: results with 39 currently used food additives. Sasaki YF, Kawaguchi S, Kamaya A, Ohshita M, Kabasawa K, Iwama K, Taniguchi K, Tsuda S., Mutation Research 2002 Aug 26;519(1-2):103-19
We determined the genotoxicity of 39 chemicals currently in use as food additives. . . Of all the additives, dyes were the most genotoxic. Amaranth, Allura Red, New Coccine, Tartrazine, Erythrosine, Phloxine, and Rose Bengal induced dose-related DNA damage in the glandular stomach, colon, and/or urinary bladder. All seven dyes induced DNA damage in the gastrointestinal organs at a low dose (10 or 100mg/kg). Among them, Amaranth, Allura Red, New Coccine, and Tartrazine induced DNA damage in the colon at close to the acceptable daily intakes (ADIs). Two antioxidants (butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT)), three fungicides (biphenyl, sodium o-phenylphenol, and thiabendazole), and four sweeteners (sodium cyclamate, saccharin, sodium saccharin, and sucralose) also induced DNA damage in gastrointestinal organs. Based on these results, we believe that more extensive assessment of food additives in current use is warranted.- Effect of erythrosin B (FD&C Red 3) on hyperpolarizing responses to catecholamines in amphibian sympathetic ganglia. Smith PA, Dombro KR, Zidichouski J. J Pharmacol Exp Ther. 1984 Jul;230(1):221-7.
" . . . .Xanthine dyes such as erythrosin B have also been reported to inhibit Na-K-adenosine triphosphatase. In agreement with this possibility we found that erythrosin B promoted irreversible inhibition of the (nicotinic) acetylcholine after-hyperpolarization. This response is generated by the electrogenic activity of the Na+ pump. . . The irreversible antagonism of epinephrine and dopamine by erythrosin was specific in that hyperpolarizing responses to muscarinic antagonists such as methacholine were relatively insensitive to the dye. It is therefore concluded that erythrosin B selectively antagonizes responses to catecholamines in amphibian sympathetic ganglia..."This study is important as it demonstrates an irreversible effect of food dyes in body cells.
- Evidence for direct-acting oxidative genotoxicity by reduction products of azo dyes. Sweeney EA, Chipman JK, Forsythe SJ, Environ Health Perspect 1994 Oct;102 Suppl 6:119-22
"...The ingestion of azo dyes has been proposed as one source of potential genotoxic agents. Many intestinal bacteria are able to reduce the azo bond (termed azofission), which liberates the substituted naphthol compounds. ... The superoxide free radical was produced by the azo dyes only after reduction by the intestinal bacteria Enterococcus faecalis and Bacteroides thetaiotaomicron."- Effects of amaranth on F1 generation mice. Tanaka T. Toxicology letters 1992 May;60(3):315-24
" The color additive, amaranth, (Red No. 2) was given in the diet to provide dietary levels of 0 (control), 0.03, 0.09 and 0.27%, from 5 weeks of age in F0 generation mice to 9 weeks of age in F1 generation mice. . . There was no effect on the parameters of litters, litter size, pup weight and litter weight. The body weight of pups during the lactation period in the treatment groups increased less significantly, and the survival index at postnatal day (PND) 21 of the amaranth 0.27% group was reduced. Developmental parameters, direction of swimming on PND 4 in male pups and olfactory orientation in each sex were significantly reduced in the treatment groups. The dose levels of amaranth in this study influenced some reproductive, developmental and behavioral parameters in mice. "- Reproductive and neurobehavioral effects of amaranth administered to mice in drinking water. Tanaka T., Toxicology and industrial health. 1993 Nov-Dec;9(6):1027-35
" The color additive amaranth [Red #2] was given in the drinking water at levels of 0 (control), 0.025, 0.075, and 0.225% from 5 weeks of age in F0 generation until F1 generation mice were weaned,. . . Average body weight in both sexes of the F1 mice was significantly increased in the 0.025% group in both sexes. Survival index at postnatal day (PND) 21 was reduced in the 0.025% amaranth group. For the neurobehavioral parameters, surface righting at PND 4 in female offspring and olfactory orientation in both sexes were significantly affected by treatment. Several parameters of movement activity of male offspring at 3 weeks of age were affected in amaranth 0.075% group . . . "- Reproductive and neurobehavioral effects of Sunset yellow FCF administered to mice in the diet. Tanaka T., Toxicol Ind Health 1996 Jan-Feb;12(1):69-79
Selected reproductive and neurobehavioral parameters were measured in mice given the color additive Sunset Yellow [FD&C Yellow #6] FCF in the diet. The additive was given at levels of 0 (control), 0.15, 0.30, and 0.60%, from five weeks of age in the F0 generation to nine weeks of age in the F1 generation. There were few adverse effects on litter size, weight, or sex ratio. Average body weight . . . was significantly increased . . . In the neurobehavioral parameters, swimming direction was significantly affected in a dose-related manner in male and female offspring . . . Also in the early lactation period, surface righting and negative geotaxis were significantly affected in male offspring in the middle-dose group, and swimming head angle was significantly affected in female offspring in a dose-related manner. The dose levels of Sunset Yellow FCF in this study did produce some adverse effects in reproductive and neurobehavioral parameters.- Reproductive and neurobehavioural toxicity study of erythrosine administered to mice in the diet. Tanaka T. Food Chem Toxicol 2001 May;39(5):447-54
" Erythrosine was given in the diet to provide levels of 0 (control), 0.005, 0.015 and 0.045% from 5 weeks of age of the F(0) generation to 9 weeks of age of the F(1) generation in mice, and selected reproductive and neurobehavioural parameters were measured. . . .In movement activity of exploratory behaviour, several parameters were significantly changed in the high-dose group, and those effects were dose related in adult females in the F(0) and F(1) generations and in male offspring in the F(1) generation. . . . "- Reproductive and neurobehavioural toxicity study of tartrazine administered to mice in the diet. Tanaka T., Food Chem Toxicol. 2005 Aug 5 (epub ahead of print)
" Tartrazine was given in the diet . . . and selected reproductive and neurobehavioural parameters were measured. In movement activity of exploratory behaviour in the F(0) generation, number of vertical activity was significantly increased ...The average body weight . . .was significantly increased . . . In behavioural developmental parameters, surface righting . . . was significantly accelerated . . . Cliff avoidance at PND 7 was significantly accelerated . . . Negative geotaxis at PND 4 was significantly delayed . . . number of movement showed a significant tendency to be affected . . . Nevertheless, . . . the actual dietary intake of tartrazine is presumed to be much lower. It would therefore appear that the levels of actual dietary intake of tartrazine is unlikely to produce any adverse effects in humans. "Please click on the link to the entire abstract and read it carefully. It is astonishing that in the face of these clear adverse effects on mice, he would conclude that it is not a problem for humans. And his basis for such a conclusion? Simply that we would theoretically eat less than the mice did.
- Flavorings and colorings. Taylor SL, Dormedy ES. Allergy 1998;53(46 Suppl):80-2
" Food Allergy Research and Resource Program, University of Nebraska, Lincoln 68583-0919, USA. "No abstract
- The role of flavoring substances in food allergy and intolerance. Taylor SL, Dormedy ES. Adv Food Nutr Res 1998;42:1-44
" Department of Food Science and Technology, University of Nebraska-Lincoln 68583, USA. "No abstract
- DNA damage induced by red food dyes orally administered to pregnant and male mice. Tsuda S, Murakami M, Matsusaka N, Kano K, Taniguchi K, Sasaki YF. Toxicol Sci 2001 May;61(1):92-9
" We determined the genotoxicity of synthetic red tar dyes (amaranth (food red No. 2), allura red (food red No. 40), or acid red (food red No. 106), new coccine (food red No. 18). currently used as food color additives in many countries, including JAPAN: ...The assay was positive in the colon 3 h after the administration of amaranth and allura red and weakly positive in the lung 6 h after the administration of amaranth. Acid red did not induce DNA damage in any sample at any sampling time. ...The 3 dyes induced DNA damage in the colon starting at 10 mg/kg. ... 6.5 mg/10 ml of new coccine, induced DNA damage in colon, glandular stomach, and bladder. . . Because the 3 azo additives we examined induced colon DNA damage at a very low dose, more extensive assessment of azo additives is warranted. "- Developmental toxicity and psychotoxicity of FD and C red dye No. 40 (allura red AC) in rats. Vorhees CV, Butcher RE, Brunner RL, Wootten V, Sobotka TJ. Toxicology 1983;28(3):207-17
" Adult Sprague-Dawley rats were fed diets containing FD and C red dye No. 40 for 2 weeks and were then bred. The diets were continued for the females throughout gestation and lactation and were provided continuously to their offspring thereafter. T. . . Red-40 significantly reduced reproductive success, parental and offspring weight, brain weight, survival, and female vaginal patency development. Behaviorally, R40 produced substantially decreased running wheel activity, and slightly increased postweaning open-field rearing activity. Overall, R40 produced evidence of both physical and behavioral toxicity in developing rats at doses of up to 10% of the diet. (high doses) "- Evaluation of certain food additives. Fifty-first report of the Joint FAO/WHO Expert Committee on Food Additives. World Health Organ Tech Rep Ser 2000;891:i-viii, 1-168
" This report presents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of various food additives, with a view to recommending Acceptable Daily Intakes (ADIs) for humans, and to prepare specifications for the identity and purity of food additives. . . . A summary follows of the Committee's evaluations of toxicological data on specific food additives, . . .The Committee also evaluated the safety of various groups of flavouring agents and assessed the intake of specific food additives, including benzoates, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sulfites and tert-butylhydroquinone (TBHQ). Annexed to the report are tables summarizing the Committee's recommendations for ADIs of the food additives considered, changes in the status of specifications for these substances and specific flavouring agents, and further toxicological studies and other information required or desired. "- Adverse reactions to food additives. Wuthrich B, Ann Allergy 1993 Oct;71(4):379-84
" Food additives can induce a wide range of adverse reactions in sensitive individuals. ... Two typical cases of a "restaurant syndrome" due to sulfite allergy or sensitivity are described, as well as a case of disulfite-induced urticaria-vasculitis and a case of anaphylactoid purpura associated with tartrazine and benzoates."- Chewing-gum flavor affects measures of global complexity of multichannel EEG. Yagyu T, Wackermann J, Kinoshita T, Hirota T, Kochi K, Kondakor I, Koenig T, Lehmann D. Neuropsychobiology 1997;35(1):46-50
" Global complexity of spontaneous brain electric activity was studied before and after chewing gum without flavor and with 2 different flavors. . . Global Omega-Complexity appears to be a sensitive measure for subtle, central effects of chewing gum with and without flavor. "- Smell and taste of chewing gum affect frequency domain EEG source localizations. Yagyu T, Kondakor I, Kochi K, Koenig T, Lehmann D, Kinoshita T, Hirota T, Yagyu T. The International journal of neuroscience 1998 Apr;93(3-4):205-16
" We investigated brain electric field signatures of subjective feelings after chewing regular gum or gum base without flavor. . . Subjective feeling changed to more positive values after regular gum than gum base (ANOVA).--Thus, chewing gum with and without taste-smell activates different brain neuronal populations. "Now that this can be done, how about a study comparing EEG for natural and artificial flavored/colored gum?
- Skin discoloration with blue food coloring. Zillich AJ, Kuhn RJ, Petersen TJ, Ann Pharmacother 2000 Jul-Aug;34(7-8):868-70
" . . . Twelve hours after the start of enteral nutrition, the patient appeared cyanotic . . . The pediatric code response team was called. Enteral nutrition was stopped and then restarted without blue food coloring. . . . blue food coloring is used with enteral nutrition for detecting aspiration of stomach contents. . . Nurses place an unstandardized amount of blue food coloring into each enteral nutrition bag. . . . No toxicity studies exist for acute or human ingestion, but the National Academy of Sciences lists 363 mg/d of FD&C Blue No. 1 as a safe level for humans. We estimated this child ingested 780-3,940 mg of dye over a 12-hour period. CONCLUSIONS: This is the first known report of an adverse effect from blue food coloring. To prevent similar occurrences within our institution, the blue food coloring for tube feedings will be dispensed by the pharmacy department in standardized units."