2003: FDA Public Health Advisory: Reports of Blue Discoloration and Death in Patients Receiving Enteral Feedings Tinted With The Dye, FD&C Blue No. 1

2003: 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 these reports, Blue 1 was intended to help in the detection and/or monitoring of pulmonary aspiration in patients being fed by an enteral feeding tube. Reported episodes were manifested by blue discoloration of the skin, urine, feces, or serum and some were associated with serious complications such as refractory hypotension, metabolic acidosis and death. Case reports indicate that seriously ill patients, particularly those with a likely increase in gut permeability (e.g., patients with sepsis), may be at greater risk for these complications. Because these events were reported voluntarily from a population of unknown size, it is not possible to establish the incidence of these episodes.

Please note this is available on the FDA's website as this was issued by the FDA.

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Toxicity of Food Drug and Cosmetic Blue No. 1 dye in critically ill patients.

Authors: Lucarelli MR, Shirk MB, Julian MW, Crouser ED
Division of Pulmonary and Critical Care Medicine, Department of Pharmacy, The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Medical Center, 473 West Twelfth Avenue, Columbus, OH 43210-1252, USA.

Abstract

Food Drug and Cosmetic Blue No. 1 dye (FD&C Blue No. 1) is commonly added to enteral nutrition formulations in order to facilitate the detection of gastric aspirate in tracheal secretions of critically ill patients. However, reports of systemic blue dye absorption and associated adverse outcomes are emerging. We report two cases of abnormal systemic absorption of FD&C Blue No. 1 in critically ill patients who subsequently died of refractory shock and metabolic acidosis. Risk factors and mechanisms of FD&C Blue No. 1 toxicity are discussed, and alternate approaches to gastric aspiration detection in critically ill patients are considered.

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Study of Red No. 3 and Dopamine

Erythrosine B inhibits dopamine transport in rat caudate synaptosomes.

Author: Lafferman JA, Silbergeld EK

Abstract

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 in rat caudate synaptosomes "uncompetitively" in the 10- to 800-micromolar range. Half maximal inhibition of uptake occurred at 45 micromolar. Uncompetitive inhibition denotes a decrease in efficacy of the dopamine membrane transport mechanism with an increase in affinity of dopamine to the carrier. 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.

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Red No.3 and Neuromuscular Synapse Affects

Neurotransmitter Release from a Vertebrate Neuromuscular Synapse Affected by a Food Dye.

Authors: Augustine GJ Jr, Levitan H

Abstract

The food dye erythrosine (Erythrosin B; FD & C No. 3) was applied to isolated neuromuscular synapses in the frog, and its effects on the spontaneous quantal release of acetylcholine were examined with electrophysiological techniques. At concentrations of 10 muM or greater this anionic dye produced an irreversible, dose-dependent increase in neurotransmitter release. This increase did not depend on the presence of calcium ions in the bathing medium. These increase did not depend on the presence of calcium ions in the bathing medium. 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 reexamined.

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Study of Developmental Toxicity of Red No. 40

Developmental toxicity and psychotoxicity of FD and C red dye No 40 (allura red AC) in rats.

Authors: Vorhees CV, Butcher RE, Brunner RL, Wootten V, Sobotka TJ

Abstract

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. The treatment groups were: FD and C red dye No. 40 as 0.0, 2.5, 5.0 or 10.0% of the diet, and a positive control group treated with the toxin hydroxyurea on days 2-10 of life with 50 mg/kg/day given s.c. as a positive control group. Parental animals were evaluated for weight and food consumption, and females for reproductive success. The offspring were assessed on a series of tests using the Cincinnati Psychoteratogenicity Screening Test Battery. Additional measures were weight, food consumption, physical landmarks of development, and brain weight. 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.

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Study of Reproductive Toxicity of Red No. 3

A study on the reproductive toxicity of erythrosine (Red No. 3) in male mice.

Authors: Abdel Aziz AH, Shouman SA, Attia AS, Saad SF
Pharmacology Department, Faculty of Pharmacy, Al-Azhar, Egypt.

Abstract

Worldwide usage of different colouring agents in the food industry prompted us to study their toxicity. The potential adverse effects of erythrosine (ER, FD & C Red No. 3) on the spermatogenesis process were investigated in adult mice. Testicular lactic dehydrogenase isoenzyme activity (LDH-X), a pachytene spermatocyte marker of testicular toxicity, was significantly decreased to 71.8% and 68.6% of the control value after daily p.o. administration of ER (21 days) in doses of 68 and 136 mg kg-1 respectively. At the same time, the normal average epididymal 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. Thus, after 5 daily p.o administrations of ER in doses of 680 and 1360 mg kg-1 (equivalent to 10 and 20% of its LD50) 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.

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Red No. 3 and Breast Cancer

Estrogenic and DNA-damaging activity of Red No. 3 in human breast cancer cells.

Authors: Dees C, Askari M, Garrett S, Gehrs K, Henley D, Ardies CM
Health Sciences Research Division, Oak Ridge National Laboratory, Tennessee, USA. genase@aol.com

Abstract

Exposure to pesticides, dyes, and pollutants that mimic the growth promoting effects of estrogen may cause breast cancer. The pesticide DDT and the food colorant Red No. 3 were found to increase the growth of HTB 133 but not estrogen receptor (ER) negative human breast cells (HTB 125) or rat liver epithelial cells (RLE). Red No. 3, beta-estradiol, and DDT increase ER site-specific DNA binding to the estrogen response element in HTB 133 cells and increase cyclin-dependent kinase 2 activity in MCF-7 breast cancer cells. Site-specific DNA binding by p53 in RLE, HTB 125, HTB 133, and MCF-7 cells was increased when they were treated with Red No. 3, which suggests that cellular DNA was damaged by this colorant. 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.

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Another Study of FD&C Red No. 3 - Erythrosine

Reproductive and neurobehavioral toxicity study of erythrosine (Red 3) administered to mice in the diet.

Author Tanaka T.
Department of Toxicology, Tokyo Metropolitan Research Laboratory of Public Health, 3-24-1, Hyakunincho, Tokyo 169-0073, Shinjuku-ku, Japan. tanaka@tokyo-eikwn.go.jp

Abstract

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. There were no adverse effects of erythrosine on either litter size, litter weight or sex ratio at birth. The average body weight of the offspring was significantly increased in the middle-dose group in both sexes during the lactation period. In behavioural developmental parameters, any variables showed no significant adverse effects in either sex in the lactation period. 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. The dose level of erythrosine in the present study produced few adverse effects in reproductive and neurobehavioural parameters in mice.

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A study of FD&C Red No. 40, 2, 106, 18

DNA damage induced by red food dyes orally administered to pregnant and male mice.

Authors: Tsuda S, Murakami M, Matsusaka N, Kano K, Taniquchi K, Sasaki YF
Laboratory of Veterinary Public Health, Department of Veterinary Medicine, Faculty of Agriculture, Iwate University, Ueda 3-18-8, Morioka, Iwate 020-8550, Japan. s.tsuda@iwate-u.ac.jp

Abstract

We determined the genotoxicity of synthetic red tar dyes currently used as food color additives in many countries, including JAPAN: For the preliminary assessment, we treated groups of 4 pregnant mice (gestational day 11) once orally at the limit dose (2000 mg/kg) of amaranth (food red No. 2), allura red (food red No. 40), or acid red (food red No. 106), and we sampled brain, lung, liver, kidney, glandular stomach, colon, urinary bladder, and embryo 3, 6, and 24 h after treatment. We used the comet (alkaline single cell gel electrophoresis) assay to measure DNA damage. 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. None of the dyes damaged DNA in other organs or the embryo. We then tested male mice with amaranth, allura red, and a related color additive, new coccine (food red No. 18). The 3 dyes induced DNA damage in the colon starting at 10 mg/kg. Twenty ml/kg of soaking liquid from commercial red ginger pickles, which contained 6.5 mg/10 ml of new coccine, induced DNA damage in colon, glandular stomach, and bladder. The potencies were compared to those of other rodent carcinogens. The rodent hepatocarcinogen p-dimethylaminoazobenzene induced colon DNA damage at 1 mg/kg, whereas it damaged liver DNA only at 500 mg/kg. Although 1 mg/kg of N-nitrosodimethylamine induced DNA damage in liver and bladder, it did not induce colon DNA damage. N-nitrosodiethylamine at 14 mg/kg did not induce DNA damage in any organs examined. Because the 3 azo additives we examined induced colon DNA damage at a very low dose, more extensive assessment of azo additives is warranted.

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A study of FD&C Red No. 3 - Erythrosine

Short-term erythrosine B-induced inhibition of the brain regional serotonergic activity suppresses motor activity (exploratory behavior) of young adult mammals

Dalal A, Poddar MK. Pharmacology, Biochemistry, and Behavior,2009 Jun;92(4):574-82. Epub 2009 Mar 3.

Department of Biochemistry, University of Calcutta, 35 B.C., Road, Kolkata-700 019, India

Abstract

Previous studies showed that repeated ingestion of erythrosine B (artificial food color) developed behavioral hyperactivity, but nothing is known about its single administration effect as well as the neurochemical (s) involvement. The present study provides evidence that a single higher dosage (10, 100 or 200 mg/kg, p.o.) of erythrosine administration to young adult male rats reduced motor activity (MA) maximally at 2 h and brain regional (medulla-pons, hippocampus and hypothalamus) serotonergic activity (measuring steady-state levels of 5-HT and 5-HIAA, pargyline-induced 5-HT accumulation and 5-HIAA declination rate and 5-HT receptor binding) under similar experimental condition. The degree of erythrosine-induced inhibition of both MA and brain regional serotonergic activity was dosage dependent. Lower dosage (1 mg/kg, p.o.) did not affect either of the above. Erythrosine (100 or 200 mg/kg, p.o.)-induced MA suppression was also observed in the presence of specific MAO-A inhibitor, clorgyline (5 mg/kg, i.p.) or MAO-B inhibitor, deprenyl (5 mg/kg, i.p.); but their co-application (5 mg/kg, i.p., each) effectively prevented the erythrosine-induced motor suppression. Altogether these results suggest that a single higher dosage of erythrosine (10–200 mg/kg, p.o.) may reduce MA by reducing serotonergic activity with modulation of central dopaminergic activity depending on the brain regions.

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