The effect of 2-acetyl-4-tetrahydroxybutylimidazole on lymphocyte subsets in peripheral blood of the rat

Gobin, Stéphanie; Legg, R.F.; Paine, Alan J.; Phillips, J. A.

doi:10.1016/0192-0561(89)90116-1

Cited by 17 publications

(4 citation statements)

References 14 publications

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“…The effect ofTHI in rats was prevented by the addition ofpyridoxine to the diet [17] but it was reported thai ihc effect ofTHI was not materially affecicd by diclary levels ofpyridoxine. Gobin et al [8] gave THI to rats by gavage at a dose of 1 mg/kg body weight per day for 7 days and reported that peripheral blood T and B cells were reduced within 1 day. It is not certain how this compares with continuous administration in drinking water but it is certainly very much less than the dose given in our study, A normal mouse drinks about 5 ml of water a day [18], anti therefore each animal would have ingested approximately 2 mg of THI.…”

Section: Discussionmentioning

confidence: 99%

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Prevention of spontaneous and cyclophosphamide-induced diabetes in non-obese diabetic (NOD) mice with oral 2-acetyl-4-tetrahydroxybutyIimidazole (THI), a component of caramel colouring III

Mandel

Koulmanda

Mackay

1992

Clinical and Experimental Immunology

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SUMMARY The effect of oral administration of THI, a compound present in ammonia caramel food colouring, was studied in spontaneous and induced murine diabetes mellitus. Continuous administration of THI at400 ppm in drinking water reduced the prevalence of spontaneous diabetes in female NOD/Lt mice from 63% in untreated controls to 8% in treated animals. Since cyclophosphamide (CP) accelerates and intensifies diabetes in NOD mice, we also studied the effect of THI in this model. Diabetes incidence was reduced from 100% in mice given only CP to 13–14% in mice given THI either concurrently or from 14 days previously. Histologically.THI greatly reduced the severity of insulitis. As measured by flow cytometry, all THI‐treated mice had a 60–80% reduction in splenic CD4+ and CD8+ T cells. THI‐treated mice showed no untoward effects and specifically no weight loss, or pathological changes in their livers, kidneys or lungs. However, there was moderate atrophy of the thymus cortex. THI is a small imidazole‐containing compound with structural similarity to histamine and urocanic acid, both known to have immunosuppressive properties. It is a widely used food additive with no known long‐term toxic effects al low dosage. Thus, THI could be a useful immunosuppressive agent.

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Section: Discussionmentioning

confidence: 99%

“…The Waller and Eliza Hall Institute of Medical Research, Parkvillc 3050. Australia, toxic effects in rats and mice [5][6][7][8]. and affects immune competence in the rat even in quite small amounts, e.g.…”

mentioning

confidence: 99%

Prevention of spontaneous and cyclophosphamide-induced diabetes in non-obese diabetic (NOD) mice with oral 2-acetyl-4-tetrahydroxybutyIimidazole (THI), a component of caramel colouring III

Mandel

Koulmanda

Mackay

1992

Clinical and Experimental Immunology

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“…Gobin and co-workers examined the effect of giving THI at a level of 1 mg/kg bw/day by gavage for 7 days on the numbers of lymphocytes in subsets in peripheral blood (Gobin et al, 1989). Both immunoglobulin light chain-bearing B-cells (MARK-1+) and CD5 marker-bearing T-cells (OX-19+) were reduced in number within 1 day of treatment.…”

Section: Annex Dmentioning

confidence: 99%

Scientific Opinion on the re‐evaluation of caramel colours (E 150 a,b,c,d) as food additives

2011

EFS2

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The ANS Panel provides a scientific opinion re-evaluating the safety of the caramel colours (E150a (Class I), E150b (Class II), E150c (Class III), E150d (Class IV)) used as food additives. The caramel colours are a complex mixture of compounds produced by heating carbohydrates under controlled heat and chemical processing conditions; they are divided into four classes according to the manufacturing reactants used. The caramel colours were previously evaluated by the SCF and by JECFA, which concluded that a numerical ADI was not necessary for Class I, but established ADIs for the other classes of caramels, ranging from160-200 mg/kg bw/day. Given the consistency in the toxicological database, the Panel establishes a group ADI of 300 mg/kg bw/day for the caramel colours, by applying an uncertainty factor of 100 to a NOAEL of 30 g/kg bw/day (highest dose tested) identified in 13-week rat studies with Class IV and a similar NOAEL identified in a rat reproductive toxicity study, also with Class IV. Comparable NOAELS for Classes II, III and IV were reported in the SCF and JECFA evaluations. Within this group ADI, the Panel establishes an individual ADI of 100 mg/kg bw/day for Class III due to new information regarding the immunotoxicity of THI. The Panel concludes that the anticipated dietary exposure of child and adult populations may exceed the ADIs for Classes I, III and IV caramels, but exposure estimates to Class II were below the ADI. Exposure estimates for the caramel constituents THI, 4-MEI and SO 2 are not of concern, but the Panel welcomes additional studies to clarify remaining uncertainties regarding effects of THI on the immune system. The Panel notes that other constituents of caramel colours including 5-HMF and furan may be present at levels that may be of concern, and considers that the specifications should include maximum levels for these constituents. © European Food Safety Authority, 2011 KEY WORDSPlain Caramel, Caustic Caramel, caramel colour I, E 150a, Caustic Sulphite Caramel, caramel colour II, E 150b, Ammonia Caramel, caramel colour III, E 150c, Sulphite Ammonia Caramel, caramel colour IV, E 150d, CAS Registry Number 8028-89-5, food colouring substance. Re-evaluation of caramel colours (E 150 a,b,c,d) SUMMARYFollowing a request from the European Commission, the Panel on Food Additives and Nutrient Sources added to Food (ANS) was asked to deliver a scientific opinion re-evaluating the safety of caramel colours (E 150a,b,c,d) when used as food colouring substances.Caramel colours are colouring substances authorised as food additives in the EU, and are classified according to the reactants used in their manufacture as follows: Class I Plain Caramel or Caustic Caramel (E 150a); Class II Caustic Sulphite Caramel (E 150b); Class III Ammonia Caramel (E 150c) and Class IV Sulphite Ammonia Caramel (E 150d).The four classes of caramel colours have been previously evaluated by the EU Scientific Committee for Food (SCF), by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and by the ...

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“…The toxicity of THI was first recognized as a lymphopenic effect, i.e., a reduction in circulating lymphocyte counts, when fed at high concentrations to rats receiving a diet deficient or marginal in vitamin B 6 . − Inhibition of pyridoxal kinase has been suggested as a possible mechanism but has not been further evaluated. Additional research revealed that THI also impairs the immunity of rats and mice by modifying splenocyte function. − Mice fed with THI showed less CD4 + and CD8 + T-cells, and THI probably prevents the recruitment of CD4 + T-cells in draining lymph nodes. , These and further reports of immunotoxicity have been evaluated by international food safety authorities, and maximum levels of THI in caramel class III food colorings have been defined. − While the Joint FAO/WHO Expert Committee on Food Additives (JECFA) recommends a maximum amount of THI below 40 or 25 mg/kg on an equivalent color basis, the European Commission sets the maximum at 10 mg/kg on an equivalent color basis . No maximum levels have been defined for caramel class IV food colorings, which are considered free of THI to date…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Application of ¹³C-Labeled 2-Acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI), an Immunosuppressant Observed in Caramel Food Colorings

Elsinghorst

Raters²,

Dingel³

et al. 2013

J. Agric. Food Chem.

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2-Acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI) is a minor toxic contaminant observed in caramel food colorings and was shown to exert immunosuppressant activity when fed to rodents. Because of this toxicity, maximum levels of THI in caramel food colorings have been defined by international and European authorities. Several reports of THI analysis using external standardization have been published for liquid foods such as beers and soft drinks. However, no suitable internal standard has yet been described allowing THI analysis in more complex samples. In this paper we describe the preparation of a labeled [(13)C6]THI analogue and its application for the successful validation of the first stable isotope dilution assay (SIDA) of THI in caramel food colorings. A brief survey of THI levels in commercially available caramel class III (E 150c) and IV (E 150d) food colorings is also included, corroborating that THI occurs only in caramel class III food colorings.

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The effect of 2-acetyl-4-tetrahydroxybutylimidazole on lymphocyte subsets in peripheral blood of the rat

Cited by 17 publications

References 14 publications

Prevention of spontaneous and cyclophosphamide-induced diabetes in non-obese diabetic (NOD) mice with oral 2-acetyl-4-tetrahydroxybutyIimidazole (THI), a component of caramel colouring III

Prevention of spontaneous and cyclophosphamide-induced diabetes in non-obese diabetic (NOD) mice with oral 2-acetyl-4-tetrahydroxybutyIimidazole (THI), a component of caramel colouring III

Scientific Opinion on the re‐evaluation of caramel colours (E 150 a,b,c,d) as food additives

Synthesis and Application of ¹³C-Labeled 2-Acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI), an Immunosuppressant Observed in Caramel Food Colorings

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The effect of 2-acetyl-4-tetrahydroxybutylimidazole on lymphocyte subsets in peripheral blood of the rat

Cited by 17 publications

References 14 publications

Prevention of spontaneous and cyclophosphamide-induced diabetes in non-obese diabetic (NOD) mice with oral 2-acetyl-4-tetrahydroxybutyIimidazole (THI), a component of caramel colouring III

Prevention of spontaneous and cyclophosphamide-induced diabetes in non-obese diabetic (NOD) mice with oral 2-acetyl-4-tetrahydroxybutyIimidazole (THI), a component of caramel colouring III

Scientific Opinion on the re‐evaluation of caramel colours (E 150 a,b,c,d) as food additives

Synthesis and Application of 13C-Labeled 2-Acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI), an Immunosuppressant Observed in Caramel Food Colorings

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Synthesis and Application of ¹³C-Labeled 2-Acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI), an Immunosuppressant Observed in Caramel Food Colorings