WHO FOOD ADDITIVES SERIES: 48
First draft prepared by G.J.A. Speijers1, M.E. Van Apeldoorn1 and D.G. Hattan2
1Section on Public Health, Centre for Substances & Risk Assessment, National Institute of Public Health and Environmental Protection, Bilthoven, Netherlands
2Division of Health Effects Evaluation, Center for Food Safety and Applied Nutrition, Food and Drug Administration, Washington DC, USA
D-Tagatose is a ketohexose, an epimer of D-fructose inverted at C-4, with a sweet taste. It is obtained from D-galactose by isomerization under alkaline conditions in the presence of calcium.
D-Tagatose was evaluated by the Committee at its fifty-fifth meeting (Annex 1, reference 149), when it concluded that the available data indicated that D-tagatose is not genotoxic, embryotoxic, or teratogenic. It also concluded that the increased liver weights and hepatocellular hypertrophy seen in Sprague-Dawley rats occurred concurrently with increased glycogen deposition; however, the increased glycogen storage was reversed after removal of D-tagatose from the feed more rapidly than regression of the liver hypertrophy. Although the gastrointestinal symptoms seen in adult humans who had the expected daily intake of D-tagatose were minor, the Committee was concerned about the increased serum uric acid concentrations seen in a number of studies in humans after either single or repeated doses of D-tagatose. Similar increases are seen with other sugars, such as fructose, but D-tagatose appears to be a more potent inducer of this effect. The Committee noted that this effect of D-tagatose had not been studied in persons prone to higher serum uric acid concentrations. The Committee concluded that an ADI could not be allocated for D-tagatose because of concern about its potential to induce glycogen deposition and hypertrophy in the liver and to increase the concentrations of uric acid in serum.
Two studies of up to 7 days in Wistar and Sprague-Dawley rats given repeated doses, which might help to resolve the relevance of the liver glycogen deposition and hypertrophy, were submitted, but the reports were received only in draft form and were not suitable for consideration at the time of the fifty-fifth meeting of the Committee. The Committee therefore asked for the final reports and for further data to clarify the extent, mechanism, and toxicological consequences of the increased uric acid concentrations observed in human subjects in some studies. At the present meeting, the results of four studies in experimental animals (including the two reports of which only drafts were available previously), the result of a study in volunteers (on the relevance of the glycogen deposition and liver hypertrophy), and some publications on the increased uric acid concentrations in serum after intake of D-tagatose, other sugars, and other food components were reviewed.
The increase in normal liver mass seen in fasted rats fed 10 or 20% D-tagatose has been hypothesized to be triggered by increased postprandial storage of liver glycogen. In order to support this hypothesis, a series of studies was carried out on the effects of separate and simultaneous administration of D-tagatose and glycogen precursors on liver weight and glycogen level in Wistar and Sprague-Dawley rats.
The animals were kept under a light–dark regime of 12 h each, the light period lasting from 9:00 h to 21:00 h and the dark period from 21:00 h to 9:00 h. The sugars were given by gavage in two portions during the light period, 5 and 8 h after the dark period, which is the normal feeding period for rats. Four groups of 20 male Wistar rats received one of the following regimens for 7 days:
After 7 days, 10 rats from each group were killed at the end of the dark period and 10 at the end of the light period. Treatment (by diet or gavage) continued until sacrifice.
Weight loss occurred in all groups, probably due to restricted feeding and low energy intake. Simultaneous administration of D-tagatose and glucose was assumed to result in glycogen deposition and to increase the normal liver mass, as indicated by the significantly lower glycogen deposition and weight of the liver in rats on regimen (ii) that were killed at the end of the light period (after polycose by gavage) than in rats on regimen (iii) that were killed at the end of the dark period. In rats on regimen (iii) that were killed at the end of the light period, no glycogen was found, but the liver weight was significantly higher than that of controls on regimen (i) killed at the same time, probably reflecting early liver growth in response to increased glycogen deposition induced by D-tagatose. Rats on regimen (iv) that were killed at the end of the dark period showed slightly increased liver weights and glycogen concentrations similar to that of controls on regimen (i), indicating that separation of feeding into two parts resulted in more even feed intake, with no peak of glycogen and no triggering of glycogen deposition and liver growth by D-tagatose (Lina & de Bie, 2000a).
In a study of similar design, three groups of 18 adult male Sprague-Dawley rats received one of the following regimens for 5 days:
After 5 days on the diets, six rats from each group were killed at 06:00 h during the dark period, at 12:00 h before gavage, and at 18:00 h after the last gavage.
Weight loss was seen in all groups, due to the restricted feeding. Rats on regimen (iii) that were killed at 06:00 h had a higher glycogen concentration and liver weight than controls on regimen (i). In rats killed at 12:00 and 18:00, when no food was available, the glycogen concentrations of those on regimens (i) and (iii) were decreased, but the glycogen concentrations and liver weights remained slightly higher in rats on (iii) than in controls on (i). Rats on regimen (ii) that were killed at 06:00 and 12:00 h had a lower glycogen concentration and liver weight than rats on regimen (iii) or on regimen (i). Rats on regimen (ii) killed at 18:00 h had liver weights comparable to those of controls on (i), but their glycogen concentration was higher than that of rats on (iii) or (i), probably because the glucose-free diet was administered during the dark period and polycose was given during the light period.
Three additional groups of 12 rats were intended for various hepatic examinations after 4 weeks on the above diets. However, during week 2 of treatment, the condition of the rats declined and gavage became increasingly difficult. The study was therefore aborted on day 10 (Lina & de Bie, 2000b).
In a study of similar design, the gavage dose was given in two or three (group ii) portions during the light period; 5, 6, and 8 h after the dark period. Four groups of 12 adult male Sprague-Dawley rats received one of the following regimens for 26 days:
On day 26, all groups were fed regimen (i) ad libitum from the start of the dark period (19:00 h). On day 27, all rats were deprived of food in the afternoon (from 17:00 h) until necropsy in fasted condition on the morning of day 28. The daily portions of diets were restricted to ensure that each rat received the same amount of nutrients either via the diet or by gavage. As the daily portions of diets were generally completely consumed, the overall daily intake of D-tagatose was similar in groups (i), (ii), and (iii) and amounted to about 7 g/kg bw per day. Food consumption, body weights, absolute and relative liver weights, the concentrations of total lipid, glycogen, glucose, and protein, total moisture, and amount of DNA per liver were determined. The livers were not examined histologically.
The glycogen concentrations in the liver were low in all groups, as would be expected in rats killed after fasting. The total moisture content, total lipid concentration, and DNA and total protein per liver were significantly higher in rats on regimen (iii) than in those on (i). The liver weights were increased in all groups receiving D-tagatose in the diet during the dark period. No significant differences were observed in DNA concentration among rats on regimens (i), (ii), and (iv). Total moisture content and lipid and protein concentrations were similar in all groups receiving D-tagatose. The authors concluded that the results of these studies neither supported nor invalidated the hypothesis that the increase in normal liver mass is triggered by increased postprandial storage of liver glycogen resulting from simultaneous feeding of D-tagatose and glucose equivalents (Lina & de Bie, 2000c).
The consequences of prolonged dietary administration of D-tagatose and/or fructose were examined in a 6-month study that involved five groups of 60 male Wistar rats. The control group received a diet containing 20% barley, while the treated groups received diets containing 5% or 10% D-tagatose, 20% fructose, or 10% D-tagatose plus 10% fructose. The additions of the sugars were at the expense of barley (5–20%). Ten rats from each group were killed after 3, 7, 14, and 28 days and 3 and 6 months of treatment. The time-weighted average intakes over 6 months were 2.4 and 4.8 g/kg bw per day of D-tagatose in the groups receiving 5% and 10% D-tagatose, 9.4 g/kg bw per day of fructose in that receiving 20% fructose, and 4.9 g/kg bw per day each of D-tagatose and fructose in the group receiving 10% D-tagatose plus 10% fructose. The animals were fasted overnight before necropsy.
The general condition and behaviour of the animals were not affected by the treatments. One rat given 10% D-tagatose died, but the death was considered unrelated to treatment. The mean body weight was slightly decreased for rats fed 10% D-tagatose alone or in combination with fructose, and the food intake in these groups was slightly decreased during the first week of the study. There were no consistent, relevant changes in clinical chemical parameters and no significant changes in the absolute or relative weight of the liver at any time. Gross examination of all rats killed at the various times and microscopic examination of the liver of rats killed after 6 months did not reveal any treatment-related changes. Unfortunately, the livers of rats killed at other times were not examined microscopically. No consistent differences in the labelling index (per cent of BrdU-positive cells) or in the nuclear density (number of nuclei/area of tissue) were found in hepatocytes of rats receiving D-tagatose and the controls. Rats fed 20% fructose had a slightly increased labelling index up to 28 days, but the differences from controls were statistically significant at day 7 only. Feeding of D-tagatose did not cause any consistent changes in the lipid, protein, DNA, glycogen, or glucose content of the liver. In rats fed diets containing 20% fructose or 10% D-tagatose plus 10% fructose, the protein content per gram of liver or per total liver were occasionally increased. The carcass weight and the moisture, fat, protein, and ash contents of rats receiving 5% or 10% D-tagatose, 20% fructose, or 10% D-tagatose plus 10% fructose were similar to those of the controls. It was concluded that administration of D-tagatose at 10% in the diet, equal to 4.8 g/kg bw per day, did not cause any adverse effects. No hypertrophy or other hepatic changes were seen at the end of the study (Lina & de Bie, 2000d).
A study was conducted to test the hypotheses that partial substitution of dietary sucrose by D-tagatose for 28 days increases the volume of the human liver and the concentration of liver glycogen. Twelve healthy male volunteers were included in a double-blind cross-over study involving ingestion of D-tagatose (three times 15 g/day) or placebo (sucrose, three times 15 g/day) for 28 days. Body weight, blood pressure, and heart rate were measured, and urine analysis (dipstick method) was performed; glucose and insulin concentrations were determined in serum, and glucagon and uric acid concentrations were determined in plasma. Blood samples collected before breakfast on days 1 and 29 were analysed for routine haematological and other clinical chemical parameters. Triglycerides and cholesterol (high- and low-density and total) were analysed in serum, and glucose, creatinine, urea, and bilirubin concentrations and the activities of alanine and aspartate aminotransferases and alkaline phosphatase and gamma-glutamyl transpeptidase in plasma. Liver volume and glycogen concentrations were determined by magnetic resonance imaging and spectroscopy, accompanied by routine medical examinations. Magnetic resonance imaging before and after treatment revealed no effects of treatment on liver volume or glycogen concentration. A steady increase in liver volume, independent of intake of D-tagatose or placebo was observed during the study, in parallel with a slight increase in body weight. Treatment with D-tagatose was not associated with clinically relevant changes in the medical, clinical chemical, or haematological parameters examined, including liver enzymes and uric acid. The plasma uric acid concentration was 340–360 µmol/l in the group given D-tagatose and 340–350 µmol/l in that given placebo (Boesch et al., 2001).
D-Fructose increases uric acid production by accelerating the degradation of purine nucleotides, probably by hepatocellular depletion of inorganic phosphate (Pi) resulting from accumulation of ketohexose-1-phosphate. The hyperuricaemic effect of D-tagatose, a stereoisomer of D-fructose, may be more prolonged than that of D-fructose as the subsequent degradation of D-tagatose-1-phosphate is slower than that of D-fructose-1-phosphate. The effect of oral intake of 30 g of D-tagatose dissolved in drinking-water on plasma uric acid concentration and other metabolic parameters was compared with that of 30 g of D-fructose in drinking-water or drinking-water alone in eight male volunteers in a double-blind cross-over study.
Both the peak concentration and the area under the curve of concentration–time at 4 h of serum uric acid were significantly higher after intake of D-tagatose than with either D-fructose or plain drinking-water. The decline in serum Pi concentration was greater 50 min after intake of D-tagatose than after that of D-fructose. The thermogenic and lactacidaemic responses to D-tagatose were smaller than with D-fructose. D-Tagatose attenuated the glycaemic and insulinaemic responses to a meal consumed 255 min after its administration. Both D-fructose and D-tagatose increased the plasma concentrations of cholecystokinin and glucagon-like peptide-1. The metabolic effects of D-tagatose were seen despite its putatively poor absorption. A peak serum uric acid concentration of 410 µmol/l was seen 50 min after intake of D-tagatose; a lower peak of 370 µmol/l was seen 250 min after intake of fructose, when the serum uric acid concentration of men who received D-tagatose was still 390 µmol/l. The normal serum concentrations of uric acid are 360–365 µmol/l (Buemann et al., 2000a).
D-Tagatose is phosphorylated to D-tagatose-1-phosphate by fructokinase in the liver. Because the phosphate degrades slowly, it may accumulate, and ingested D-tagatose may therefore cause longer reductions in Pi and ATP levels in the liver than D-fructose. As seen in patients with hereditary fructose intolerance, D-tagatose may increase purine nucleotide degradation and thereby increase uric acid production. The effect of administration of 30 g of D-tagatose or D-fructose in drinking-water on ketohexose-1-phosphate, ATP, and Pi levels in the liver was studied by 31P-magnetic resonance spectroscopy in groups of five young male volunteers. Blood and urine were collected to detect any increased uric acid production.
A peak of 5.2 mg/l D-tagatose-1-phosphate, equivalent to about 1 mmol/l, was found in the spectra of all subjects within 30 min after administration of D-tagatose. Concomitantly, the concentration of ATP was reduced by about 12% (p < 0.05). Both parameters had returned to baseline values after 150 min. The serum uric acid concentration was increased by 17% 50 min after administration of D-tagatose (p < 0.05) and had not returned to baseline when the experiment was terminated 230 min after the load. The 12% decrease in renal fractional extraction of uric acid could not explain the acute hyperuricaemic effect of D-tagatose. No changes in 31P-magnetic resonance spectra or serum uric acid concentration were found after administration of D-fructose. These results suggest that moderate intake of D-tagatose can affect liver metabolism by phosphate trapping, despite incomplete absorption of the sugar. The baseline serum uric acid concentrations of D-tagatose, D-fructose, and water were 360–375 µmol/l. A peak serum concentration of uric acid of 430 µmol/l was reached 50 min after intake of D-tagatose, and a peak of 390 µmol/l was reached 180 min after intake of D-fructose. The area under the concentration–time curve for serum uric acid at 250 min was 9.0 mmol.min/l after D-tagatose intake and 3.6 mmol.min/l after D-fructose intake. The serum uric acid concentration was similar in all groups 35 min after consumption of a meal at 245 min, with a value of 400 µmol/l (Buemann et al., 2000b).
Three studies are described below to provide a basis for comparison of changes in serum uric acid concentrations induced by other dietary components and or physiological states.
Serum and urinary uric acid concentrations were measured before and after ingestion of 80 g each of casein, lactalbumin, and soya bean isolate in 10 healthy subjects. The serum concentration had decreased significantly 3 h after ingestion of lactalbumin and casein but had increased after consumption of soya bean isolate. Clearance of urate was significantly increased after ingestion of each of the three proteins. Multivariate analysis of urate clearance with lactalbumin and casein loads showed an independent correlation between serum alanine and urea concentration. These results indicate that milk protein acutely decreases the serum uric acid concentration. Analysis of the effect of lactalbumin and casein on urinary uric acid elimination suggested that the uricosuric effect of proteins is a multifactorial phenomenon. The serum uric acid concentrations of casein, lactalbumin, and soya protein were 300, 300, and 280 µmol/l at baseline and 270, 270, and 310 µmol/l, respectively, at 180 min (Garrel et al., 1991).
Ten hyperinsulinaemic and 11 men with normal blood insulin consumed a diet in which 20% of the calories were from either fructose or high-amylose cornstarch (at current consumption levels in the USA), for 5 weeks, each in a cross-over design to determine the effects of the two diets on various blood metabolites considered to be risk factors associated with heart disease. In the hyperinsulinaemic men, ingestion of fructose as compared with cornstarch significantly increased the concentrations of several blood lipid and uric acid. In the men with normal blood insulin, the concentrations of certain blood lipids and uric acid were significantly greater after consumption of fructose than after cornstarch. The results indicate that, in a diet high in saturated fatty acids and cholesterol, fructose increases the levels of risk factors associated with heart disease, especially in hyperinsulinaemic men. The baseline concentration of serum uric acid was 345 µmol/l in the group given fructose and 315 µmol/l in that given high-amylose cornstarch; in both cases, the peak concentrations were reached 120 min after dosing and were 360 µmol/l for fructose and 325 µmol/l for cornstarch. With both treatments, the serum uric acid concentration had returned to normal within 3 h (Reiser et al., 1989).
Twelve healthy male nonsmokers drank red wine, phenol-stripped red wine, dealcoholized red wine, or water, each at a separate visit (cross-over experiment), in random order and 1 week apart. The beverages were consumed over 30 min, and blood was sampled just before and 1, 2, and 4 h after consumption for measurement of serum uric acid and selected additional parameters.
The uric acid concentrations in serum increased significantly (p < 0.001) after ingestion of red wine, phenol-stripped red wine, and dealcoholized red wine. The serum values for uric acid were 340–360 µmol/l at baseline, whereas they were 400 µmol/l for the group given red wine or phenol-stripped red wine and 390 µmol/l for that given dealcoholized red wine 1 h after ingestion, and 390, 390, and 380 µmol/l, respectively, after 2 h, and 370, 370, and 350 µmol/l, respectively, after 4 h. There were no effects on ex vivo serum or low-density lipoprotein oxidation after ingestion of any of the beverages (Caccetta et al., 2000.).
The upper limit of the reference interval of serum uric acid concentrations for healthy Danish males is 450 µmol/l (Buemann et al., 2000a). Handbooks of clinical chemistry reveal similar ranges for normal values: 240–500 µmol/l for men and 160–430 µmol/l for for women (Henry, 1979); 210–440 µmol/l for men, 150–330 µmol/l for women, and 120–330 µmol/l for children (Tietz, 1982). Watts (1979) indicated that children had lower serum uric acid concentrations than adults until puberty, and women had slightly lower serum uric acid concentration than men until menopause.
Review of the results of the studies considered by the Committee at its fifty-fifth meeting and comparisons with the data reviewed at the present meeting revealed a difference between Wistar and Sprague-Dawley rats. Sprague-Dawley rats given 5% D-tagatose for 28 days showed increased hepatic glycogen only when they were not fasted the night before sacrifice, but this effect was not associated with any changes in the liver when examined by electron microscopy. In a 90-day study in which Sprague-Dawley rats were killed under fasted conditions, 5% D-tagatose had no adverse effect on the liver. In a 6-month study in Wistar rats in which the animals were killed under fasted conditions after 3, 7, 14, and 28 days and 3 and 5 months, D-tagatose at concentrations up to 10% had no adverse effects. Wistar rats are therefore less susceptible to the hepatic effects of D-tagatose than Sprague-Dawley rats. As D-tagatose stimulated glycogen deposition to a similar degree in the two rat strains in short-term studies, the difference is likely to occur at a later stage, namely glycogen-induced or other stimulation of liver growth.
The authors suggested that the increase in normal liver mass seen in fasted rats fed diets containing 10 or 20% D-tagatose is triggered by increased postprandial storage of liver glycogen, resulting from simultaneous feeding of D-tagatose and glucose equivalents. In order to test this hypothesis, the effects of separate and simultaneous administration of D-tagatose and glycogen precursors on liver weight and glycogen level were investigated in Wistar and Sprague-Dawley rats. The results neither supported nor invalidated the hypothesis.
As several studies have been performed in healthy volunteers and in patients with diabetes, the number of persons varying from 4 to 73, the Committee based its toxicological evaluation on the human data. The length of these studies varied from several days to several weeks and one study of 12 months’ duration, which included only a limited number of patients with type 2 diabetes. The toxicological aspects investigated included gastrointestinal effects, increased serum uric acid concentrations, and hepatic effects. Mild gastrointestinal symptoms were reported in only one study, in three of 10 patients with type 2 diabetes receiving 10 g of D-tagatose for several days, whereas in other studies diarrhoea was observed only in patients receiving 25 g three times daily for 8 weeks. In healthy individuals, administration of 30 g induced diarrhoea in some individuals only, whereas other studies showed no laxative effect of single doses of D-tagatose as high as 75 g.
The serum or plasma concentration of uric acid was increased transiently in some studies in human subjects, but the increased uric acid concentration was above the normal range for a number of days in only one study of persons receiving 75 g daily. The other studies showed either no increase or a transient increase in serum uric acid concentrations within the normal range.
In a 28-day study in which 15 g of D-tagatose or 15 g of sucrose were given three times daily, magnetic resonance imaging was used to determine liver volume, and glycogen concentrations and several clinical chemical parameters were measured. The results did not reveal any relevant effect on the liver. In addition, no diarrhoea and no increase in serum uric acid concentration were observed. Therefore, the NOEL was 45 g/person per day, equivalent to 0.75 g/kg bw (for a person weighing 60 kg).
D-Tagatose is proposed for use as a bulk sweetener in low-energy foods, such as edible ices (at a concentration of 3 g/kg), chewing-gum and confectionery (at 15 g/kg), breakfast cereals (at 15 g/kg), and soft drinks (at 1 g/kg). At its fifty-fifth meeting, the Committee considered that the predicted intakes of D-tagatose based on the manufacturers’ proposed levels of use and individual dietary records from several countries were conservative estimates because use had been assumed in the entire food category rather than only in the low-energy food component. The mean consumer intakes of D-tagatose predicted for Australia, the Member States of the European Union, and the USA ranged from 3 to 9 g/day (63–190% of the ADI), and the predicted intakes for consumers at high percentiles were up to 18 g/day (375% of the ADI). On the basis of the information on possible uses, the ADI for D-tagatose may be exceeded.
The Committee considered the 28-day study in which humans received a daily dose of 45 g of D-tagatose or sucrose in three divided doses as most representative of human dietary intake and therefore most relevant for assessing the acceptable intake of D-tagatose and other sugars accurately. While effects were observed after a single dose of 75 g, no effects were observed with three daily doses of 15 g of D-tagatose, equivalent to 0.75 g/kg bw per day. The Committee established an ADI of 0–80 mg/kg bw on the basis of this NOEL and a safety factor of 10.
Boesch, C., Ith, M., Jung, B., Bruegger, K., Erban, S., Diamantis, I. & Bär, A. (2001) Effect of oral D-tagatose on liver volume and hepatic glycogen accumulation in healthy male volunteers. Submitted for publication to Regulatory Toxicology and Pharmacology.
Buemann, B., Gesma, H., Astrup, A. & Quistorff, B. (2000a) Effects of oral D-tagatose, A stereoisomere of D-fructose, on liver metabolism as examined by 31P-magnetic resonance spectroscopy. Metabolism, 49, 1335–1339.
Buemann, B., Toubro, S., Holst, J.J., Rehfeld, J.F., Bibby, B.M. & Astrup, A. (2000b) D-Tagatose, a stereoisomere of D-fructose, increases blood uric acid concentration. Metabolism, 49, 969–97.
Caccetta, R.A., Croft, K.D., Beilin, L.J. & Puddey, I.B. (2000) Ingestion of red wine significantly increases plasma phenolic acid concentrations but does not acutely affect ex vivo lipoprotein oxidizability. Am. J. Clin. Nutr., 71, 67–74.
Garrel, D.R., Verdy, M., PetitClerc, C., Martin, C., Brulé, D. & Hamet, P. (1991) Milk- and soy-protein ingestion: Acute effect on serum uric acid concentration. Am. J. Clin. Nutr., 199, 665–669.
Henry, J.B., ed. (1979) Todd Sanford Division Clinical Diagnosis and Management by Laboratory Methods, 16th Ed., Philadelphia: W.B. Saunders Co., p. 745.
Lina, B.A.R. & de Bie, A.T.H.J. (2000a) Investigation into the consequences of administering D-tagatose spaced from, and simultaneously with, the ingestion of precursors of glycogen in Wistar rats (7-day study). Unpublished report V99.1094 dated April 2000 from TNO Nutrition and Food Research Institute, Bilthoven, at the request of MD Foods Denmark. Submitted to WHO by Bioresearch Management and Consulting Ltd, Basel, Switzerland.
Lina, B.A.R. & de Bie, A.T.H.J. (2000b) Investigation into the consequences of administering D-tagatose spaced from, and simultaneously with, the ingestion of precursors of glycogen in male Sprague-Dawley rats. Unpublished report V2529 dated October 2000 from TNO Nutrition and Food Research Institute, Bilthoven, at the request of MD Foods Denmark. Submitted to WHO by Bioresearch Management and Consulting Ltd, Basel, Switzerland.
Lina, B.A.R. & de Bie, A.T.H.J. (2000c) Investigation into the consequences of administering D-tagatose spaced from, and simultaneously with, the ingestion of precursors of glycogen in male Sprague Dawley rats (28-day study). Unpublished report V2678 dated November 2000 from TNO Nutrition and Food Research Institute, Bilthoven, at the request of MD Foods Denmark. Submitted to WHO by Bioresearch Management and Consulting Ltd, Basel, Switzerland.
Lina, B.A.R. & de Bie, A.T.H.J. (2000d) Investigation into the consequences of feeding D-tagatose and fructose on liver parameters in Wistar rats (6-month study). Unpublished report V99.1123 dated October 2000 from TNO Nutrition and Food Research Institute, Bilthoven, at the request of MD Foods Denmark. Submitted to WHO by Bioresearch Management and Consulting Ltd, Basel, Switzerland.
Reiser, S., Powell, A.S., Scholfield, D.J. Panda, P., Ellwood, K.C. & Canary, J.J. (1989) Blood lipids, lipoproteins, apoproteins, and uric acid in men fed diets containing fructose or high-amylose cornstarch. Am. J. Clin. Nutr., 49, 832–839.
Tietz, N.W., ed. (1982) Fundamentals of Clinical Chemistry, 2nd Ed., Philadelphia: W.B. Saunders Co., p. 1225.
Watts, R.W.E. (1979) Purines and nucleotides. In: Brown, S.S., Mitchell, F.L. & Young, D.S., eds, Chemical Diagnosis of Disease, Amsterdam: Elsevier-North Holland Biomedical Press, p. 1090.
See Also: Toxicological Abbreviations