XYLITOL
Explanation
Toxicological monographs were issued in 1977 and 1978 (see Annex
I, Refs. 44 and 49). Since the previous evaluation, additional data
have become available and are summarized and discussed in the
following monograph.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Absorption, distribution and excretion
Sixty Wistar albino rats were gradually adapted to 20% dietary
xylitol. Fully adapted and control rats were fasted overnight and
dosed by oral intubation with 5 µCi of U-14C xylitol, U-14C sorbitol
or 1-14C mannitol. Each isotope dose was mixed with corresponding
("cold") polyol to obtain a final dose of 0.625 g/kg bw. Tail vein
blood samples were obtained and counted. In several experiments
0.5 mol of calcium were given together with xylitol.
Xylitol adapted rats did not exhibit diarrhoea following the dose
administration. There was a significant increase in peak xylitol blood
levels as determined by radioactivity in xylitol adapted rats as
compared to controls. Xylitol adaptation also enhanced sorbitol and
mannitol absorption when compared to controls. Calcium caused an
initial rise in blood levels of radioactivity but the effect was not
statistically significant (Salminen, 1982).
Pig
Six male castrated pigs (39-75 kg weight range) were subjected to
feeding trials based on a Latin square design with either a polyol
mixture (a by-product of xylitol production containing xylane) or
xylitol supplementations. The transition period between diets was five
days, preliminary period seven days, and collection period seven days
(seven days feeding per diet). The basic diet consisted of skim milk
powder with minerals and vitamins, to which polyol mixture (levels of
5 or 2.5% dry matter) or xylitol (2.5 or 5% dry matter) were added.
Wheat starch (5.0 or 2.5%) served as control supplement. Faeces and
urine were collected twice a day and frozen until analysed. Venous
blood samples were obtained one, two, or four hours after feeding.
Glucose, plasma insulin and various clinical chemical parameters were
determined.
There was a slight decrease in the nitrogen balance of diets
supplemented with 10% of polyol mixture or 5% of xylitol. There was no
detectable xylitol or sugar alcohol in the faeces; a small quantity of
xylitol was found in the urine of pigs when fed polyol mixture but not
when fed xylitol. There was a significant rise in plasma glucose
levels in xylitol fed pigs. Urine N decreased slightly in polyol or
xylitol fed animals. Albumin concentration was significantly raised.
There were increases in plasma alanine and asparate transferases
(transaminases) (ALAT and ASAT also called serum glutamic pyruvic and
glutamic-oxaloacetic transaminases (SGPT and SGOT)).
The ALAT and SGPT levels increased significantly in a dose-
related manner and indicated possible liver toxicity. Only the high
dose level was statistically significantly different from the control.
There were increases in insulin concentrations following xylitol
feeding, and values two hours after feeding were higher than control
levels. This increase was also dose-related. The peak of insulin
levels was between 40-60 minutes after feeding (Nasa & Tanhuanpaa,
1981).
Metabolism
Wistar albino rats were either adapted to 20% xylitol diets or
given a 20% xylitol diet without adaptation or given a control diet.
These rats were placed in individual metabolism cages, and urine and
faecal samples collected. Body weight and levels of urinary pH,
sodium, potassium, calcium, and oxalic acid were determined. Weight
gains of non-adapted rats were smaller than those of adapted or
control rats. Urinary output of non-adapted rats was decreased
initially, but when diarrhoea disappeared the urinary volume returned
to the control range. Urinary pH was somewhat reduced. Urine
osmolality was decreased in xylitol treated rats. Higher net stool
weight was seen in both dietary groups.
Excretion of Calcium was significantly increased in xylitol
treated rats. A smaller increase was seen with sodium excretion
(Salminen, 1982).
Metabolism in diabetic versus normal rats
The effect of xylitol in Long-Evans rats was compared to
fructose, glucose or no carbohydrate supplement on levels of ascorbic
acid, ketonic metabolites and certain serum hormones in the normal and
streptozotocin-diabetic state. Liver glycogen levels were determined.
The livers of rats not treated with streptozotocin, glucose or xylitol
(4% dietary level) contained significantly smaller glycogen levels
than fructose or control groups. In xylitol treated rats, serum
insulin levels were slightly decreased as compared to controls and
serum glucagon was markedly depressed as compared to the other groups.
The liver total ascorbic acid concentrations in untreated rats
were significantly smaller than in fructose or xylitol fed rats.
Rendering the rats diabetic with streptozotocin produced similar
metabolic consequences regardless of dietary carbohydrates tested. The
above result is in contrast with previously observed antiketogenic
effects of fructose and xylitol (Hamalainen & Makinen, 1982).
TOXICOLOGICAL STUDIES
Special studies on the occurrence of adrenal medullary hyper and
neoplasia in diets containing xylitol
Rat
A review of the available adrenal sections from a two-year
toxicity study in rats (Hunter et al., 1978) was carried out.
Additional sections were also cut from stored paraffin blocks. It was
concluded that xylitol caused a significant increase in the incidence
of adrenal medullary hyperplasia in male and female rats in all dose
levels tested (5%, 10% and 20%). There was an increased incidence of
pheochromocytomas (diagnosed on the basis of morphological but not
functional effects) in males and females in the 20% xylitol group.
However, this increase was not statistically significant. No
pheochromocytomas were diagnosed at the lower levels. Similar effects
were observed in rats fed comparable levels of sorbitol (Russfield,
1981).
A study was carried out to determine if the diagnostic criteria
used in human pathology were also applicable for the diagnosis of
pheochromocytomas in rats. In this study, groups of 100 and 200 male
Wistar rats were used. The animals were maintained on standard stock
diet. The first group of 100 was sacrificed at 24 months, and the
second group of 200 at 30 months. Systolic blood pressure was measured
in rats group 1 at age 22-23 months, and in group 2 at an age of 27-28
months. Two weeks later, three-day urine samples were taken and
analysed from creatinine as well as 4-hydroxy-3-methoxy mandilic acid
(VMA - the major metabolite of both adrenaline and non-adrenaline in
man) and 4-hydroxy-3-methoxyphenylglycol (MHPG) - the principal
catecholamine metabolite in rats. Surviving rats were sacrificed at 24
and 30 months of age (group 1 = 70 animals, group 2 = 45 animals), and
autopsied. Adrenals of animals dying before sacrifice were also
examined. In addition to the normal microscopic examination, the
adrenals were examined histochemically for the presence of
catecholamine-containing granules. Neither elevations in the
measurement of blood pressure nor the excretion of VMA and MHPG
revealed the presence of pheochromocytoma of the adrenal medulla.
Hyperplastic and neoplastic lesions showed little or no chromaffinity.
These data show a lack of functionality of the tumours (Bosland &
Baer, 1981).
A recent literature review of pheochromocytomas in rats indicates
that the tumour is not unusual for the species, and that the nature of
the diet, cage conditions, and hormone imbalance may affect the
prevalence, which may be quite variable even within a specific strain
(Cheng, 1980).
Statistical re-evaluation of a two-year dog study
A statistical re-evaluation was carried out on xylitol versus
control groups in the chronic feeding study in dogs. The major
findings in the feeding study were increased liver weight, a rarefied
appearance of periportal hepatocytes in some of the treated dogs, and
an increased group mean values of serum enzymes including SGOT, LDH,
SAP and SGPT, as well as serum protein, serum albumin and cholesterol
(Heywood et al., 1981). The re-evaluation demonstrated that liver
weights were not significantly increased in xylitol-treated animals in
either the combined male and female data or when the sexes are
analysed separately. A minimum effect was observed at the 20% levels
for males. Total serum protein, serum albumin, SGOT, LDH and
cholesterol did not show a significant difference between groups that
could be related to treatment. Although group mean SAP and SGPT levels
in the 20% xylitol group showed a trend towards minimal increases from
weeks 12 to 46 and from weeks 25 to 100, respectively, individual
increases of enzyme levels above normal range contributed to this
observation. However, these changes were not persistent, progressive
or systematic. The histological changes reported (rarefied appearance
of periportal hepatocytes) in a proportion of the dogs receiving 10%
or 20% xylitol for two years, was also reported in all other treatment
groups (Bär & Christeller, 1980).
Comments on the statistical re-evaluation provided an additional
analysis of the statistical method used for re-evaluation. It was
concluded that there was a significant difference between the liver
weights of the animals in the 20% xylitol and 20% starch group. There
was no evidence for a treatment-related progressive shift to abnormal
values for total serum protein and serum albumin. There was agreement
with the analysis used for evaluating serum levels for liver enzymes,
but it was pointed out that because of the erratic fluctuations in
levels shown by some animals in all treatment groups it was difficult
to provide a coherent interpretation of these data. Finally, there was
no evidence of a relationship between the parameters considered when
this is looked for within treatment groups, but there is some evidence
for a relationship between SGPT and the rarefied appearance of
periportal hepatocytes when the differences between treatment groups
are taken into account (Chanter, 1981).
In another report commenting on the hepatic changes observed in
the two-year xylitol Study in the dog, it was stated that a rarefied
appearance and occasional slight enlargement of periportal hepatocytes
was observed in 3/12 dogs in the 10% xylitol group, and in 5/12 dogs
in the 20% xylitol group. There was no evidence of necrosis or
degeneration of the liver cells. It was concluded that glycogen
accumulation as indicated by electron microscopy in slightly enlarged
periportal hepatocytes was associated with the marginal liver weight
increase, and that the enzyme leakage was due to altered membrane
permeability of the distended cell (Prentice, 1980).
Special studies on the effects of caecal flora
Wistar albino rats were either fed a control diet or adapted to
20% xylitol. The ability of caecal suspensions from control and
xylitol adapted rats to metabolize xylitol was assessed by
determination of xylitol concentration and pH changes.
The adaptation to 20% dietary xylitol increased the ability of
caecal flora preparations to utilize xylitol in vitro as the sole
carbon source; this was principally seen among anaerobic bacteria.
Aerobic incubations with xylitol as the sole carbon source did not
appear to promote acid production whereas aerobic incubations of these
preparations with glucose resulted in rapid acid production (Salminen,
1982).
Faecal samples of control, xylitol (20% diet) adapted rats or
rats receiving 20% xylitol, without prior adaptation, were collected
and homogenized with deaerated Ringer's medium. A 20% suspension was
centrifuged and standard loopfuls of caecal suspensions were heat
fixed and stained. The relative amounts of Gram positive and Gram
negative bacteria were estimated. The dry weight and moisture content
of faeces were determined. Anaerobic organisms were isolated in stored
media. Xylitol was determined by high pressure liquid chromatography.
There was an initial decrease in pH of faeces when dietary
xylitol was fed to unadapted rats, but the pH returned to normal
during the adaptation period. The gradual adaptation was associated
with a gradual increase in the relative proportion of Gram positive
bacteria from 25 to 30% of faecal bacteria count to 70% when fully
adapted. There was a statistically significant decrease in the numbers
of aerobic streptococci.
To investigate the cause of xylitol induced dose-related
diarrhoea, caecal bacterial flora were investigated. Using a rapid and
sensitive radioisotope bioassay, in which 14CO2 production from
i.v.-14C labelled xylitol was measured, it was possible to show that
caecal microflora obtained from rats can metabolize xylitol. This
activity was increased 10-, 15-, 30- and 40-fold in caecal flora taken
from rats fed diets containing 2, 5, 5, 10 and 20% xylitol
respectively (Krishnan et al., 1980 a,b).
Special studies on oxalate formation and metabolism
Oxalate formation - mice
Twelve groups of 8 BLU-HA male weanling mice received one of six
different dietary levels of xylitol (0, 10, 12.5, 17.5 and 20%) with
(20%) or without (O) fructose at each xylitol level. The mice were
adapted to the xylitol diets by daily increment of 2.5% each day until
the specified level was reached. The mice were sacrificed after 22
days of feeding, and liver, brain, bladder, right kidney and right
thigh muscle were collected.
The presence of xylitol in the diet resulted in a slight but
significant increase in weight gain. Fructose had no effect on weight
gain. There was a significant effect of xylitol on oxalate levels in
brain and muscle but not in the liver. There was no consistent
response of oxalate levels to xylitol dose. Fructose also had a
significant effect on brain and muscle oxalate levels, but again there
was no consistent trend. Less than half of the kidney samples had
measurable levels of oxalate and none of the bladder samples had
detectable levels of oxalate (1.0 µg/g wet weight) (Barngrover, 1982).
Metabolic study of oxalate formation in pyridoxine deficient mice
Five groups of four BLV/HA male weanling mice (initial weight of
10 g) were adapted to 10 or 20% xylitol administered in a semi-
synthetic diet with glucose beginning at 5% xylitol level with 45%
glucose and increasing the xylitol level by 5%, while decreasing
glucose by 5% stepwise every other day until the desired xylitol
dietary level was achieved. Two control groups received glucose only.
Three of the groups received similar diets which were deficient in
pyridoxine. The diets were fed for 25 days to establish a pyridoxine
deficient condition; urine and faeces were collected for one week, and
body weights were determined weekly. The mice were then sacrificed and
the livers collected. The pyridoxine adequate group fed glucose only
as a sugar source grew best (final mean weight 25 g). The three
xylitol groups (10%, 20% dietary levels, pyridoxine deficient; 20%
pyridoxine adequate) gained less weight and had approximately similar
mean weights (20 g); the glucose, pyridoxine deficient group did not
gain weight and had three deaths before the end of the study. The 20%
xylitol, pyridoxine deficient group excreted the highest level of
urinary oxalate, with the 10% xylitol deficient and 20% xylitol,
pyridoxine adequate group excreting intermediate amounts and the
glucose, pyridoxine adequate group the lowest levels, whereas the two
groups fed 20% xylitol had higher urinary levels (Barngrover, 1982).
Oxalate formation - rats
Six groups of three Sprague-Dawley male weanling rats received
semi-synthetic diets for 28 days; four of the groups were pyridoxine
deficient. Diets contained either 50% glucose by weight or 30% glucose
and 20% fructose. On day 28 the rats were injected three times at
spaced intervals with either 15% glucose; 10% xylitol + 5% glucose;
15% fructose; or 10% xylitol + 5% fructose. Urine was collected on
days 28 and 29 and rats were sacrificed and livers collected 30
minutes after a final injection on day 30.
The final body weights for the rats show that the group with the
best growth received fructose + xylitol injections and was pyridoxine
adequate (mean weight 216.6 g) versus the group receiving fructose +
fructose injection (15%) and were pyridoxine deficient (119.7 g). The
poorest growing groups received glucose diets only and either xylitol
or glucose and glucose injections, and were pyridoxine deficient
(107.1 g, 103.1 g).
The rats on the pyridoxine deficient diets tended to excrete more
oxalate and have higher liver oxalate levels. Within the pyridoxine
deficient group only, rats injected with xylitol tended to excrete
more oxalate and have higher liver oxalate levels, but these
differences were not significant. Fructose had no effect on oxalate
excretion or liver oxalate levels in the rats injected with xylitol
(Barngrover, 1982).
Special studies on reproduction
A three-generation reproduction study was conducted in NMRI mice.
Initially groups of 12 females and three males were allocated to a
control group and a group adapted to 20% xylitol. Diets and water were
constantly available. Body weights were recorded weekly.
No abnormalities of condition or behaviour were observed in any
of the successive generations of the control or xylitol treated
groups. However, the body weights of xylitol treated animals at birth
were decreased as compared to controls and significantly lower weight
gains were observed in the Fo litters of xylitol fed animals. Even
though the growth rates were lower in xylitol dosed litters, no
significant differences were noted in food consumption after weaning.
There were no significant differences in mean numbers of pups per
litter. The mean birth weights were similar in both groups and minor
variations were observed only in relation to litter size. No treatment
related differences in mortality figures were observed during
lactation periods. Gross examination revealed no abnormalities or
differences attributable to xylitol treatment. Only slight increases
in the caecum size were observed in xylitol treated mice (Salminen,
1982).
Special studies on the effect of xylitol on absorption and excretion
of oxalic acid
Mouse
Male (30) and female (20) CD-1 mice were either gradually adapted
to 20% xylitol diets or fed a control diet. After a 12-hour fast the
mice received a single oral dose of 2 µCi of U14C-oxalic acid in
water or in an xylitol solution (a total dose of 0.625 g/kg bw). For
five xylitol adapted male mice the oxalic acid dose was given with
sorbitol (0.625 g/kg bw) and for another group of five with mannitol
(0.625 g/kg bw). Urine and faeces were collected at intervals for 72
hours to monitor the excretion of the label.
A similar study was conducted with 40 male and 40 female NMRI
mice. In this study, samples of the intestine, kidney, liver and brain
were also analysed for radioactivity.
Adaptation of male mice to 20% dietary xylitol increased the
urinary excretion of the label fourfold (4.5 versus 20%). No major
changes were seen in faecal excretion. Both sorbitol and mannitol
increased the urinary excretion of the label while only sorbitol also
affected faecal excretion of the label.
Urinary excretion of oxalic acid was significantly higher in
xylitol adapted mice when compared to controls receiving oxalic acid
only.
Even greater urinary recovery of label was observed in control
mice receiving oxalic acid with xylitol. In female mice xylitol
appeared to induce an even more pronounced increase in oxalic acid
excretion (Salminen, 1982).
Rat
Diets containing 20% of xylitol or one of the following
carbohydrates: glucose, fructose, sucrose, xylose, sorbitol or
mannitol were fed to groups of five Wistar rats for seven days. The
rats were fasted for 12 hours and given a 5 µCi dose of U14C-oxalic
acid mixed with 0.625 g/kg of xylitol or respective carbohydrate.
Urine and faeces were collected for 72 hours and counted for recovery
of activity. Ten rats were gradually adapted to 20% xylitol diets.
After a 12-hour fast these rats and 20 controls received 5 µCi of
U14C-oxalic acid mixed with water only or together with 0.625 g/kg
xylitol/body weight. Urine and faeces were collected from five
rats/group; tail vein blood from the other rats at intervals up to 24
hours. Urinary excretion of the label was virtually identical in all
groups. The mean excretion of label in faeces of control rats
receiving oxalic acid was significantly lower (P <0.001) than in
control rats receiving oxalate alone, or xylitol adapted rats
receiving oxalate with xylitol (faecal recoveries were 77.8 and 83%
respectively). The urinary excretion of label was also significantly
higher among control rats receiving oxalate with xylitol when compared
to control rats receiving oxalate alone. However, xylitol adapted rats
excreted a significantly smaller proportion of oxalate in urine
compared to controls receiving oxalate alone.
The mean plasma levels of radioactivity in control rats receiving
oxalic acid with xylitol were significantly higher (P <0.05)
immediately after the start of the study when compared to controls
receiving oxalic acid with water only or xylitol adapted rats.
When samples of plasma, urine and faeces were analysed by use of
thin layer chromatography, the major part of the radioactivity was
recovered as oxalic acid (Salminen, 1982).
Acute oral toxicity
The acute oral toxicity of xylitol was determined in fasted NMRI
mice in unadapted versus fully xylitol adapted mice (five
mice/sex/dose group).
Toxic signs consisted of staggering gait and a prone position.
Slight diarrhoea was noted in adapted mice as compared to extensive
diarrhoea in controls. The median lethal doses (LD50) were between
20.96 and 23.62 g/kg with no statistical difference between sexes and
whether or not adapted to xylitol diets. Death occurred in one to
three hours. Necropsy revealed reddening of intestinal mucosa, swollen
intestines and gas formation in Caecum (Salminen, 1982).
Subchronic toxicity
Groups of Wistar rats (70 rats/group) were allocated to diets of
either 20% xylitol (two groups, one group was gradually adapted
beginning with a 5% diet to prevent diarrhoea) or control diet (one
group). Periodically rats were killed at intervals up to 150 days and
subjected to gross necropsy. Sections of liver, kidney, adrenals,
stomach, caecum and bladder were prepared for histopathological
examination. Initially non-adapted rats showed a decrease in body
weight, and decreased food consumption. Rats receiving xylitol without
prior adaptation exhibited caecal enlargement. This was present to
only a slight extent in adapted rats. There were small changes in the
relative organ weights. The bladders of many rats showed one or more
white precipitates. Histopathologically no changes were seen in liver,
kidney, spleen, adrenals or stomach. Histopathologically many rats
showed focal hyperplasia of the bladder wall associated with the
precipitates (control 2/55, xylitol adapted 2/55, xylitol unadapted
9/55). In the non-adapted rats showing diarrhoea inflammatory changes
were observed on the bladder at the time Of diarrhoea (Salminen,
1982).
OBSERVATIONS IN MAN
Effect of xylitol on urinary oxalate excretion in humans
Five healthy human volunteers (two males and three females)
received an orange flavoured drink containing 30 g xylitol with
breakfast. Before dosing, urine was collected for 24 hours and
collections were continued 24 hours after the dose of xylitol. During
the collection period no foods rich in oxalate were permitted. No
significant changes in urinary oxalate excretion could be detected
(Salminen, 1982).
Oxalate formation in human liver tissue
The biochemical pathways for formation of oxalate after
intravenous injection of xylitol in humans were studied using enzymes
derived from human liver. It was concluded that metabolic pathways
based on a combination of the transketolase, fructokinase, and
aldolase reactions can account for the production of glucose, lactate,
tertronates (D-threonic and D-erythronic acids) and oxalate
(precursors) during the metabolism of xylitol administered
parenterally (James et al., 1982).
Special study on xylitol loading
A study was carried out on nine subjects who had consumed xylitol
for 4.8 to 5.3 years. During the years 1972-1974 these individuals
consumed amounts ranging from 376-2520 mg/kg/day, and at the end of
1977, from 46 to 354 mg/kg/day. In 1978 the diets of these individuals
were loaded with 82.3 to 1400 mg/kg/day (females 70 g/day, males
100 g/day) for 14 days using a strictly controlled diet, and
subsequently for seven days while on a normal diet. During these
periods, and also during period of normal diet + sucrose loading the
following plasma and urinary parameters were measured. For serum;
alanine aminotransferase, aspartate aminotransferase, alkaline
phosphatase, gamma-glutamyltranspeptidase, lactate dehydrogenase,
amylase: blood acid base balance. For urine; Uric acid, oxalic
acid, 3-methoxy-4-hydroxymandelic acid, catecholamines (adrenalin,
noradrenalin), metanephrines (m-o-methylnorepinephrine and
m-o-methylnorepinephrine) urine: deposits, sediments and
microcrystals, specific gravity, pH, U.V. and visible spectrum,
volume; acid excretion in urine; urinary electrolytes; as well as the
usual haematological, plasma and urinary parameters. There were no
significant changes in any of the serum or urinary parameters measured
(Makinen et al., 1981).
Special studies on tolerance
In another study the tolerance of increasing amounts of dietary
xylitol in 13 healthy children, aged seven to 16 years was
investigated. Xylitol was administered as a supplement in addition to
the children's regular diet. The daily dose was increased during
successive 10-day periods from 10 to 25, 45, 65 and 80 grams.
Gastrointestinal symptoms (flatulence, occasional abdominal pain and
diarrhoea) were recorded daily throughout the study. Prior to xylitol
supplementation and after 20-50 days of dietary supplement serum uric
acid and total cholesterol were measured. Flatulence was the most
common side effect occurring relatively infrequently in almost every
other subject during the 45 g/day intake, and in most subjects with
greater frequency at the 80 g/day intake. Transient diarrhoea occurred
in four children on 65 g xylitol/day and in one child at 80 g/day.
After 50 days of xylitol consumption, there was an increase in serum
uric acid and Cholesterol. However, the values were within the normal
ranges for children (Akerblon et al., 1981).
Comments
Additional studies have been carried out in the metabolism of
xylitol in the rat and pig. Xylitol adaptation in the rat increased
the absorption of xylitol. Pigs fed xylitol showed a significant
increase in plasma glucose, as well as a sharp rise in insulin levels.
Administration of xylitol to experimental animals and man was shown to
cause a change in the relative proportion of different bacteria
normally present in the gastrointestinal tract. A three generation
reproduction study in mice adapted to a 20% xylitol showed no
significant compound-related effects.
Metabolic studies on oxalate formation in mice indicate that
diets deficient in vitamin B6 contribute to oxalate formation.
Similar effects were observed in rats. Ca excretion was also
increased, Studies in normal humans have shown that ingestion of
xylitol is not associated with oxalate secretion. In a study in which
human volunteers, who had been exposed to xylitol for several years
received a single dose of xylitol, there was no evidence of increased
oxalate excretion related to xylitol intake. Xylitol loading of the
exposed individuals did not result in an increase in urinary oxalate
excretion or calcium excretion. It is not known if marginal vitamin
B6 deficiency in individuals would result in increased oxalate
formation.
The occurrence of adrenal medullary hyper- and neoplasia in rats
fed xylitol has been the subject of an additional review. It was
concluded that xylitol caused a significant increase in the incidence
of adrenal medullary hyperplasia in male and female rats in all dose
levels tested (5%, 10% and 20%). At a previous meeting (the twenty-
sixth Joint FAO/WHO Executive Committee on Food Additives), the
production of adrenal medullary hyperplasia in rats in a feeding study
with 20% of sorbitol in the diet was considered. It was the view of
the committee that such a high level of sorbitol produced gross
dietary imbalance, which may produce metabolic imbalance, and
considered that the adrenal medullary hyperplasia produced by high
dietary levels of sorbital and certain other nutrients might occur as
a physiological consequence of the stress induced in the aging rat. An
increased incidence of pheochromocytomas was only observed in the 20%
group, and this increase was not statistically significant. In a study
on functional effects of pheochromocytomas in aged rats, neither
raised blood pressure nor urinary excretion of the major metabolites
of adrenaline or non-adrenaline revealed the presence of
pheochromocytomas of the adrenal medulla. In addition the lesions
showed little or no chromaffinity. Thus, the normal diagnostic
criteria used in human pathology is not applicable to the diagnosis of
pheochromocytomas in the rat. Further, since the occurrence of
pheochromocytomas is species specific, and of grossly variable
incidence in untreated rats, this toxicological significance to man
cannot be assessed.
Clinical studies in humans who had ingested xylitol for 4.3-5.3
years showed no abnormal urinary parameters or blood pressure
associated with adrenal changes.
A statistical re-evaluation of the data on serum enzyme levels
and liver weights derived from the two-year dog study indicate that
there is a significant increase in liver weight of the dogs in the 20%
xylitol group. However, although group mean values of SAP and SGPT
showed some trend towards minimal increase, interpretation is
difficult because of erratic fluctuations in the enzyme. Although
electron microscopy demonstrates the presence of glycogen deposits in
the liver of the test animals, no data are available on histochemical
or other tests for glycogen, nor is it known if this effect is
reversible. The significance of this hepatoxic effect is not known.
Only a transient increase in liver weight was observed in the rat.
EVALUATION
Estimate of an acceptable daily intake for man
ADI not specified.*
* The statement "ADI not specified" means that, on the basis of the
available data (chemical, biochemical, toxicological, and other),
the total daily intake of the substance, arising from its use at
the levels necessary to achieve the desired effect and from its
acceptable background in food, does not, in the opinion of the
Committee, represent a hazard to health. For this reason, and for
reasons stated in the individual evaluations, the establishment
of a numerical figure of an acceptable daily intake (ADI) is not
deemed necessary.
REFERENCES
Akerblom, H. K. et al. (1981) The tolerance of increasing amounts of
dietary xylitol in children, Int. J. Vit. Nutr. Res. (In press)
A. & Christeller, S. (1980) Chronic feeding study in dogs. Statistical
re-evaluation of data on xylitol versus controls. Unpublished
internal report from F. Hoffmann-La Roche & Co. Ltd., Basle,
Switzerland. Submitted to WHO/FAO
Barngrover, D. A. (1982) Xylitol Metabolism, An Alternative Pathway,
Ph.D. Thesis, Cornell U., University Microfilms Int., Ann
Arbor, Mich. No. 82110811
Bosland, M. C. & Baer, A. (1981) Some functional characteristics of
spontaneous adrenal medullary tumors in aged male Wistar rats
(Internal report of CIVO Institute of Toxicology and Nutrition
TNO, Zeist, the Netherlands and F. Hoffmann-La Roche and Co.
Ltd., Basle
Boum, B. et al. (1978) Action des extraits de Carica papaya sur un
ictere experimental Cree chez le rat par des saponosides
provenant du Brenania Brieyi, Tox. Appl. Pharmacol, 46,
352-362
Chanter, C. O. (1981) Comments on "Chronic Feeding Study in Dogs:
Statistical Re-evaluation of Data on Xylitol vs Controls". Report
from Huntingdon Research Centre. Submitted to WHO/FAO
Cheng, L. (1980) Pheochromocytoma in rats, incidence, etiology,
morphology and functional activity, Journal of Environmental
Pathology and Toxicology, 4, 219-229
Hamalainen, M. M. & Makinen, K. O. (1982) Metabolism of glucose,
fructose and xylitol in normal and streptozotocin-diabetic rats,
J. Nutr., 112, 1369-1378
Heywood, R. et al. (1981) Revised report: Xylitol toxicity study in
the beagle dog (Report of Huntingdon Research Centre)
Hunter, G. et al. (1978) Xylitol tumorigenicity and toxicity study in
long-term dietary administration to rats. Unpublished report from
Huntingdon Research Centre, Huntingdon, Cambridgeshire, England,
for F. Hoffmann-La Roche & Co. Ltd., Basle, Switzerland.
Submitted to WHO/FAO
James, H. M. et al. (1982) Models for the metabolic production of
oxalate from xylitol in humans: A role for fructokinase and
aldolase, Austral. J, Exp. Biol. Med. Sci., 60, 117-122
Krishnan, R. et al. (1980a) Some biochemical studies on the adaptation
associated with xylitol ingestion in rats, Austral. J. Exp.
Biol. Med. Sci., 58, 627-638
Krishnan, R. et al. (1980b) The effect of dietary xylitol on the
ability of rat cecal flora to metabolize xylitol, Austral J.
Exp. Biol. Med. Sci., 58, 639-652
Makinen, K. K. et al. (1981a) Turku sugar studies XXII. A re-
examination of the subjects, Int. J. Vit. Nutr. Res. (In press)
Makinen, K. K. et al. (1981b) Turku sugar studies XIII. Comparison of
metabolic tolerance in human volunteers to high oral doses of
xylitol and sucrose after long-term regular consumption of
xylitol, Int. J. Vit. Nutr. Res. (In press)
Nasi, M. & Tanhuanpaa, E. (1981) The effects of sugar alcohols on
metabolism of growing pigs, Acta Vet. Scand., 22, 344-354
Prentice, D. E. (1980) Xylitol two-year study: Comments on hepatic
changes (letter to Huntingdon Research Centre)
Russfield, A.D. (1981) Two-year feeding study of xylitol, sorbitol and
sucrose in Charles River (UK) rats: Adrenal Medulla. Unpublished
report
Salminen, S. J. (1982) Investigations of the toxicological and
biological properties of xylitol. A thesis submitted in
accordance to the requirements of the University of Surrey for
the Degree of Doctor of Philosophy, Robens Inst. of Indust.
Environ. Hlth Safety and Dept. of Biochem. U. of Surrey,
Guildford, Surrey, UK