alpha-TOCOPHEROL
EXPLANATION
alpha-Tocopherol and mixed tocopherol concentrate were evaluated
for acceptable daily intake at the sixth and seventeenth meetings of
the Joint FAO/WHO Expert Committee on Food Additives (Annex 1,
references 6 and 32). Toxicological monographs were published after
both meetings (Annex 1, references 6 and 33). At the seventeenth
meeting, the Committee allocated an ADI of 0-2 mg/kg b.w. Because it
is a nutrient, an ADI was established, even though the available
toxicological studies were less than would normally be required for
foreign substances used as food additives. A daily dietary allowance
of from 3 mg in neonates to 10 mg in adult males has been recommended
by the United States National Academy of Sciences/National Research
Council (NAS/NRC, 1980).
Since the previous evaluation, additional data have become
available and are summarized and discussed in the following monograph.
The previously-published monograph has been expanded and is reproduced
in its entirety below.
BIOLOGICAL DATA
Biochemical aspects
The metabolic fate of alpha-tocopherol is not fully known. When
rats were given 3.5 mg daily by month, 3 to 15% appeared in the
faeces. With larger doses, up to 25% appeared in the faeces. There is
practically no urinary excretion of tocopherol but, from studies with
labelled material, it appeared that one or more metabolites of
tocopherol are excreted in the urine (Sternberg & Pascoe-Dawson,
1959).
When more than the daily requirement is administered, there is
some storage of tocopherol in the liver (Sebrell & Harris, 1972).
Certain microsomal hydroxylations appear to be regulated by
alpha-tocopherol (Carpenter, 1972), and d-alpha-tocopherol acetate
given as a single oral dose or in 3 consecutive daily doses of
450 mg/kg to rats caused a significant increase in aminopyrine
demethylase activity in the liver (Cawthorne et al., 1970).
Toxicological studies
Special studies on carcinogenicity
Early reports that high doses of tocopherol, in the form of wheat
germ extracts, induced sarcomas in rats proved unrepeatable
(Dingemanse & van Eck, 19391 Evans & Emerson, 1939).
Mice treated with carcinogenic doses of dibenzanthrene had a
higher incidence of lung tumours when given 2 mg alpha-tocopherol
every 2 days than when fed a vitamin E-deficient diet (100% incidence
versus 712); subcutaneous tumours were also more common (Telford,
1949). Conversely, in more recent studies, vitamin E has been found to
reduce skin tumour incidence induced by 7,12-dimethylbenzanthrene/
croton oil (Shamberger & Rudolph, 1966; Shamberger, 1972; Slaga &
Bracken, 1977).
Special studies on mutagenicity/clastogenicity
The addition of dl-alpha-tocopherol to leucocyte cultures at a
concentration of 10 µM reduced by 63% the number of chromosome breaks
induced by 1.6 µM 7,12-dimethylbenz(a)anthracene (Shamberger et al.,
1973).
dl-alpha-Tocopherol markedly reduced the mutagenic effect of
malonaldehyde and ß-propiolactone in five strains of Salmonella
typhimurium, which mutated with a frameshift mechanism
(Shamberger et al., 1979).
Special study on reproduction
Rats
At the end of a 90-day study on d-alpha-tocopherol (polyethylene
glycol) 1000 succinate (TPGS), a water-soluble form of vitamin E (see
rat study under Short-term studies), half the rats from each dose
group were maintained on their respective diets and used for a
reproduction study. The dietary concentrations of TPGS were 0, 0.002,
0.2, & 2%. The animals were mated on day 112 of treatment to produce
the F1a generation and on day 175 to produce the F1b generation.
The F0 animals were maintained on their respective diets to 265-265
days of treatment, then sacrificed and examined histopathologically.
Reproductive indices (mean gestation period, litter size, sex
ratio, and mortality of pups or parents) were unaffected by treatment.
Clinical chemical and haematological parameters were normal in the
F0 generation 10 days before terminal sacrifice (Krasavage &
Terhaar, 1977).
Special studies on teratogenicity
Mice
Pregnant ICR mice were given daily doses of 591 mg d-alpha-
tocopherol by gavage on days 7 to 11 of pregnancy; control
animals were untreated or received the same volume of saline by
gavage. In a total of 91 offspring from 7 litters, one malformation
(exencephaly, open eye, and micrognathia) was observed in the
offspring from treated animals; no malformations were seen in 177
offspring (13 litters) from untreated dams or 117 offspring
(8 litters) from dams given saline by gavage. This type of
malformation has never been seen in control animals of this strain in
this testing laboratory, but it can be induced by known teratogens
(Book et al., 1974).
Rats
Groups of 15 pregnant Charles River CD rats were given TPGS in
the diet at concentrations of 0, 0.002, 0.2, or 2% on days 6 to 16 of
gestation. On day 20 of gestation, the dams were sacrificed, the uteri
excised, and the number of implantation sites (live fetuses, dead
fetuses, or resorption sites) were counted. All the fetuses were
examined for gross anomalies; half were examined for soft-tissue
abnormalities (Wilson technique) and half were examined for skeletal
defects (alizarin red stain). No differences were observed between
controls and any of the treatment groups with respect to the
parameters studied (Krasavage & Terhaar, 1977).
Acute toxicity
The LD50 value for alpha-tocopherol is not known, but the acute
oral LD50 values for TPGS and d-alpha-tocopheryl succinate are >
7000 mg/kg b.w. for young adult Charles River CD rats of both sexes
(Krasavage & Terhaar, 1977).
Short-term studies
Mice
It has been found that mice will tolerate oral doses of 50 g/kg
daily for two months (Demole, 1939).
Rats
Rats were reported to tolerate doses of 4 g/kg daily for two
months (Demole, 1939).
Rats receiving alpha-tocopherol at a dosage of 100 mg/rat/day for
19 weeks showed an increase in phosphorus metabolism, but no effect
was found when the dose was 10 mg/rat/day (Weissburger & Harris,
1943).
Rats treated with weekly oral doses of about 50 mg of a vitamin E
concentrate were found to have fatty changes in the liver. In
addition, intimal sclerosis of the aorta was seen, with the
over-development of collagenous tissue at the base of the aortic valve
and in the medial coat of the aorta (Marxs et al., 1947).
Rats given high doses of alpha-tocopherol had elevated liver
cholesterol levels and altered tissue fatty acids (Alfin-Slater
et al., 1972).
Vitamin E itself, at a dietary level of 500 mg dl-alpha-
tocopheryl acetate/kg, had little effect on liver triglycerides.
However, it accentuated the fatty changes produced by ethanol in
weanling F344 rats given 20% ethanol in drinking water for 35-39
days (Levander et al., 1973).
Five groups of weanling rats were fed a control diet containing
the normal level of 35 mg d-alpha-tocopheryl acetate/kg diet or 25,
50, 100, or 1000 times this amount. After 8 weeks, rats in the
highest-dose group had significantly lower feed and protein
efficiencies. Serum and liver vitamin E levels increased progressively
with dose. After 13 weeks, haemoglobin, serum cholesterol, and urinary
creatine and creatinine were unaffected by treatment, but SGPT was
elevated in the highest-dose group. Dietary levels of 25 and 50 times
the normal allowance of vitamin E (i.e. 875 and 1750 mg dl-alpha-
tocopheryl acetate/kg diet) produced no detectable adverse effects
(Dysmsza & Park, 1975).
Groups of 30 Charles River CD rats of each sex were fed diets
containing TPGS at dietary concentrations of 0, 0.002, 0.2, or 21 for
90 days. Haematological and clinical chemical examinations were made
on 15 rats of each sex in the control and high-dose groups at 42 and
84 days. At terminal necropsy, organ weights were determined for
liver, spleen, brain, pituitary, kidneys, gonads, adrenals, and
thyroids, and a histopathological examination was performed. TPGS at
the doses studied had no effect on body-weight gain, food consumption,
haematology, organ weights, serum chemistry, or histopathology
(Krasavage & Terhaar, 1977).
Chicks
The effects of feeding dl-alpha-tocopheryl acetate to white
leghorn chicks at dietary levels of 220 to 2200 IU/kg diet were
studied in a series of experiments of 3-8 weeks duration. Growth rate
was unaffected by dietary levels of up to 1000 IU/kg, but it was
depressed at the 2200 IU/kg level. Thyroid hypertrophy in response to
a thiouracil challenge was reduced at the 220 IU/kg level, as were
thyroidal uptake and release of 131I. The respiration rate of
mitochondria from skeletal muscle isolated from chicks fed 2200 IU
dl-alpha-tocopheryl acetate/kg diet for 55 days was only two-thirds
that of control mitochondria. Bone calcification was depressed when
excess vitamin E was fed to, or injected into, chicks fed either a
calcium- or vitamin D-deficient diet; it was concluded that excess
vitamin E increased the requirement for vitamin D. At a level of
2200 IU/kg diet, dl-alpha-tocopheryl acetate caused prolonged
prothrombin times, reticulocytosis, and a reduced haematocrit value.
The prolonged prothrombin times were rapidly reversed by injection of
vitamin K (March et al., 1973).
Long-term studies
Groups of weanling female Wistar rats were fed diets containing
0, 25, 250, 2500, 10,000, or 25,000 IU vitamin E/kg diet for 8 and 16
months. Vitamin E depressed body-weight gain at concentrations of
10,000 and 25,000 IU/kg diet, and increased relative heart and spleen
weights were seen at 8 months and 16 months, respectively. There was
an increase in plasma alkaline phosphatase and a decrease in the ash
content of bone after 16 months at these two dose levels. Prothrombin
time was reduced at 12 months, but not at 9 or 16 months. Urinary
excretion of creatine and creatinine was normal at 11 months. No
histological examinations were reported (Yang & Desai, 1977).
Groups of 60 male and 60 female Charles River CD rats, initial
body weight 134 g (males) or 130 g (females), were fed a diet
supplemented with dl-alpha-tocopheryl acetate at levels calculated to
give a dose of 500, 1000, or 2000 mg/kg b.w./day. A control group
received unsupplemented basal diet stated to contain 39 mg vitamin
E/kg b.w. and 10 mg vitamin K3/kg b.w. Through weeks 24, 25, and 26,
vitamin K1 was administered in the drinking water at 7 mg/l to
counteract an observed haemostatic failure. Subsequently, the vitamin
K1 supplement was added to the diet at a concentration of 5 mg/kg.
Control rats were given the same vitamin K supplement as test rats.
Food intake and body weights were recorded weekly. After 4, 8, 13, 26,
52, 78, and 95 weeks of treatment, blood samples from 10 male and 10
female animals of the control and highest-dose groups were examined
haematologically (RBC and total leucocyte counts, haematocrit,
haemoglobin, differential leucocytes, and prothrombin time) and
urinalysis was carried out (SG, reducing substances, glucose, ketones,
protein, sedimentary cell counts, and blood and bile pigments). At
similar times, half this number of rats were examined in respect of
serum biochemical parameters (urea, glucose, bilirubin, total protein,
electrophoretic protein fractionation, alkaline phosphatase, aspartate
aminotransferase, alanine aminotransferase, sodium, and potassium).
Whenever there were significant or suggestive differences between
controls and the high-dose group, some of these tests were extended to
the intermediate and low-dose groups. After 52 weeks of treatment, 10
rats/sex/dose were killed, necropsied, and examined histologically.
The remaining animals remained on the respective diets until
termination at 104 weeks. Rats which died on test or which were killed
at termination were necropsied and absolute and relative organ weights
determined for adrenals, brain, heart, liver, lungs, testes or
ovaries, pituitary, spleen, thyroid, and prostate or uterus. Detailed
histopathological examination was performed on control and high-dose
groups; in other dose groups, histopathology was restricted to the
liver and any macroscopically-abnormal tissue.
Occasional difficulties in arresting bleeding were observed when
blood samples were collected after 8 weeks and frank haemorrhages were
observed in males only from week 15 (high-dose), week 16
(intermediate-dose), or week 18 (low-dose). Haemorrhages occurred
variously in the gut, urinary tract, orbit and meninges, and from
minor injuries to the claws or vibrissal pits. Vitamin K
supplementation was effective in bringing about recovery within one to
three days. In all other respects, the appearance and behaviour of
treated animals were similar to controls, and food consumption and
body-weight gain were similar to or slightly greater than controls.
Mortality due to haemorrhage in males during the first 26 weeks,
maximally 10% in the high-dose group, was balanced by a similar number
of deaths in control males between weeks 26 and 52, and thereafter
alpha-tocopherol did not adversely affect survival. At termination,
there were no significant differences in mortality between any
treatment groups of either sex and their respective controls.
Pro-thrombin times were prolonged in males of all treatment groups at
week 4 until week 13, but these returned to normal by week 26 (after
initiation of vitamin K supplementation in week 24); females were
unaffected. No other haematological differences between treated and
control animals were seen except for a transient, slight lowering of
the haematocrit and haemoglobin at week 8 in both males and females in
the highest-dose group. Serum alkaline phosphatase was occasionally
significantly elevated (p < 0.05) in the high-dose group, but the
differences were not consistent nor progressive with time; no such
changes were seen at lower-dose levels. A dose-related elevation of
alanine aminotransferase was observed in treated males at week 4,
persisting to week 26, but later it lost statistical significance.
Aspartate aminotransferase and all other blood chemical parameters
were unaffected, and no significant changes were seen on urinalysis.
At necropsy, no macroscopic changes related to treatment were
observed. In females (but not males) of the high-dose group, a
slightly elevated absolute liver weight was seen at the interim
sacrifice, but the relative liver weight was not increased and no
significant differences in relative or absolute organ weights were
seen at termination of the study. Histopathological examination of the
livers did not reveal any treatment-related changes with the exception
of agglomerations of vacuolated ("foamy") macrophages in the
centriacini of some treated rats, distributed among the treated rats
without dose-relation, but never occurring in controls. The foamy
macrophages stained strongly with periodic acid schiffs (PAS) and Oil
Red O, which distinguished them from occasional peribiliary
macrophages seen in controls; they were seen in 17% of treated males
and 77% of treated females across the study as a whole. No other
treatment-related effects were observed. Whether considered separately
by tumour type, or in aggregate, the tumour incidence did not reveal
any neoplastic effects of treatment. In both sexes, there were
indications of an inverse relationship between dosage and incidence of
mammary fibro-adenomas, but this effect was statistically significant
only in females (Wheldon et al., 1983).
Observations in man
Adult humans have tolerated 1 g per day alpha-tocopherol for
months or larger doses for shorter periods with no undesirable
effects. Therapeutically, daily doses of 20 to 600 mg of
alpha-tocopherol or its acetate salt are often taken with no toxic
effects (Finkler, 1949; McLaren, 1949; Sebrell & Harris, 1954).
The clinical literature contains references to complaints of
gastric distress and other symptoms in patients receiving much smaller
dosages; these symptoms are probably attributable to fatty substances
present in alpha-tocopherol concentrates or, in some instances, to
psychic factors (Sebrell & Harris, 1954).
Side effects reported in clinical use of vitamin E supplements
include severe weakness and fatigue induced in healthy adults by daily
doses of around 720 mg alpha-tocopherol (Cohen, 1973a, b). These side
effects were observed in a double-blind study on two healthy young
males receiving 720 mg alpha-tocopherol daily (Briggs, 1974; Briggs &
Briggs, 1974). In the latter study, the symptoms were associated with
an increase in serum creatine kinase activity and greatly increased
24-hour urinary creatine excretion; asymptomatic creatinuria was
reported in a young male taking high doses of vitamin E
(Hillman, 1957).
A 55 year-old patient presented with ecchymoses and prolonged
prothrombin time after self-administration of a vitamin E preparation
at up to 1200 IU/day for two months while receiving warfarin and
clofibrate therapeutically. The prothrombin time returned to its
baseline value after vitamin E administration was stopped while
warfarin and clofibrate treatment continued. In a subsequent challenge
study, vitamin E (90% alpha-tocopherol) was given for 7 weeks at a
daily dose of 800 IU/day; at the same time the patient received his
normal medication of digoxin (0.25 mg/day), sodium warfarin (5 mg/day
alternating with 2.5 mg/day), clofibrate (500 mg four times a day),
and procainamide (500 mg four times a day). By the fourth week the
prothrombin time was increased from an initial value of 20.7 seconds
to 24 seconds and continued to increase to 29.2 seconds after 7 weeks;
levels of Factors II, VIII, IX, and X were depressed. At this time,
multiple ecchymoses and a small haematoma were evident, so vitamin E
was discontinued. The prothrombin time and levels of clotting factors
returned to baseline values within 7 days and clinical signs of
haemorrhage disappeared (Corrigan & Marcus, 1974).
The haematological response to iron therapy by children with
iron-deficiency anaemia has been reported to be significantly impaired
if vitamin E supplements are given simultaneously (Melhorne & Gross,
1969).
Allergic reactions shown by some individuals to topical creams or
sprays containing vitamin E were shown by patch tests to be due to
alpha-tocopherol (Brodkin & Bleiberg, 1965; Minkin et al., 1973;
Aeling et al., 1973).
Skin rashes and gastrointestinal irritation were reported in
early studies of oral vitamin E supplementation in the form of
wheat-germ oil, but it is not known whether this was due to
alpha-tocopherol (Shute, 1938).
Effects of alpha-tocopherol on some biochemical parameters have
been reported in man. A group of 52 patients (average age 72 years)
showed a mean increase in serum cholesterol of 74 mg/dl while
receiving 300 mg alpha-tocopherol daily (Dahl, 1974), but no such
increase was seen in a small group of healthy young men taking 800 mg
daily (Briggs, 1974; Briggs & Briggs, 1974).
When patients with porphyria cutanea tarda were given daily doses
of 1000 mg alpha-tocopherol for 3 months, there were marked increases
in 24-hour urinary excretion of androsterone and etiocholanone +
dehydroepiandrosterone and a large decrease in 24-hour excretion of
pregnanediol (Pinelli et al., 1972).
Comments
alpha-Tocopherol was non-mutagenic and non-carcinogenic, and the
results of reproduction/teratology studies did not indicate that
alpha-tocopherol had adverse effects on reproductive function.
However, in a long-term study in rats, a no-effect level could not be
established with respect to effects on blood clotting and liver
histology, and there was evidence from human studies that excessive
intakes of alpha-tocopherol could cause haemorrhage. Other adverse
effects noted in clinical studies at doses of > 720 mg
alpha-tocopherol/day included weakness, fatigue, creatinuria and
effects on steroid hormone metabolism.
Clinical studies indicate that, generally, intakes of below about
720 mg/day are without adverse effects in man, but one investigation
in elderly patients showed an increase in serum cholesterol at doses
of 300 mg alpha-tocopherol daily. Incidences of allergic reactions
seem to be very rare.
alpha-Tocopherol may be an essential nutrient. The U.S. National
Academy of Sciences/National Research Council has recommended a
dietary allowance of 0.15 mg/kg b.w./day. However, excessive intakes
of alpha-tocopherol produce adverse clinical and biochemical effects,
and self-medication with large doses of vitamin E preparations could
present a hazard.
The previously-allocated ADI was amended to include a lower
value, which reflects the fact that alpha-tocopherol may be an
essential nutrient. The upper value, which represents the maximum
value for the AID, is based on clinical experience in man.
EVALUATION
Estimate of acceptable daily intake for man
0.15-2 mg/kg b.w.
Further work or information
Desirable
Studies on the mechanisms by which alpha-tocopherol interferes
with vitamin K-dependent blood clotting factors.
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See Also:
Toxicological Abbreviations