TURMERIC AND CURCUMIN
Explanation
These compounds have been evaluated for acceptable daily intake
for man by the Joint FAO/WHO Expert Committee on Food Additives in
1969, 1974 and 1979 (see Annex I, Refs. 20, 34 and 48). Toxicological
monographs were prepared in 1969, 1974 and 1978 (see Annex I, Refs.
20, 35 and 49).
Since the previous evaluation, additional data have become
available and are summarized and discussed in the following monograph.
The previously published monographs have been expanded and are
reproduced in their entirety below.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Curcumin at 0.1% in the diet lowered the serum and liver
cholesterol levels of rats fed cholesterol at 1% in their diet for 7
weeks. Faecal output of bile acids was increased in rats fed curcumin
with or without added cholesterol. Cholesterol excretion was also
enhanced by feeding curcumin (Rao et al., 1970).
Absorption, distribution and metabolism
Five male Sprague-Dawley rats were given by gavage a dose of
1 g/kg of curcumin suspended in arachis oil. Between 67-87% of the
dose was eliminated in the faeces within 72 hours. Excretion was
highest in the initial 48 hours. Urinary excretion was negligible.
Three hours after gavage, curcumin was detected in the plasma of 1 of
4 animals. Biliary concentration of curcumin was 1 µg/ml after 30
minutes and remained stable throughout the experiment. The amount
collected in the bile during 3 hours was less than 0.0006% of the
dose. About 0.015% of the administered curcumin was accumulated in the
liver, kidneys and body fat after 3 hours. Perfusion of curcumin
through the liver resulted in a transitory increase in bile flow; 10%
of the dose was excreted in the bile within 3 hours. Of the curcumin
excreted in the bile, 49% was in the conjugated form. Curcumin
was rapidly metabolized when added to hepatocytes or microsomal
suspensions - concentrations of up to 5 µg/ml were mostly metabolized
within 30 minutes. The metabolites were not identified. Because of the
poor absorption, rapid metabolism and excretion of curcumin it is
unlikely that substantial concentrations of curcumin occur in the body
after ingestion (Wahlstrom & Blennow, 1978).
Male wistar rats weighing 150-200 g were given by gavage 400 mg
of a suspension of curcumin in water containing 0.1% Tween 20. About
40% of the dose was excreted unchanged in the faeces over a 5-day
period; excretion tapered off after the first 3 days. The remaining
60% of the curcumin was assumed to have been absorbed. Curcumin was
not detected in the urine. However, the influence of curcumin
administration was noticed in the increased excretion of conjugated
glucuronides and sulfates. Negligible amounts of curcumin were found
in the blood, liver and kidney. The authors concluded that curcumin is
probably undergoing transformation even as it is being absorbed from
the gut (Ravindrath & Chandrasekhara, 1980).
Male Sprague-Dawley rats (250-300 g) were dosed orally with
14C-labelled curcumin (0.6 mg in a 60% DMSO solution). Eighty-nine
per cent. of the administered 14C radioactivity was excreted in the
faeces and 6% in the urine within 72 hours. Biliary excretion of
14C-labelled curcumin was measured after i.v. administration; 85% of
the radioactivity was found in the bile from cannulated rats after
6 hours. The major biliary metabolites were glucuronides of
tetrahydrocurcumin and hexahydrocurcumin, minor biliary metabolites
were dihydroferulic acid and ferulic acid (Holder et al., 1978).
In another study, groups of 4 male albino rats of the Wistar
strain were starved for 24 hours and then given oral doses of 400, 80
or 10 mg of [3H] curcumin suspended in water containing 0.1% Tween
20. The major route of elimination of the label was the faeces, the
urinary excretion was very low (4-1% in 12 days) regardless of the
dose. With 10 mg (50 mg/kg) and 80 mg (400 mg/kg) [3H] curcumin most
of the label was excreted in 72 hours, while with 400 mg (2 g/kg)
considerable amounts of the label were present in the tissues after 12
days (about 60% of the label had been excreted). Regardless of the
dose, the absorption of curcumin remained in the range of 60-66%. As
the majority of the label was excreted in the faeces, biliary
excretion is thought to take place. Furthermore, only about a third of
the excreted radioactivity was present as curcumin, indicating
biotransformation of the absorbed curcumin (Ravindranath &
Chandrasekhara, 1982).
Studies of the absorption of curcumin carried out in vitro
with everted rat intestinal sacs indicated curcumin undergoes
transformation during absorption from the intestine (Ravindrath &
Chandrasekhara, 1981).
TOXICOLOGICAL STUDIES
Special studies on mutagenicity
Extracts of curcumin, prepared by crushing the rhizomes of
curcumin and diluting the extract with water, caused abnormalities in
the metaphase state of division of root tip cells of Alluim cepa.
The predominant type of aberration produced was chromosome breakage.
In addition, other effects observed included C-mitosis, somatic
segregations, binucleate cells and multipolar anaphases (Abraham et
al., 1976).
Studies on the effect of alcoholic extracts of turmeric on
mammalian cells in vitro, using cells of the Chinese hamster
(Cencetulus griseus), cell line Don of the cactus mouse
(Peromyseus eremicus) and of the Indian munja (Muntiacus
muntjac), and short-term human lymphocyte cultures, showed changes
in chromosome morphology (chromatid separation, breakage and
disintegration), as well as mitotic arrest. The incorporation of
labelled nuclosides into Chinese hamster cells was greatly inhibited
by concentrations of the turmeric extract that did not cause
detectable changes in chromosome morphology (Goodpasture & Arrighi,
1976).
Weanling Swiss albino mice fed control diets or diets containing
0.5% turmeric or 0.015% curcumin for 12 weeks were used in the
following genetic toxicity studies. Groups of 8 females given curcumin
or turmeric exhibited no effect in the micronucleus test. Groups of 5
males and 5 females given turmeric or curcumin showed no cytogenic
effect on the bone marrow chromosomes. Similarly no effect of the
substances was noted in a dominant lethal study in which 15 male and
45 female mice were exposed to the test diets (Vijayalaxmi, 1980).
In another study, groups of 5 male and 5 female rats were fed
cooked diets containing 0, 0.05 or 0.5% of turmeric. A fourth group of
rats was fed an uncooked diet with 0.5% turmeric. The feeding was
carried out for 12 weeks. No effect was seen on the incidence of
chromosomal abberrations in their bone marrow (Vijayalaxmi, 1980).
Turmeric was not active in a test for induction of gene
conversion in diploid yeast strain B234 (Murthy, 1979; Sankaranayavan
& Murphy, 1979).
Curcumin was studied in a battery of short-term assays of genetic
toxicity. The compound was not active in the following systems:
Salmonella/microsome test using strains TA-98 and TA-100, sister
chromatid exchange using hamster lung fibroblasts and human embryo
fibroblasts, and mutation in silk worms. Positive results were
reported in the rec assay (B. subtilis) and for chromosomal
aberrations in hamster lung fibroblasts (Kawachi et al., 1980).
Neither curcumin nor commercial turmeric oleoresin (containing
17.5% of curcumin) at the dose levels of 1.28, 6.4, 32.0 and
160 µg/plate were active in the Salmonella/mammalian microsome test
using strains TA-1535, TA-100 and TA-98 (Jensen, 1982).
Turmeric did not induce sex-chromosome loss and dominant lethal
mutations did not occur when hot water extracts of turmeric were
administered to male Drosophila (Abraham & Kesavan, 1978).
Curcumin was reported not to induce chromosome damage in Chinese
hamster ovary cells in vitro (Au & Hsu, 1979).
Special studies on pharmacology
Curcumin administered orally was found to inhibit the
inflammatory response in several test systems using mice and/or rats
(Ghatak & Basu, 1972; Srimal & Dhawan, 1973). Oral doses of up to
160 mg/kg of curcumin failed to prevent phenylquinone-induced writhing
in mice. An oral dose of 80 mg/kg did not lower the temperature of
pyretic rats, and blood pressure and respiration in anaesthetized cats
were not effected by an i.v. dose of 10 mg/kg (Srimal & Dhawan, 1973).
Groups of 10 albino Porter strain rats received oral doses of 50
or 100 mg/kg of curcumin administered as a 2% suspension in gum arabic
daily for 6 days. At the high dose, gastric erosion was reported.
Changes in the mucin content were reported to be the cause of the
ulceration. Pretreatment with adrenergic, cholinergic, tryptaminergic
and histaminergic receptor antagonists provided partial protection
while metiamide pretreatment completely prevented the development of
the lesions (Gupta et al., 1980).
In vitro lipid peroxidation of rat brain preparation showed a
95% inhibition in the presence of 5.15 × 10-3 M curcumin (Sharma,
1976).
Special studies on reproduction
The petroleum ether, alcoholic and aqueous extracts of rhizomes
of Curcuma longa inhibited fertility when administered by gavage on
days 1-7 of pregnancy at doses of 100 or 200 mg/kg to female albino
rats. Studies in rabbits indicated doses of up to 200 mg/kg of the
extracts did not produce anti-ovulatory effects (Garg, 1974).
Groups of 10 male and 20 female albino rats were fed either
500 mg/kg/day of turmeric or 60 mg/kg/day of an alcoholic extract of
turmeric; two comparable groups of rats were used as controls. The
feeding of this F0 generation was started when the animals were 28
days of age. The first mating was initiated (1 male + 2 females) after
12 weeks on the test diet. Lactation was permitted for 3 weeks.
Following weaning the females were allowed a 2-week rest period before
remating. The first litters were discarded at weaning. From the second
litters 10 males and 20 females were selected from each group. This
F1 generation was raised to maturity and mated like the parent
generation.
The study will be continued up to the F2 generation. So far,
only results from the first 2 matings in the F0 generation are
available. There were no significant differences in fertility,
gestation, viability and lactation indexes, weight and numbers of pups
in the different groups (WHO, 1980).
Acute toxicity
LD50
Animal Route (g/kg bw) Reference
Mouse Oral 2 Srimal & Dhawan, 1973
Rat Oral 5 Wahlstrom & Blennow, 1978
Short-term studies
Rat
Groups of 5 male and 5 female Wistar rats were fed a diet
supplying 2.5 g of turmeric/kg bw or 300 mg/kg bw of an alcoholic
extract of turmeric for 1 day. The animals were then put on control
diets and observed for another 3 weeks. Compared to controls, no
effect of treatment was observed on mortality, body weight or weight
or gross or microscopic pathology of the heart, liver or kidney
(Shankar et al., 1980).
Groups of 7 male and 7 female albino rats were fed either basal
diet or basal diet containing turmeric corresponding to a level of
500 mg/kg bw per day for 3 months. There were no statistically
significant differences between the groups as regards gain in body
weight, haematological parameters studied and relative weight and
histopathology of liver and kidneys (WHO, 1980).
Turmeric at 0.3, 1.0 and 10% and curcumin at 0.1, 0.5, 1.0 and
2.0% were included in a synthetic diet and fed to groups of 10 male
Wistar strain albino rats for a period of 8 weeks. Ten per cent. of
turmeric lowered the food efficiency ratio, probably because of
reduced food intake. No effects were seen in the other dosed groups as
regards growth, haematological values, total serum protein, albumin,
globulin and cholesterol. No mortality was seen and no histo-
pathological changes were observed in the gastrointestinal tract,
liver, spleen and kidneys (WHO, 1980).
Guinea-pig
Groups of 5 male guinea-pigs were fed a diet supplying 2.5 g of
turmeric/kg bw or 300 mg/kg bw of an alcoholic extract of turmeric for
1 day. The animals were then maintained on a control diet and observed
for an additional 3 weeks. Compared to controls, no treatment-related
effects were observed with respect to mortality, body weight or weight
or gross or microscopic pathology of the heart, liver or kidney
(Shankar et al., 1980).
Groups of 5 adult male guinea-pigs were fed 500 mg/kg bw turmeric
or 60 mg/kg bw of an alcoholic extract of turmeric along with basal
diet for 3 months. No deaths were reported during the observation
period. The test substances did not affect weight gain or the
haematological parameters studied and relative weights and
histopathology of liver, kidneys and heart (WHO, 1980).
Dog
Groups of 3 male pups were fed 500 mg/kg bw turmeric or 60 mg/kg
bw of an alcoholic extract of turmeric in milk for 3 months. No deaths
were reported during the observation period and the test substances
did not affect weight gain or the haematological parameters studied
and relative weights and histopathology of liver, kidneys and heart
(WHO, 1980).
Pig
Groups of 4 male and 4 female pigs were given 57, 286 or
1430 mg/kg bw per day of turmeric oleoresin (curcumin content 17.5%)
for 3 months. Six male and 6 female pigs served as controls. No
changes were noted on autopsy. Detailed biological, biochemical, and
histopathological reports are not yet available (Poulsen, 1982).
Monkey
Groups of 3 adult female monkeys were fed a diet supplying 2.5 g
of turmeric/kg bw or 300 mg/kg of an alcohol extract of turmeric for
3 weeks. Compared to controls, no treatment-related effects were
observed with respect to mortality, body weight or gross or
microscopic pathology of the heart, liver or kidney (Shankar et al.,
1980).
Four male monkeys were given 500 mg turmeric/kg bw per day
concealed in a banana for a period of 9 months. A similar group served
as a control. No effects were seen in blood and urine analysis and
histopathology of liver, kidneys, heart, brain, spleen and testes.
Details are not available (WHO, 1980).
Long-term studies
Rat
Groups of 20 male and 20 female rats were fed for 420 days on a
diet containing 0.5% of commercial turmeric with a control group of 15
males and 15 females. The average life span of the test animals was
16-1/2 months compared with 17 months for the controls. Growth,
haematology or reproductive function were undisturbed as well as
survival of the pups. Passive congestion of the liver was seen equally
in test and control animals. No tumours were found. A follow-up of the
first filial generation for their life span showed no abnormalities
except for 1 benign tumour in a female rat (Truhaut, 1958).
Dog
Two dogs were fed for 1 year on a diet containing approximately
1% commercial turmeric. No adverse effects were noted compared with 2
controls (Truhaut, 1958).
Comments
Metabolic data from studies in the rat suggest that some 60% of a
dose of curcumin suspended in water is absorbed. Suspension in oil may
increase the absorption. Unchanged curcumin is not detected in the
urine or blood and does not accumulate in the tissues or fat. Curcumin
undergoes rapid metabolism and although the metabolites have not been
completely identified, use of 14C-labelled curcumin has shown that
major biliary metabolites are glucuronides of tetrahydrocurcumin and
hexahydrocurcumin; minor biliary metabolites are dehydroferulic acid
and ferulic acid. Metabolic studies have not been carried out in man.
Curcumin was shown to be non-mutagenic in a battery of short-term
genetic assays (including the Ames test, sister chromatid exchange
using human lung fibroblasts and human embryo fibroblasts). It was
inactive in a dominant lethal study in mice, and in Drosophila.
Short-term studies have been carried out with turmeric and an
alcoholic extract of turmeric in rats, guinea-pigs, dogs and monkeys.
Although the studies have only been presented in summary no adverse
effects were apparent. The Committee was informed that the adequate
short-term feeding study with turmeric in a non-rodent specie
requested in 1980 is under way, and that a long-term study on curcumin
is being planned.
The long-term study in rats, in which single dose levels of
turmeric were fed, provided the basis for the previous evaluation.
The single level tested revealed no adverse effects and the true
no-effect level may well be higher than the test level chosen.
Turmeric is known to contain an average of 3% curcumin. On this basis
it is possible to evaluate both turmeric and curcumin temporarily
until the results of the further studies requested are made available.
EVALUATION
Turmeric
Level causing no toxicological effect
Rat: 0.5% (= 5000 ppm) in the diet equivalent to 250 mg/kg bw.
Estimate of temporary acceptable daily intake for man
0-2.5 mg/kg bw.
Curcumin (considered to be present in turmeric at 3%)
Estimate of temporary acceptable daily intake for man
0-0.1 mg/kg bw.
FURTHER WORK OR INFORMATION
Required by 1986
Turmeric
(1) Adequate short-term feeding study in a non-rodent species.
Curcumin*
(1) Adequate long-term feeding carcinogenicity study in a rodent
species.
(2) Multigeneration reproduction/teratology study.
* Using an oleoresin of turmeric with a well-defined curcumin
content.
REFERENCES
Abraham, S., Abraham, S. K. & Radhammany, G. (1976) Mutagenic
potential of the condiments, ginger and turmeric, Cytologia
(Tokyo), 41, 591-595
Abraham, S. K. & Kesavan, P. C. (1978) Evaluation of possible
mutagenicity of ginger, turmeric, asafoetida, clove and cinnamon,
Mutat. Res., 53, 142
Au, W. & Hsu, T. C. (1979) Studies on the clastogenic effects of
biologic strains and dyes, Environmental Mutagenesis, 1,
27-35
Garg, S. K. (1974) Effects of Curcuma longa on fertility, Planta
medica, 26, 225-227
!!
Ghatak, N. & Basu, N. (1972) Sodium curcumate as an effective anti
inflammatory agent
Goodpasture, C. E. & Arrighi, F. E. (1976) Effects of food seasonings
on the cell cycle and chromosome morphology of mammalian cells in
vitro with special reference to turmeric, Food Cosmet.
Toxicol., 14, 9-14
Gupta, B. et al. (1980) Mechanisms of curcumin induced gastric ulcer
in rats, Indian J. Med. Res., 71, 806-814
Holder, G., Plummer, J. & Ryan, A. (1978) The metabolism and excretion
of curcumin (1,7-Bis-(4-hydroxy-3-methoxyphenyl-1,6-heptadiene-
3,5-dione) in the rat, Xenobiotica, 8, 761-768
Jensen, N. J. (1982) Lack of mutagenic effect of turmeric oleoresin
and curcumin in the Salmonella/mammalian microsome test.
Unpublished paper submitted to WHO
Kawachi, T. et al. (1980) Cooperative program on short-term assays for
carcinogenicity in Japan, IARC Sci. publ., 27, 323-330
Murthy, M. S. S. (1979) Induction of gene conversion in diploid yeast
by chemicals: Correlation with mutagenic action and its relevance
in genetoxicity screening, Mutat. Res., 64, 1-17
Poulsen, E. (1982) Personal communication to WHO
Rao, D. S. et al. (1970) Effect of curcumin on serum and liver
cholesterol levels in the rat, J. Nutr., 100, 1307-1315
Ravindrath, V. & Chandrasekhara, N. (1980) Absorption and tissue
distribution of curcumin in rats, Toxicology, 16, 259-265
Ravindrath, V. & Chandrasekhara, N. (1981) In vitro studies on the
intestinal absorption of curcumin in rats, Toxicology, 20,
251-257
Ravindaranath, V. & Chandrasekhara, N. (1982) Metabolism of curcumin -
Studies with [3H] curcumin, Toxicology, 22, 337-344
Sankaranayavan, N. & Murthy, M. S. S. (1979) Testing of some permitted
food colors for the induction of gene conversion in diploid
yeast, Mutat. Res., 67, 309-314
Shankar, T. N. B., Shantha, N. V., Ramesh, H. P., Murthy, Indira A. S.
& Sreenivasa Murthy, V. (1980) Toxicity studies on turmeric
(Curcuma longa): Acute toxicity studies in rats, Indian
J. Exp. Biol., 18, 73-74
Sharma, O. P. (1976) Antioxidant activity of curcumin and related
compounds, Biochem. Pharmacol., 25, 1811-1812
Srimal, R. C. & Dhawan, B. N. (1973) Pharmacology of deferulolyl
methane (curcumin) a non-steroidal anti-inflammatory agent,
J. Pharm. Pharmacol., 25, 447-452
Truhaut, R. (1958) Resultats des expériences de toxicité à long terme
effectuées avec les colorants d'origine naturelle, le curcuma et
l'orseille. C.R. du 18ème Congrès de la Féderation Internationale
de Pharmacologie, 8-15 September 1958
Vijayalaxmi (1980) Genetic effects of turmeric and curcumin in mice
and rats, Mutat. Res., 79, 125-132
Wahlstrom, B. & Blennow, G. (1978) A study on the fate of curcumin in
the rat, Acta Pharmacol. et Toxicol., 43, 86-92
World Health Organization (1980) Unpublished report from Central Food
Technological Research Institute, Mysore, and National Institute
of Nutrition, Hyderabad, India (1978), submitted to WHO by Chr.
Hansens Lab., Copenhagen
See Also:
Toxicological Abbreviations
Turmeric and curcumin (WHO Food Additives Series 6)