CURCUMIN
First draft prepared by
Dr. C.B. Johnson and Dr. A.N. Mattia
Division of Health Effects Evaluation
Office of Premarket Approval
Center for Food Safety and Applied Nutrition
Food and Drug Administration
Washington, DC, USA
Explanation
Biological data
Biochemical aspects
Toxicological studies
Acute toxicity studies
Short-term toxicity studies
Long-term toxicity/carcinogenicity studies
Reproductive toxicity studies
Special studies on teratogenicity
Special studies on genotoxicity
Special studies on anti-mutagenicity
Special studies on pharmacology
Observations in humans
Comments
Evaluation
References
1. EXPLANATION
Turmeric and curcumin (the main colouring component of turmeric)
were considered at the thirteenth, eighteenth, twenty-second,
twenty-fourth, twenty-sixth, thirtieth, and thirty-fifth meetings of
the Committee (Annex 1, references 19, 35, 47, 53, 59, 73, and 88).
At the eighteenth meeting, a temporary ADI of 0-0.1 mg/kg bw was
established for curcumin based on the ADI for turmeric and an assumed
average level of 3% curcumin in turmeric (Annex 1, reference 35). The
temporary ADI for curcumin was extended after the twenty-second,
twenty-fourth, twenty-sixth, and thirtieth meetings following the
evaluation of new data (Annex 1, references 47, 53, 59, and 73).
The temporary ADI of 0-0.1 mg/kg bw for curcumin was again
extended at the thirty-fifth and thirty-ninth meetings (Annex 1,
references 88 and 101). At the latter meeting the Committee requested
the results of carcinogenicity studies in mice and rats given tumeric
oleoresin (which were known to have been completed) and the results of
a reproductive toxicity/teratogenicity study with curcumin.
The results of the carcinogenicity studies, together with new
biochemical and genotoxicity data, were available to the Committee
for evaluation. Information previously requested on the reproductive
effects of curcumin was not provided, although a published
reproductive toxicity study on turmeric was available.
Relevant information from the previous monographs and information
received since the previous evaluation are summarized and discussed in
the following monograph addendum.
2. BIOLOGICAL DATA
2.1 Biochemical aspects
Male Swiss mice were initially treated with carbon tetrachloride,
paraquat or cyclophosphamide (compounds known to induce free radicals)
and then given daily gavage doses of 250 mg/kg bw curcumin (98% pure)
suspended in 1% gum acacia for 14 days. Mice fed curcumin showed
significant decreases in lipid peroxidation in liver, lung, kidney and
brain in comparison to control mice that did not receive curcumin,
regardless of the nature of the free radical inducer (Soudamini
et al., 1992).
Curcumin at a level of 0.1% in the diet was reported to lower
serum and liver cholesterol in rats fed 1% cholesterol-containing
diets for 7 weeks (Rao et al., 1970).
Triton-induced hyperlipidemic rats (inbred colony, strain not
identified) were fed 3000 mg/kg bw of an ethanolic extract (50% v/v)
of defatted Curcuma longa and the serum lipid profile was determined
from tail vein blood taken every 6 h for 48 h after feeding. Rats fed
the Curcuma extract had lower levels of serum cholesterol and
triglycerides and elevated high density lipoprotein (HDL)-cholesterol
compared to controls (n=10 rats/group). It appeared that the Curcuma
extract was fed repeatedly every 6 h; however, methodological details
were not clearly presented (Dixit et al., 1988).
A series of experiments were conducted to determine the effect of
powdered Curcuma xanthorrhiza Roxb.(a plant from the same genus as
Curcuma longa L.) and curcuminoids from Curcuma xanthorrhiza
(consisting mainly of curcumin and desmethoxycurcumin) on lipid
metabolism in normal male Sprague-Dawley rats and in a special strain
of exogenous hyper-cholesterolemic (ExHC) rats.
In the first experiment, 4% powdered Curcuma xanthorrhiza was
fed to normal rats in a cholesterol-free diet for 34 days. In treated
rats, the serum lipid profile was affected in the following manner
compared to controls: levels of triglycerides and phospholipids were
decreased and HDL cholesterol and apolipoprotein A-I (Apo A-I)
increased. In the liver, the lipid profile was affected as follows
compared to controls: levels of cholesterol and triglycerides were
decreased and phospholipids increased. Additionally, the activity of
liver fatty acid synthase, but not glycerophosphate dehydrogenase, was
decreased.
In the second experiment, 4% powdered Curcuma xanthorrhiza was
fed to ExHC rats in a diet with 10% olive oil and 1% cholesterol for
21 days. Analysis of serum lipids showed that the test material
elevated cholesterol level, HDL-cholesterol, triglycerides and Apo A-I
compared to controls, while in the liver, it decreased cholesterol and
triglycerides but elevated phospholipids levels.
In the third experiment, 0.2% curcuminoid extract was fed to ExHC
rats in a cholesterol-free diet for 28 days and in a cholesterol-
containing diet (both with 10% olive oil) for 14 days. The curcuminoid
extract did not influence lipid parameters in this experiment
(Yasni et al., 1993).
Long-term studies in rats reported discoloration of the fur in
curcumin-exposed rats and mice and discolored faeces in rats receiving
50 000 mg/kg curcumin (equal to 2 g/kg bw/day) indicating that
significant absorption and bioaccumulation of curcumin occurs at the
high doses employed in the studies (NTP, 1993). This is in agreement
with absorption studies previously reviewed by JECFA (Annex 1,
reference 60) which indicated that after a single high oral dose of
400 mg/rat (equal to 2 g/kg bw) of [3H]-labeled curcumin
administered to rats, only 60% of the dose was excreted by 12 days.
However, at the lower doses of 10 and 80 mg/rat (equal to 0.05 and
0.4 g/kg bw), most of the label was excreted within 72 h. The
percentage of dose absorbed (60-66%) was constant regardless of the
dose administered (Ravindranath & Chandrasekhara, 1982). In rats
receiving a single oral dose of 0.6 mg curcumin, 89% of the dose was
excreted in the faeces and 6% in the urine within 72 h
(Holder, et al., 1978).
In vitro studies indicated that curcumin was rapidly
metabolized when incubated with hepatocytes or microsomal suspensions
(Wahlstrom & Blennow, 1978). Metabolism also appeared to be rapid
in vivo. When labelled curcumin was administered to cannulated rats
by i.v. injection, 85% of the dose was recovered in the bile by 6 h.
Major metabolites included the glucuronides of tetrahydrocurcumin and
hexahydrocurcumin, with dihydroferulic acid and ferulic acid present
as minor metabolites (Holder et al., 1978).
2.2 Toxicological studies
2.2.1 Acute toxicity studies
No new information.
2.2.2 Short-term toxicity studies
No new information.
2.2.3 Long-term toxicity/carcinogenicity studies
2.2.3.1 Mice
Groups of 60 male and 60 female B6C3F1 mice were fed ad libitum
diets containing 0, 2000, 10 000 or 50 000 mg/kg turmeric oleoresin
(79% 85% curcumin) for 103 weeks, equal in males/females to daily
doses of 0, 220/320, 1520/1620 or 6000/8400 mg turmeric oleoresin/kg
bw/day. Dose levels were based on the results of a 13-week study.
Mice were housed one per cage and observed twice daily, 7
days/week. Individual animal weights were recorded weekly for the
first 13 weeks, then once every 4 weeks thereafter; food consumption
was monitored once every 4 weeks. An interim sacrifice of 9 or 10
randomly selected mice/group was conducted at 15 months, which
included complete gross and microscopic evaluations, assay of a
standard set of haematology and clinical chemistry parameters and
weights of 7 selected organs. At termination, a complete necropsy was
done on all animals, including both gross and microscopic evaluations.
Survival rates were unaffected by dietary turmeric. For male
mice, the survival ranged from 74%-86% and for female mice, from
68%-84%. At dietary levels of turmeric oleoresin of 10 000 mg/kg
(females only) and 50 000 mg/kg (males and females), final group mean
body weights were significantly lower than controls: however, food
consumption in these groups of mice was the same relative to controls.
At 15 months, absolute and relative liver weights were elevated in
mice of both sexes fed 10 000 and 50 000 mg/kg but returned to
control levels at terminal sacrifice. No significant differences in
haematological and clinical chemistry parameters were reported,
although at 15 months alkaline phosphatase levels were elevated in
males and females at the mid and high doses. In female mice, turmeric
oleoresin was also associated with thyroid gland follicular cell
hyperplasia. Table 1 summarizes significant results from the
statistical analyses of primary tumour data which were presented in
the original report. Under the conditions of the study these data
showed a marginal increase of neoplasms in mice which were not
considered to be treatment-related (NTP, 1993).
2.2.3.2 Rats
Groups of 60 male and 60 female F344/N rats were fed ad libitum
diets containing 0, 2000, 10 000 or 50 000 mg/kg turmeric oleoresin
(79% -85% curcumin) for 103 weeks, equal in males/females to daily
doses of 0, 80/90, 460/440 or 2000/2400 turmeric oleoresin/kg bw/day.
The rats were housed 5/cage and observed twice daily 7 days/week.
Individual animal weights were recorded weekly for the first 13 weeks,
then once every 4 weeks thereafter; food consumption was monitored by
cage once every 4 weeks. An interim sacrifice of 10 randomly selected
rats/group was conducted at 65 weeks, which included complete gross
and microscopic evaluations, assay of a standard set of haematology
and clinical chemistry parameters and weights of 7 selected organs. At
termination, a complete necropsy was done on all animals, including
both gross and microscopic evaluations.
No differences in survival rates between treated and control rats
were observed. Survival rates ranged from 30%-36% for males and
54%-68% for females. No explanation for the lower survival rate in
males compared to females was given; survival rates in treated males
were similar to the survival rate in male controls. Hyperactivity was
observed at the highest dose of curcumin during some observation
periods. The final mean group body weights of the high-dose males and
females were slightly less than the controls despite similar food
intake. At 15 months, relative liver weights were significantly
elevated in females fed 10 000 and 50 000 mg/kg. At 15 months for the
50 000 mg/kg groups, haematocrit, haemoglobin and red cells were
significantly lower while platelet and reticulocytes (males only) were
significantly higher.
Table 1. Incidence of primary tumours in individual organs in
male and female B6C3F1 mice after dietary exposure to
turmeric oleoresin for 103 weeks (NTP, 1993).
Sex Site Tumour mg/kg of feed Incidencea
morphology
M Liver Hepatocellular 0 25/50
adenoma 2000 28/50
10 000 35/50*
50 000 30/50
M Liver Hepatocellular 0 30/50
carcinoma 2000 38/50
or adenoma 10 000 41/50*
(combined) 50 000 37/50
M Small Adenoma or 0 0/50
Intestine carcinoma 2000 3/50
10 000 3/50
50 000 0/50
F Liver Hepatocellular 0 7/50
Adenoma 2000 8/50
10 000 19/51*
50 000 14/50
F Liver Hepatocellular 0 13/50
carcinoma 2000 12/50
or adenoma 10 000 25/51*
(combined) 50000 19/50
F Pituitary Adenoma 0 0/46
Gland (Pars 2000 2/49
Distalis) 10 000 4/50
Adenoma 50 000 5/50*
a Incidence was adjusted for mortality
* Asterisks indicate significant p values (p<0.05 or 0.01) for
paired comparisons between the control and the dosed groups.
In the GI tract of high-dose male rats, the following
non-neoplastic effects were reported: ulcers, hyperplasia and
hyperkeratosis of the forestomach; ulcers, hyperplasia and
inflammation of the caecum and colon; and sinus ectasia of the
mesenteric lymph node. These lesions were considered likely to be
regenerative and not neoplastic in nature. Non-neoplastic GI effects
reported in high-dose female rats included ulcers, hyperplasia and
inflammation of the caecum and sinus ectasia of the mesenteric lymph
node. Neoplasms were not reported in males. In females, however,
clitoral gland adenoma and carcinoma were reported (Table 2); however,
the incidence of hyperplasia of the clitoral gland was similar in all
groups of female rats. The marginal increase of clitoral gland adenoma
was neither dose-related nor associated with a corresponding increase
in hyperplasia (NTP, 1993).
Table 2. Incidence of primary tumours in individual organs (excluding
mammary gland tumours) in female F344/N rats after dietary
exposure to turmeric oleoresin for 104 weeksb (NTP, 1993)
Site Tumour morphology mg/kg of feed Incidencea
Clitoral Adenoma 0 5/50
Gland 2000 12/48*
10 000 15/47*
50 000 16/49*
Clitoral Carcinoma 0 1/50
Gland 2000 4/48
10 000 0/47
50 000 0/49
Clitoral Adenoma or 0 6/50
Gland carcinoma (combined) 2000 16/48*
10 000 15/47*
50 000 16/49*
a Incidence was adjusted for mortality
* Asterisks indicate significant p values (p<0.05 or 0.01) for
paired comparisons between the control and the dosed groups.
b No neoplasms were found in male rats.
2.2.4 Reproductive toxicity studies
Groups of 10 male and 20 female weaned Wistar rats were
maintained throughout the experimental period on diets containing
either (a) turmeric (2.5% curcumin) at 500 mg/kg bw/day or (b) an
alcoholic extract of turmeric fed at 60 mg/kg bw/day (equivalent in
curcumin content to a dose of 500 mg turmeric/kg bw/day). Matings were
initiated after 12 weeks on the two test diets using 1 male per 2
females. Lactation was permitted for 3 weeks. The first litters were
discarded and the females were re-mated after a 2-week post-weaning
rest. From the second litters, 10 male and 20 female rats were
selected from each group after weaning (F1 generation), they were
raised to maturity and then mated like the F0 parent generation; the
matings continued until the first litters from the F2 generation
were weaned at which time the F0 generation rats were two years old.
Pups were weighed at birth and at 4, 12 and 21 days.
The following indices were calculated from observations and
records of performance: fertility index (FI), the percentage of
matings resulting in pregnancy; gestation index (GI), the percentage
of pregnancies resulting in the birth of live litters; viability index
(VI), the percentage of pups born that survived for 4 days or longer;
and the lactation index (LI), the percentage of pups alive at 4 days
that survived the 21-day lactation period. Liver, kidney, heart,
brain, spleen, gonads, pituitary, adrenals and thyroid were examined
histologically.
No differences in the FI, GI, average number of pups born alive,
or VI were reported. In the 2nd litter of the F1 generation, LI was
higher than control for rats fed the alcohol extract. This difference
was statistically significant but is not likely to be of biological
importance; no other differences in treated versus control rats were
reported for LI. The following differences in average weight of pups
were reported for rats fed the alcohol extract versus controls:
decreased weight at 12 days in the 2nd litter of the F0 generation;
and increased weight at birth in the 2nd litter of the F1 generation
and in the 1st litter of the F2 generation. These changes in pup
weights are not likely to be of biologically importance. No
histological abnormalities were reported. The authors concluded that
the consumption of turmeric and its alcoholic extract appeared safe at
the doses tested (Bhavanishankar & Murthy, 1987).
2.2.5 Special studies on teratogenicity
No new information.
2.2.6 Special studies on genotoxicity
The results of genotoxicity studies on turmeric or curcumin are
summarized in Tables 3 and 4.
No mutagenic activity was demonstrated in bacteria treated with
curcumin preparations of purity up to 85%, or of unknown purity. A
79-85% purity preparation induced chromosomal aberrations and SCEs
in vitro. In vivo, a curcumin preparation of unknown purity
administered to mice by intraperitoneal injection did not induce
micronuclei in bone marrow cells, whereas a low level of chromosomal
aberrations was reported in the same cell population (Jain et al.,
1987). In another in vivo study in mice injected J.p. with curcumin
of unknown purity there was some evidence of SCE induction at low
frequency above 25 mg/kg bw, while in rats fed curcumin of unknown
purity there was equivocal evidence for the induction of chromosomal
aberrations (Giri et al., 1990). It was concluded that there was no
adequate evidence for the genotoxicity of curcumin. In reaching this
conclusion, the SCE data in particular was considered to be of little
relevance in the evaluation, while other studies could not be reliably
interpreted because of the impurities in the curcumin preparations
used.
2.2.7 Special studies on anti-mutagenicity
In contrast to some results presented in Tables 3 and 4,
several studies have indicated that curcumin possesses in vitro
anti-mutagenic activity. Using the Ames test, curcumin itself a
non-mutagen, inhibited the mutagenic effects of chili extract and
capsaicin (Nagabhushan & Bhide, 1986). Similarly, curcumin was
reported to inhibit the activity of known environmental mutagens which
require metabolic activation, although it was reported to be
ineffective against mutagens which do not require metabolic activation
(Nagabhushan et al., 1987; Nagabhushan & Bhide, 1987).
There was a significant time-dependent reduction in the number of
radiation-induced micronucleated polychromatic erythrocytes in mice
given single gavage doses of 5, 10 or 20 mg/kg bw curcumin in peanut
oil (Abraham et al., 1993).
In another in vivo study to determine the anti-mutagenic
effects of turmeric, rats were fed turmeric for up to 3 months at
dietary levels of 0.1, 0.5, 1, 5, or 10%, then given single
intraperitoneal injections of 5 mg benzo[a]pyrene (BP) or 1 mg of
3-methylcholanthrene (3-MC). After injecting BP or 3-MC, 24-h urine
samples were collected and assayed for mutagenic activity by
determining the frequency of histidine revertants with Salmonella
typhimurium strains TA98 and TA100, with and without S-9 metabolic
activation. The number of revertants was reduced in urine samples from
rats fed turmeric at dietary levels of 0.5% and higher. Feeding
turmeric for one month appeared as effective as feeding for longer
time periods (Polasa et al., 1991).
Table 3. Summary of recently published data on the mutagenic potential of turmeric or
curcumin in several strains of Salmonella typhimurium (i.e., the Ames assay).
Test Test Test Material Dose Result Reference
System Strain (µg/plate)
Amesa TA100 3 TLC curcumin 60.2 -/- Nagabhushan &
TA98 components 125 -/- Bhide, 1986
250 -/-
500 -/-
Amesa TA100 turmeric (fresh) Nagabhushan &
TA98 extract 360 -/- Bhide, 1986
TA1535 with 40% (dried)
TA1538 curcumin 250 -/-
(pyrolyzed) 200
-/-
Amesa,b TA100 turmeric 50 -/- Shah & Netrawali,
TA98 extract 100 -/- 1988
TA97a with 33-35% 200 -/-
curcumin
Ames TA1535 turmericc 50 +weak Sivaswamy et al.,
TA1537 100 - 1991
TA1538 100 -
Amesa TA100 turmeric 5 doses up to -/- NTP, 1993
TA1535 ole-oresin 333 µg/plate -/-
TA1537 containing (higher doses -/-
TA98 79%-85% were toxic) -/-
curcumin
a activation with and without rat liver S9
b activation with rat caecal microorganisms
c estimated curcumin content of 3% (actual not specified)
2.2.8 Special studies on pharmacology
Recent reviews indicate that curcumin has a broad spectrum of
pharmacological activity (Ammon & Wahl, 1991; Srimal, 1987). Some
studies which appeared in the literature following the 1986 JECFA
evaluation (Annex 1, reference 73) are briefly summarized below to
indicate the range of activities reported, however, a comprehensive
review of all of the published literature was not undertaken.
Table 4. Summary of recently published non-microbial genetic toxicological
studies with curcumin or turmeric
Test System Test Object Test Dose Result Reference
Material
Micronucleus mouse turmeric 100, iph - Jain et al.,
bone marrow extracta 200 - 1987
500 -
Chromosome mouse turmeric 100, iph 2.00b Jain et al.,
aberration bone marrow extracta 200 1.73 1987
500 6.22
Sister chromatid mouse curcumin, 5, iph - Giri et al.,
exchange bone marrow at 24h 10 - 1990
25 +
50 +
100 +
200 +
Chromosome rat curcumin months Giri et al.,
aberrationc bone marrow chronic 3 6 9 1990
dietary 100i - - -
exposure 200 - - -
500 - - +
1000 - - +
Sister chromatid CHO cells turmeric 0.16 µg/ml +, - NTP, 1993
exchanged,e oleoresin 0.50 -, -
with 1.60 -, +
79%-85% 5.00 -, +
curcumin
Table 4. (cont'd).
Test System Test Object Test Dose Result Reference
Material
Chromosome CHO cells turmeric 5 µg/ml -, - NTP, 1993
aberrationd,g oleoresin 10 -, -
with 15 +, +
79%-85%
curcumin
a actual curcumin content not specified: typically, the curcumin content of
turmeric is approximately 3%
b of aberrant cells (negative and positive controls produced 0.5 and 12.8%
responses, respectively)
c gaps not included
d two trials
e with S9 metabolic activation
f negative results were obtained in a single trial with S9 metabolic
activation up to 10/µg/ml
g estimated curcumin content of 3% (actual not specified)
h doses in mg/kg bw
i doses in mg/kg of feed
2.2.8.1 Anti-tumour effects
Topical application of curcumin inhibited 12- O-tetradecanoyl-
phorbol-13-acetate (TPA)-induced epidermal ornithine decarboxylase
activity, epidermal DNA synthesis, and skin tumour promotion in female
mice initiated with 7,12-dimethyl-benz[a]anthracene (DMBA)
(Huang et al., 1988).
In another similar study, mice were treated with 3 dose levels of
topical curcumin and with TPA (5 nmol) twice weekly for 19 weeks
following tumour initiation with DMBA. At 1, 3, and 10/µmol, curcumin
inhibited the number of tumours by 39, 77 and 98%, respectively,
indicating a marked inhibitory effect on tumour promotion (Conney
et al., 1991). This anti-tumour effect of curcumin is supported in
another study of skin carcinogenesis in mice by Soudamini & Kuttan
(1989).
A DMBA-initiation/TPA-promotion organ culture model was used to
demonstrate an anti-initiator effect of 10-6 M curcumin on mammary
lesions induced in cultured mouse mammary glands. Under the conditions
of the model, areas of alveolar growth that develop during incubation
with the carcinogen and certain growth promoting hormones are termed
mammary lesions if the growths do not regress after withdrawal of the
hormones (except insulin) (Mehta & Moon, 1991).
The anticarcinogenic effects of oral and topically applied
curcuminoids (i.e. curcumin I and curcumin III prepared via
chromatographic separation of an alcoholic extract of powdered
turmeric) on different stages in the development of cancer in mice and
rats was discussed and it was concluded that curcuminoids inhibit
cancer at various stages including initiation, promotion and
progression (Nagabhushan & Bhide, 1992).
Commercial grade curcumin (77% curcumin, 17% demethoxycurcumin
and 3% bisdemethoxycurcumin) was fed to different strains of 6-week
old mice (14-46/group) for variable time periods (up to 24-27 weeks)
to determine its effects on BP-induced forestomach tumorigenesis,
N-ethyl-N'-nitro-N-nitroso-guanidine-induced duodenal tumorigenesis
and azoxymethane-induced colon tumorigenesis. In addition, a single
group of azoxymethane-treated mice was fed 2% pure curcumin (> 98%
pure). Mice were fed curcumin at levels up to 4% during one of the
following periods of the study: (a) during the initiation phase of
tumorigenesis (i.e. 2 weeks before and 1 week after the carcinogen was
given); (b) during the post-initiation phase (i.e. beginning 1 week
after the carcinogen was given and continuing until the study was
terminated); and (c) during both the initiation and post-initiation
phases of tumorigenesis.
In female A/J mice receiving dietary curcumin (0.5-2%), the
incidence of tumours (papillomas and squamous cell carcinomas) of the
forestomach were significantly decreased (51%-67%) during the
initiation or post-initiation phases and tumour size was reduced. In
male C57BL/6 mice, curcumin at a level of 0.5% in the diet
significantly reduced the number of adenomas and the total number of
duodenal tumours per mouse (44-77%) during the post-initiation phase;
however, the inhibition of tumorigenesis was not statistically
significant at dietary levels of 1% and 2%. A non dose-related
reduction in the size of duodenal adenomas and a trend toward
increased duodenal adenocarcinoma size was observed.
Curcumin during the initiation or post-initiation phase (0.5-2%
dietary level), or during both phases (0.5-4% dietary level)
significantly reduced the number and size of colon tumours in CF-1
female mice. Similar to the effects of curcumin on tumour incidence
and size, the percentage of mice with tumours was reduced in groups
fed curcumin. Dietary commercial grade curcumin also decreased the
acute lethal effects of azoxymethane, but pure curcumin did not
(possibly due to reduced solubility and bioavailability of the pure
compound). The authors noted that 0.5% curcumin was as effective as
higher levels in inhibiting chemically-induced tumorigenesis in the
gastrointestinal tract of mice (Huang et al., 1994).
Comparable anti-tumour effects were observed in animal studies
with turmeric. A 1% dietary turmeric inhibited the formation of
BP-induced forestomach tumours in female Swiss mice by 58% and lowered
the incidence of spontaneous mammary tumours in C3H Jax mice by 60%
(Nagabhushan & Bhide, 1987).
In a 13-month oral study in hamsters, the inhibitory effects of
betel-leaf ( Piper betel L.) extract, ß-carotene and alpha-tocopherol
in drinking-water on methyl(acetoxy-methyl)-nitrosamine-induced oral
carcinogenesis were enhanced when 5% turmeric was added to the diet
(the antioxidants, ß-carotene and alpha-tocopherol, are components of
betel-leaf extract). Curiously, the combination of betel-leaf extract
with turmeric was apparently toxic and decreased survival in hamsters
receiving the combination in this study (Azuine & Bhide, 1992).
These data describing anti-tumour effects of curcumin and
turmeric support previous results which indicated that turmeric
extract and curcumin (which are cytotoxic to normal human lymphocytes,
leukemic lymphocytes and Dalton's lymphoma cells in vitro) reduced
tumour formation in mice injected intraperitoneally with Dalton's
lymphoma cells (Kuttan et al., 1985). The precise mechanism by which
curcumin exhibits its anti-tumour effect is unknown, although
inhibition of arachidonic acid metabolism (Huang et al., 1988)
and/or an antioxidant effect (Kunchandy & Rao, 1990) may be involved.
2.2.8.2 Anti-inflammatory effects
Topical curcumin and related derivatives are reported to inhibit
TPA-and arachidonic acid-induced inflammation in mouse epidermis using
the ear edema test (Huang et al., 1991b; Conney et al., 1991).
These effects parallel the ability of these compounds to inhibit
lipoxygenase and cyclooxygenase; thus, Huang et al. (1991b)
suggested that inhibition of arachidonic acid metabolism is
responsible for curcumin's ability to inhibit inflammation as well as
tumour promotion in mouse skin (Huang et al., 1988). However, the
oxygen radical scavenging activity of curcumin has also been
implicated in its anti-inflammatory effects (Kunchandy & Rao, 1990).
These effects were investigated at the molecular level where curcumin
has been shown to have an inhibitory effect on phorbol ester-induced
protooncogene activity in mouse fibroblasts (Huang et al, 1991a).
2.2.8.3 Anti-ulcer effects
An ethanolic extract of turmeric had significant anti-ulcer,
anti-secretory and cytoprotective activity in rats subjected to a
variety of ulcerogenic stresses and cytodestructive agents
(Rafatullah et al., 1990).
2.2.8.4 Anti-hepatotoxic effects
In hepatocytes from 3-methylcholanthrene-induced rats, curcumin
was reported to be protective against paracetamol-induced lipid
peroxidation, but not against cell death or glutathione depletion
(Donatus et al., 1990).
2.2.8.5 Immunological effects
Ukonan A, a polysaccharide from the rhizome of Curcuma
longa L., has been reported to have phagocytic, anti-complementary
and mitogenic activities (Gonda et al., 1992).
2.2.8.6 Phototoxicity
Phototoxicity resulted in bacterial test systems when curcumin
was irradiated with visible light (Tonnesen et al., 1987;
Dahl et al., 1989).
2.3 Observations in humans
The effects of 500 mg of curcumin (98% purity) administered
orally via capsules on serum peroxides and cholesterol levels were
compared in 10 human volunteers before and after administration for 7
days. The volunteers were between 24 and 45 years of age and weighed
46 to 70 kg; their sex was not reported. No adverse effects were
reported. The data indicated significant decreases in serum lipid
peroxides and in total cholesterol, a significant increase in
HDL-cholesterol, and a non-significant decrease in serum triglycerides
(Soni & Kuttan, 1992).
Azadirachta inica ADR (Neem) and Curcuma longa (turmeric)
ground into a paste in a proportion of 4:1 (Neem:turmeric) was
reported to be effective in curing 97% of 824 cases of scabies within
3-15 days of topical application (Charles & Charles, 1992).
One case of allergic contact dermatitis to Curcuma longa in a
64-year old male Indian spice worker has been reported. Although no
quantitative estimate of exposure was provided, the worker was
reportedly exposed to 7 different spices and worked in a dusty place
laden with spice powders. The authors concluded that turmeric is a
weak sensitizer and that allergic contact dermatitis to it is uncommon
(Gob & Ng, 1987).
3. COMMENTS
In a study previously evaluated by the Committee, extracts of
turmeric reportedly affected reproduction in rats when administered by
gavage on days 1-7 of gestation at doses of 100 or 200 mg/kg bw/day
(Annex 1, reference 60). However, no reproductive effects were
reported in Wistar rats fed 500 mg/kg bw/day turmeric or 60 mg/kg
bw/day of an alcoholic extract of turmeric (providing an equivalent
dose of curcumin) in a multigeneration reproductive toxicity study.
Data from multigeneration reproductive and/or teratogenicity studies
with curcumin itself (rather than turmeric) were not available.
Of a single oral dose of 400 mg [3H]curcumin (equivalent to
2000 mg/kg bw) administered to rats, only 60% of the radioactivity was
excreted by 12 days. At lower doses (equivalent to 50 or 400 mg/kg bw)
most of the dose was excreted within 72 hours.
No genotoxicity studies with high purity curcumin were available.
In limited studies with curcumin preparations of up to 85% purity, or
of unknown purity, no mutagenic activity was seen in bacteria and only
equivocal activity in assays for the induction of chromosomal
aberrations. The Committee concluded that there was no evidence to
show that curcumin was genotoxic.
Long-term studies on the carcinogenic potential of turmeric
oleoresin containing a high percentage of curcumin (79-85%) have been
completed in mice and rats at dose levels of 2000, 10 000 or
50 000 mg/kg in the diet, equal to 220, 1520 or 6000 mg/kg bw/day
in mice and 80, 440 or 2000 mg/kg bw/day in rats. The authors
noted statistically significant increases in the incidences of
hepatocellular adenomas (mid-dose males and females), small intestinal
carcinomas (low- and mid-dose males) and pituitary gland adenomas
(high-dose females) in mice and clitoral gland adenomas (females) in
rats. On the basis of the results of these studies, the Committee
concluded that the effects were not dose-related, and that curcumin
was not a carcinogen.
Gastrointestinal irritation (ulcers, hyperplasia and
inflammation) was common in male and female rats in the high-dose
group, but was not observed in mice. The NOEL for gastrointestinal
effects in rats was 10 000 mg/kg in the diet, equal to 440 mg/kg
bw/day.
After 15 months of treatment, absolute and relative liver weights
were increased in both male and female mice in the mid- and high-dose
groups relative to control. The NOEL for liver enlargement was
2000 mg/kg in the diet, equal to 220 mg/kg bw/day.
Results from studies with curcumin indicated a wide and varied
pharmacological activity, including anti-tumour, anti-inflammatory,
anti-ulcer, and anti-hepatotoxic effects, in vitro immunologic
activity and phototoxicity.
The Committee also considered a number of new studies with
turmeric but concluded that the test ingredient in the studies was not
comparable in composition to curcumin used as a colour additive in
food. For this reason, these turmeric studies could not be used in the
evaluation of curcumin.
4. EVALUATION
On the basis of the NOEL of 220 mg/kg bw/day in the
carcinogenicity study in mice and, using a safety factor of 200, the
Committee increased the temporary ADI to 0-1 mg/kg bw and extended it,
pending the submission of the results of a reproductive toxicity study
with curcumin for review in 1998. The Committee has made repeated
requests since the eighteenth meeting in 1974 for such a study. At its
present meeting, it reconfirmed the need for the study and reiterated
the view that previous studies with turmeric were not relevant to the
evaluation of curcumin. If such studies are not submitted for review
in 1998 it is unlikely that the temporary ADI can be further extended.
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See Also:
Toxicological Abbreviations
Curcumin (WHO Food Additives Series 52)
CURCUMIN (JECFA Evaluation)