CURCUMIN AND TUMERIC OLEORESIN
EXPLANATION
Turmeric can be considered as both a flavouring agent and a food
colour; curcumin is the main coloured component of turmeric.
These substances were previously evaluated for an acceptable
daily intake at the thirteenth, eighteenth, twenty-second, and
twenty-sixth meetings of the Committee (Annex 1, references 19, 35,
47, and 59). Toxicological monographs were prepared on each of these
occasions (Annex 1, references 20, 36, 48, and 60).
Temporary ADIs of 0-2.5 mg/kg b.w. for turmeric and 0-0.1 mg/kg
b.w. for curcumin were allocated at the twenty-second meeting of the
Committee, which were extended at the twenty-fourth meeting. New data
on these substances were reviewed at the twenty-sixth meeting of the
Committee, when the temporary ADIs were extended to 1986 pending the
results of further studies.
Since the previous evaluation, additional data have become
available, which are summarized and discussed in the following
monograph addendum. Data for turmeric oleoresin and for curcumin are
presented and evaluated separately.
CURCUMIN
BIOLOGICAL DATA
Biochemical aspects
Absorption, distribution and excretion
In the short-term study on a test material containing 79%
curcumin in Fischer 344 rats and B6C3F1 mice (see short-term studies
below), it was reported that turmeric (presumably curcuminoid
pigments) was detected in blood samples from both species at all dose
levels and that blood plasma concentrations increased linearly in a
dose-related manner over the dietary concentration range of 0.1-2.5%;
at the higher dietary level of 5.0%, plasma levels tended to plateau.
The data were claimed to be consistent with earlier reports (Wahlstrom
& Blennow, 1978; Bolder et al, 1978) that the substance is poorly
absorbed from the gut and is rapidly metabolized and excreted.
However, this summary report is impossible to evaluate since there are
obvious mistakes in the data supplied and the basis of calculations of
percentage of the dose in blood is unclear (Lilja, 1984).
Toxicological studies
Acute toxicitya
Animal Route LD50 (g/kg b.w.) Reference
Mouse Oral > 10 Lilja et al., 1983
Rat Oral > 10 Lilja et al., 1983
a The test material was estimated to contain about 79% curcumin.
Short-term studies
Mice
Groups of 10 male and 10 female B6C3F1 mice, aged 8-9 weeks,
received curcumin in the diet at concentrations of 0, 0.1, 0.5, 1.0,
2.5, or 5.0% for 13 weeks. The test material contained approximately
79% curcumin. Food intake and body-weight gain were recorded weekly.
Urinalysis was performed eight days prior to termination and blood was
collected for haematology and clinical chemical analyses at the end of
the study. Gross necropsies were performed on all animals and detailed
histological examinations were carried out on the control and 5% dose
groups only. No significant differences attributable to treatment were
observed in body-weight gain, mortality, or histopathology, but a
dose-related increase in liver weight occurred in both sexes.
Decreases were observed in lung weight, which achieved statistical
significance in males of the two highest-dose groups only, in thymus
weight, significant only at the 2.5% level, and in kidney weight,
significant in females of the top-dose group only. Haemetological
changes observed were not dose-related and the values were within
normal ranges. Clinical chemistry analyses revealed dose-related
increases in cholinesterase and phosphorus, which were significant at
the 1% and higher dose levels in males and at the top two dose levels
(cholinesterase) or top-dose group only (phosphorus) in females. A
dose-related decrease in creatinine levels occurred in females at all
but the lowest dose level and in males at the top three dose levels.
The no-effect level with respect to gross and microscopic pathological
changes was 5% of the diet, equal to a time-weighted average of 9280
and 7700 mg/kg b.w./day in females and males, respectively
(Lilja et al., 1983).
Rats
A 13-week study was carried out in F344 rats using a similar
protocol and at the same dose levels as described for mice above. No
significant differences due to treatment were observed in body-weight
gain, mortality, or histopathology. There was a dose-related increase
in liver weight in both sexes; in females there was also a
treatment-related decrease in heart and lung weights. Haematological
examination showed a dose-related increase in polymorphonuclear
lymphocytes at the 2.5 and 5% dose levels in males while in females
there was a small increase only at the 5% level. In females,
erythrocyte counts tended to be lower in a treatment-related but not a
consistent dose-related manner; other haemetological changes were not
dose-related. Clinical chemistry analyses in males revealed a number
of changes at the mid- to high-dose levels; SGPT, OCT, total protein,
globulin, urea nitrogen, creatinine, and total bilirubin were lower
while the albumin/globulin ratio, direct bilirubin, and chloride
tended to be higher than in controls. Decreased SGOT and LDH were
observed only at the highest-dose level. In females, decreases were
observed in LDH, creatinine, total bilirubin, pH, bicarbonate, and
total CO2, while phosphorus was increased at the two higher-dose
levels. Urinalysis of male rats indicated that there was a
treatment-related increase in casts and an increase in red blood cells
at the top two dose levels. Urine of females showed little or no
treatment-related change except for increased uric acid crystals at
all dose levels and a slight increase in red and white blood cells at
the top-dose levels.
The no-effect level with respect to gross and microscopic
pathological changes was 5% of the diet, equal to a time-weighted
average of 2760 and 2587 mg/kg b.w./day in females and males,
respectively (Lilja et al., 1983).
Comments
The short-term studies in rats and mice on test material
containing approximately 79% curcumin indicated a low short-term
toxicity, although evidence of minimal hepatotoxicity and
nephrotoxicity was seen in the high-dose acute toxicity study by
gavage.
It is understood that the long-term carcinogenicity study
required at the twenty-sixth meeting (Annex 1, reference 59) on
curcumin was nearing completion. No details were available regarding
the required multigeneration reproduction/teratology study on
curcumin. This evaluation is based on earlier studies pending the
results of the long-term carcinogenicity study.
EVALUATION
Estimate of temporary acceptable daily intake for man
0-0.1 mg/kg b.w.
Further work or information
Required (by 1989)
1. Adequate long-term carcinogenicity study in a rodent species.
2. Multigeneration reproduction/teratology study.
REFERENCES
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.
Lilja, H.S., Hagopian, M., Esber, H.J., Fleischman, R.W.,
Russfield, A.B., & Tiedemann, K.M. (1983). Report on the
subchronic toxicity by dosed feed of turmeric oleoresin (C60015)
in Fischer 344 rats and B6C3F1 mice. EGG Mason Research
Institute, Report No. MRI-NTP 11-83-22. Submitted to WHO by the
National Institutes of Health, Research Triangle Park, NC, USA.
Lilja, H.S. (1984). Final report amendment. EG&G Mason Research
Institute, Report No. MRI-NTP 11-83-22. Submitted to WHO by the
National Institutes of Health, Research Triangle Park, NC, USA.
Wahlstrom, B. & Blennow, G. (1978). A study on the fate of curcumin in
the rat. Acta Pharmacol. Toxicol., 43, 86-92.
TURMERIC OLEORESIN
BIOLOGICAL DATA
Toxicological studies
Special studies on mutagenicity
Turmeric oleoresin was not mutagenic in the Ames assay using
Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537, with
or without metabolic activation by S-9 preparations from Aroclor
1254-induced rats or Syrian hamsters (Spalding, 1983).
Short-term studies
Pigs
Turmeric oleoresin (containing 17.5% curcumin) was fed for
102-109 days to groups of 4 male and 4 female pigs (Danish
Landrace-Yorkshire and Danish Landrace) at dietary levels providing
intakes of 60, 296, or 1551 mg/kg b.w./day; 6 male and 6 female pigs
served as controls. The highest-dose group of both sexes showed a
reduction in body-weight gain and food conversion efficiency.
Dose-related increases in the weights of the liver and thyroid were
observed, achieving statistical significance in all treatment groups
of females and the top two dose groups of males. Histologically, all
animals (both sexes) in the top-dose group and all but one in the
intermediate-dose group showed peribiliar infiltration with
lymphocytes; in some animals lymphocytes were also present in the
smaller bile ducts, in the interstices, and in the periportal
parenchyma. In the two higher-dose groups epithelial changes were
observed in the terminal part of the kidney collecting tubules, in the
papillae, and in the urinary bladder; the changes took the form of
increased epithelial cell size, less dense cytoplasm, and nuclei
changed from a basal to intermediary position in the cells. An
increased number of cell layers in the bladder epithelium was also
observed. Hyperplasia of thyroid follicular calls was seen in the top
two dose groups and paralleled the increase in organ weight. A clear
no-effect level could not be established with respect to increased
thyroid weight, and clear morphological changes were seen in the two
highest-dose groups (Bille et al., 1985).
Comments
The short-term study in pigs on turmeric oleoresin (containing
17.5% curcumin) was in response to the previous requirement for such a
study in a non-rodent species. Histopathological changes were observed
in the liver, kidney, bladder, and thyroid of animals in the two
highest-dose groups, including hyperplasia of thyroid follicular
cells, and increased thyroid weights occurred at the lowest dose
(60 mg/kg b.w./day) tested. It was not possible to establish a
no-effect level in this study and comparison with earlier studies
suggests that the pig is more sensitive than rodents to the effects of
turmeric oleoresin.
EVALUATION
Estimate of temporary acceptable daily intake for man
0-0.3 mg/kg b.w. (based on minimal changes in the short-term
study in pigs).
Further work or information
Required (by 1989)
Results of a short-term study in the pig or another non-rodent
species. If this study is performed in a species other than the pig,
the design should enable a comparison to be made of the sensitivity of
the test species with that observed in the short-term pig study. A
clear no-effect level should be established.
REFERENCES
Bille, N., Larsen, J.C., Hansen, E.V., & Wurtzen, G. (1985).
Subchronic oral toxicity of turmeric oleoresin in pigs.
Fd. Chem. Toxicol., 23, 967-973.
Spalding, J.W. (1983). Genetic toxicity report on turmeric oleoresin
(8024-37-1). Unpublished report submitted to WHO by the National
Institutes of Health, Research Triangle Park, NC, USA.