Volume 10, Issue 11, November – 2025 International Journal of Innovative Science and Research Technology

ISSN No:-2456-2165 https://doi.org/10.38124/ijisrt/25nov222

Elucidating the Effect of Estragole: Unlocking the

Fine Line between Dose, Risk and Efficiency - A
Scientific Narrative Review
Priyanka 1; Lubna Fathima 2*; Muthulakshmi S.3; Dinesh Dhamodhar4;
Sindhu R5; Prabu D.6; Rajmohan M.7
1
Undergraduate (Bachelor of Dental Surgery), SRM Dental College, Bharathi salai, Chennai.
2,5
Master of Dental Surgery, Senior Lecturer, Department of Public Health Dentistry, SRM Dental College,
Bharathi Salai, Chennai.
3
Postgraduate, Department of Public Health Dentistry, SRM Dental College, Bharathi Salai, Chennai.
4,7
Master of Dental Surgery, Reader, Department of Public Health Dentistry, SRM Dental College, Bharathi
Salai, Chennai.
6PhD, Master of Dental Surgery, Professor and Head, Department of Public Health Dentistry, SRM Dental

College, Bharathi Salai, Chennai.

Corresponding Author: Dr. Lubna Fathima*

Publication Date: 2025/11/15

Abstract:

 Background:
Estragole is a constituent of herbs such as tarragon, basil, and fennel. It is known for its anti-inflammatory and
antimicrobial activity. There is evidence of its carcinogenic potential in animal models. Estragole carcinogenicity may be
linked to its metabolic conversion, forming 1′-sulfoxy metabolites. These metabolites can form covalent DNA adducts,
inducing hepatic tumors at high-dose repeated exposure in rodents.

 Aim:
This narrative review aimed to evaluate the carcinogenic potential of estragole by systematically analysing published
animal trials and assessing the neoplastic changes.

 Materials and Method:

A systematic review was conducted using Pubmed, Elsevier Science Direct, Wiley Online library, Scopus data bases.
The keywords “Estragole” and “Neoplasm” were used as MeSH terms. From the initially identified articles 296, 286 were
screened after duplicate removal based on inclusion criteria (English language, Full-text articles, animal trial studies on the
carcinogenic effect of estragole). 4 studies were selected for final analysis.

 Results:
The included animal trials investigated estragoles effect on mice and rats at various doses. Estragole was shown to have
high carcinogenic potential at high doses. With an increase in estragole dosage, there was an increase in hepatic tumors in
both mice and rats.

 Conclusion:
In rat and mice animal models, high dosage of estragole induces tumor formation. The risk of estragole for humans is
presently not determined, as it is consumed at low ppm levels. Estragole is a potential carcinogenic agent. Further metabolic,
and human related studies are needed to determine carcinogenic risk of estragole to human.

Keywords: Estragole, Cancer, Hepatocellular Carcinoma.

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How to Cite: Priyanka; Lubna Fathima; Muthulakshmi S.; Dinesh Dhamodhar; Sindhu R; Prabu D.; Rajmohan M. (2025)
Elucidating the Effect of Estragole: Unlocking the Fine Line between Dose, Risk and Efficiency - A Scientific Narrative Review.
International Journal of Innovative Science and Research Technology, 10(11),
474-481 https://doi.org/10.38124/ijisrt/25nov222

I. INTRODUCTION It has also been shown that estragole has anti-lipase

activity. It can also block neuronal excitability via inhibiting
One of the biggest issues facing society, public health, the Na+ channel.15 though estragole has many beneficial
and the economy is cancer. It is responsible for nearly one in properties, it has also been shown to be carcinogenic in
six deaths worldwide.1 It is a disease that begins with genetic animal models, causing hepatocellular carcinoma in mice.
alterations occurring in specific cells, caused by After oral exposure, estragole is absorbed from the
carcinogens.2 These carcinogens can be present in commonly gastrointestinal tract and undergoes metabolism, mainly in
consumed foods and drinks.3 Numerous interconnected the liver.16 Metabolism of the parent alkenylbenzene by
elements influence human tumour development, and cytochromes P450 and sulfotransferases forms 1′-sulfoxy
exposure to small food substances must be taken into account. metabolites. There is much evidence that the 1′-sulfoxy
4According to the global cancer registry, liver cancer is the metabolite of estragole can form covalent adducts with
third most common cause of cancer-related fatalities and the guanine or adenine. This compound may raise a health
sixth most common disease overall.5 Its 5-year survival rate concern because of its DNA adduct formation and
is only about 20%. Hepatocellular carcinoma accounts for carcinogenicity, inducing hepatic tumours at high-dose
about 9.2% of all new instances of cancer worldwide. 6 It repeated exposure in rodents.
accounts for 90% of liver cancer cases worldwide. It is the
most common cause of all liver cancer cases. Formation of DNA adducts may result in mutations and
increase the risk of developing cancer. It can also induce
A global health challenge, it has an estimated DNA repair. Thus, the risk of DNA adduct formation depends
occurrence of over 1 million cases by 2025.8 The on the efficiency of the repair process before repeat
pathogenesis of hepatocellular carcinoma is a complex, exposure.17 DNA adduct repair of covalently bound adducts
multistep process.9 It is closely linked to the prevalence of operates in vivo. This is seen through the rapid decrease in
chronic liver diseases. It also involves genetic susceptibility, adduct formation following exposure to methyl eugenol or
interactions between viral and no viral risk factors, cellular estragole in studies done on mice. However, a study done on
microenvironments, and various immune cells. The severity eugenol exposure in HepaRG cells or primary hepatocytes
of these factors and an altered microenvironment are key showed that the repair of the DNA adducts formed was
contributing features to cancer.10 Prolonged exposure to inefficient. With 80–90% of the adducts still remaining in
compounds that are possibly carcinogenic, particularly HepaRG cells or primary hepatocytes after 48 h and/or 4 h
during periods of hepatic dysfunction or chronic repair.18 This systematic review aims to unlock the fine line
inflammation, can significantly enhance the risk of between the dose, risk, and efficiency of estragole.
hepatocellular carcinogenesis.
II. MATERIALS AND METHODS
Compounds like estragole exhibit potential
hepatocarcinogenic properties. Estragole is a compound This systematic review was conducted to evaluate the
found in basil and other herbs and has been a staple in carcinogenic potential of estragole by systematically
traditional medicine for centuries. However, its effects on analysing published animal trials and assessing the neoplastic
human health are only now being fully understood. Estragole changes. This Systematic review
Your text
was conducted following
is a phenylpropanoid. It consists of a benzene ring replaced PRISMA Guidelines.19 here 1

by a methoxy and a propenyl group, presenting as a

constituent of essential oils of many plant species, such as  Eligibility Criteria
basil, anise, fennel, bay leaves, and tarragon.11,12 Estragole
possesses many beneficial medicinal properties, shown  Inclusion Criteria
through its antimicrobial, antidiabetic, and antioxidant
effects.13 It also shows anti-inflammatory and anti-  Studies published in English
edematogenic activity in acute and chronic inflammation  Full-text articles
animal models. The mechanism is similar to NSAIDs and  Articles on the carcinogenic effect of estragole
corticosteroids.14  Animal Trial studies

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 Exclusion Criteria:  Unrelated Articles Search Strategy

Electronic databases such as PubMed, Elsevier science
 Articles published in other languages direct, Wiley online library, Scopus were used to find
 Only abstracts available published articles on the carcinogenic effect of estragole. The
MeSH terms "Estragole" AND “Neoplasm" were used for the
search.

III. RESULTS

Fig 1 Prisma Flowchart

Figure 1 shows PRISMA flowchart resulted in 45 articles, of which 9 were full-text articles having accessibility and were
eligible for review. Ultimately, 4 articles were chosen for inclusion in this systematic review.

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Table 1 Characteristics of Intervention in the Study

S.no Author Name Year Sample Size Duration Animal Allocation
1. Drinkwater, 1976 There were 79 mice in the All animals that Estragole was injected in the nape of the
N. R. et al.22 group that received the survived were put to neck of newborn mice according to the
lower doses of estragole; death at 15 months. following dosage schedule: 0.17μ mole of
after 12 and 15 months, Each had a routine, chemical in 0.025 ml of heat-sterilized
respectively, the sample thorough autopsy. trioctanoin Bauer after 24 hours of birth,
size dropped to 60 and 47. 0.47μ mole in 0.05 ml on day 8,
0.95μmole in 0.05 ml on day 15, and
There were 19 mice in the 2.84μmoles in 0.1 ml on day 22 (total
group that received the dose=4.43μmoles).
lower doses of estragole;
after 12 and 15 months, Estragole was administered as follows:
respectively, the sample 0.35 μmole in 0.025 ml on day 1, 0.69
number dropped to 18 and μmole in 0.05 ml on day 8, 1.38 μmoles
17. in 0.05 ml on day 15, and 2.77 μmoles in
0.1 ml on day 22 (total dose=5.19
μmoles).
2. Wiseman, 1988 This team used breeding The study lasted for On Day 1, male and female C3H/HeJ and
R.W. et al.23 stock from The Jackson fourteen months. Gross CS7BL/6J mice received 0.1 μmol/25 μL
Laboratory (Bar Harbor, routine autopsies were sterile trioctanoin/mouse; on days 8, 15,
ME) to raise mice. There performed on all and 22 following birth, they received 0.04
were 38 male C3H/HeJ animals that died or μmol/10 μl/g, 0.04 μmol/5 μl/g, and 0.08
mice and 34 female were killed while μmol/7 μl/g of 1'-hydroxy estragole.
C3H/HeJ mice in one moribund and all
group and 36 male animals that lived to
C57BL/6J mice and 36 the end of a study.
female C57BL/6J mice in
another.
3. Bristol DW. 2011 Mice and rats were taken Mice were fed doses of Rats were gavaged with 5 mL/kg of maize
et al.12 for the students. In rats estragole five days per oil at doses of 0, 37.5, 75, 150, 300, or 600
F344/N rats 20 males and week for 14 weeks mg/kg.
20 females were taken. In Mice were gavaged with 10 mL/kg of
B6C3F1 mice There were corn oil at doses of 0, 37.5, 75, 150, 300,
ten men and ten females in or 600 mg/kg.
the bunch.
4. Suzuki,Y. et 2012 B6C3F1 gpt delta mice, For thirteen weeks, By gavage, the mice were given dosages
al.24 fifty male and fifty female, mice were given of 37.5, 75, 150, or 300 mg/10 mL/kg
were divided into five dosages of estragole body weight (250 mg/10 mL/kg bw for
groups at random based on five days a week. females) of estragole in corn oil.
their weight. Only maize oil was given to vehicle
control animals (0 mg/10 mL/kg bw).

Table 1 shows the Characteristics of the studies included in the systematic review with Author name, samples recruited, sample
characteristics, duration of the study and sample allocation.

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Table 2 Characteristic of the Primary Outcome and Results of Studies Included in the Current Study
S.no Author Year Effect Measure Result
Name
1. Drinkwater, 1976 The number of mice with a Fourteen of the mice under the lower doses of estragole had
N. R. et single hepatocellular cancer. single hepatocellular carcinoma, three had multiple hepatocellular
al.22 Mice having numerous carcinomas, three had lung adenomas, and three had malignantly
hepatocellular carcinomas amphora. Seven mice in the higher dose estragole group had a
were counted. How many single hepatocellular carcinoma, five had multiple hepatocellular
mice had lung adenomas? carcinomas, zero had lung adenomas, and zero had malignant
Mice having malignant lymphoma.
lymphoma in number.
2. Wiseman, 1988 Susceptibility to Hepatoma By 14 months, male C3H/HeJ mice who received cumulative
R.W. et Induction in Relation to dosages of roughly 1.5 μmol/g body weight of 1'-hydroxy
al.23 Mouse Strain, Sex, and Age estragole during the first 21 days after birth had five to ten times
of Treatment more hepatomas than male CS7BL/6J mice that received the
same treatment. This approach, which delivered the carcinogen
only before weaning, made female mice of both strains extremely
resistant to hepatoma induction. When the hepatoma responses of
male B6C3F mice treated with 1'-hydroxyestragole at 1 or 12
days of age were compared, it was shown that the 12-day-old
animals were two to three times more susceptible. Only 73 and
43% of the mice treated with 1'-hydroxyestragole at 1 and 12
days of age, respectively, survived to weaning due to acute
toxicity at the 0.15 μmol/g body weight dose.
3. Bristol 2011 Complete histopathologic In rats, both sexes' livers and male rats' kidneys showed
DW. et al.12 analyses, clinical chemistry, noticeable damage. The 300 and 600 mg/kg groups had the most
and hematology. lesions. Two male rats given 600 mg/kg developed numerous
All groups had their target liver cholangiocarcinomas, while a third had a hepatocellul
tissues analyzed. A no-effect aradenoma. Every male with 600 mg/kg had cholangiofibrosis.
level of examination was Hepatocellular hypertrophy was present in all males given 75
performed on nontarget mg/kg or more and all females given 150 mg/kg or more, and the
tissues. The kidney, liver, severity increased with increasing dose. In mice, all male dosage
lung, mesenteric lymph groups had higher absolute liver weights. The 75 and 150 mg/kg
node, nose, pituitary gland, groups showed a significant increase. Additionally, 300 mg/kg
salivary gland, glandular females had a considerably higher absolute liver weight. In those
stomach, and testis were the receiving 75 mg/kg or more, relative liver weights increased
target tissues in rats, while considerably. Hepatocellular hypertrophy and hepatocellular
the kidney, liver, mandibular degeneration were markedly elevated in 75 mg/kg females, 300
and mesenteric lymph nodes, and 600 mg/kg males, and 150 and 300 mg/kg females. Males at
nose, spleen, forestomach, 300 and 600 mg/kg and females at 75, 150, 300, and 600 mg/kg
and glandular stomach were had significantly higher levels of oval cell hyperplasia in their
the target tissues in mice. livers.

4. Suzuki,Y.et 2012 Liver weights, body weights, Two out of ten, five out of ten, and five out of six female mice in
al.24 alterations in the liver's the 75, 150, and 250 mg/kg bw groups, respectively, showed very
histology, Comparing the minor hepatocellular hypertrophy. After 13 weeks of ES
expression of mRNA in the treatment, the amounts of ES-DNA adducts, ES-3′-8-dG, 3′-N2-
livers of men and women dG, and 3′-N6-dA, in liver DNA were assessed using the LC–
ES-DNA adduct MS/MS method. While no ES-DNA adducts were found in the
concentrations in the livers controls, the DNA adducts were found in the livers treated with
of mice, In vivo tests for ES. With the exception of the females in the 250 mg/kg bw
mutations, MN test in bone group, ES-specific DNA adduct production from ES-treated mice
marrow from mice. increased in a linear dose-dependent manner.

Table 2 Shows the intervention used in the study included with the outcome.

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Table 3 Quality Assessment of all the Included Studies

Random Allocati Comparis Confou Experi Blindi Complete Exposu Outco Outco No
ization on on group nding mental ng outcome re me me othe
Concea conditi data Charac Assess Repor r
Autho lment ons terizati ment ting thre
r name on ats
Drinkw
ater, N.
R. et al.

Wisem
an,
R.W. et
al.

Bristol
DW. et
al.

Suzuki,
Y. et
al.

Risk of Bias Definitely low risk of bias Probably low risk of Probably high risk of Definitely high risk of
bias bias bias
Colour

Table 3 shows the Risk of bias in all the included studies based on the Office of Health Assessment and Translation (OHAT)
Assessment tool.

IV. DISCUSSION hydroxysafrole at the nape of the neck according to the

following dose schedule: 24 hours following delivery, on
A naturally occurring component of herbs like basil is days 8, 15, and 22. The male mice that survived the
Estragole. The estimated daily exposure dose for humans is carcinogenicity test were weaned at 22 days of age. There
between 0.01 and 0.07 mg/kg. According to reports, were only 19 mice in the group that received the greater dose
Estragole can generate certain DNA adducts in the liver and of Estragole; there were 60–79 animals in each of the other
is hepatocarcinogenic. Estragole's genotoxic testing, groups. All animals that survived were put to death at 15
however, has yielded conflicting results. It is unknown how months. Each had a standard gross autopsy that examined the
Estragole causes hepatocarcinogenicity. When administered skin, mammary tissues, and the organs of the thoracic and
at large levels, Estragole may be a potential genotoxic abdominal cavities. The incidence of pulmonary adenomas,
hepatocarcinogen in rats. It has been suggested that the malignant lymphoma, and hepatocellular carcinoma in mice
metabolic conversion of Estragole contributes to its increased with estragole exposure. The research
carcinogenicity. Cytochrome P450 enzymes primarily acknowledges that Estragole is probably negligible in terms
convert Estragole to 1-hydroxyestragole, which is then of risks to humans.
converted by sulfotransferases (SULT) into 1-
sulfooxyestragole, the final carcinogenic metabolite.1 Due to In a study conducted by Wiseman, R.W et al.,23
its instability and susceptibility to degradation in an aqueous Methyleugenol appears to be as potent a carcinogen in the
environment, sulfooxyestragole can generate a reactive liver of mice as Estragole and safrole. Compared to male
carbocation that can bind covalently to DNA.22 Modest C57BL/6J mice, male Estragoleice were much more
quantities of carcinogens are typically found in food, leading vulnerable to I'-hydroxyestragole. By 14 months, male
to modest daily intakes. Therefore, when evaluating the C3H/HeJ mice had five to ten times as many hepatomas as
results of studies on the carcinogenicity of certain chemicals male C57BL/6J mice given the same treatment. This
in animals, it is essential to consider the mechanisms by approach, which delivered the carcinogen only before
which mutagenic and other chemicals induce cancer, as well weaning, made female mice of both strains extremely
as the extent of human exposure to these chemicals. resistant to hepatoma induction. When the hepatoma
responses of male B6C3F mice treated with 1'-
In a study conducted by Drinkwater et al.,22 newborn hydroxyestragole at 1 or 12 days of age were compared, it
mice were administered estragole, 1'-hydroxyestragole, or 1'-

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was shown that the 12-day-old animals were two to three the level consumed is small at low ppm levels typically
times more susceptible. estimated to be 0.01–0.07 mg/kg/day. Further metabolic, and
human related studies are needed to determine carcinogenic
In a study by Bristol DW. et al.,12 Rats and male mice risk of estragole to humans.
given 300 or 600 mg/kg, and female mice given 75 mg/kg or
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