Recent toxicological reviews have focused on the carcinogenicity of estragole, for example those published by the Reproductive and Cancer Hazard Assessment Section in the Office of Environmental Health Hazard Assessment of the California EPA[i], and the International Program on Chemical Safety for the WHO.[ii]

This has led to some governmental regulatory agencies issuing guidelines for the use of some herbs that contain this constituent. For example the German Federal Institute for Health Protection of Consumers and Veterinary Medicine (BgVV) advises that the content of the plant constituents, estragole and methyleugenol, in foods should be reduced as far as possible on precautionary grounds.[iii] They state, for example:

• It is not possible to estimate the actual scale of the risk to the consumer from the regular consumption of estragole or methyleugenol-containing foods. It is, however, unlikely to be very high given the relatively small intake amounts of these substances. No studies have been produced up to now which confirm a concrete risk to health in man.
• For precautionary reasons, BgVV does however recommend that consumers restrict any ongoing and regular consumption of the above spices and herbal teas which goes beyond their occasional use in the kitchen. This applies in particular to fennel teas which are frequently given to children to treat wind. Tea preparations of this kind should only, therefore, be administered over longer periods after consulting a doctor or pharmacist.
• Even if the grounds for suspicion, as in the case of methyleugenol and estragole, are not sufficient in order to justify a ban of traditional foods, the consumer is at least given an opportunity to adapt his personal consumption behavior to his individual precautionary needs.

Similarly the Working Party on Herbal Medicinal Products of the European Agency for the Evaluation of Medicinal Products issued a Public Statement on the use of Herbal Medicinal Products Containing Estragole in April 2005.[iv] Note the following:

• … it is concluded that the present exposure to estragole resulting from consumption of herbal medicinal products (short time use in adults at recommended posology) does not pose a significant cancer risk.
• Nevertheless, further studies are needed to define both the nature and implications of the dose response curve in rats at low levels of exposure to estragole. In the meantime exposure of estragole to sensitive groups such as children, pregnant and breastfeeding women should be minimized.

Estragole carcinogenicity

No studies of the long-term health effects of human exposure to estragole have been reported, in fact there is no human evidence pointing to a problem.

Consider the following brief review of findings concerning cancer and estragole. Several studies have demonstrated the carcinogenic effects in mice. The mouse liver metabolizes estragole to the potentially carcinogenic compounds 1’-hydroxyestragole and 1’-sulphoxyestragole. These metabolites are potential carcinogens because of their ability to bind to DNA in vivo.[v] This

process is associated with an increased chance of genetic mutation.[vi]

                                        1’-hydroxyestragole                1’-sulphoxyestragole

Estragole administered to adult or new-born mice of different strains produced malignant liver tumors:

• Administration of estragole to adult female CD-1 mice via the diet for 12 months induced increased incidences of hepatocellular carcinomas compared with control mice.[vii]
• Administration of ten doses of estragole by oral intubation to newborn CD-1 mice produced increased incidences of liver tumors in males, but not females.[viii]
• Estragole administered by multiple intraperitoneal or subcutaneous injections to newborn male CD-1 mice or multiple intraperitoneal injections to male B6C3F1 mice resulted in high incidences of hepatocellular carcinoma.[ix]
• A single intraperitoneal dose of estragole administered to newborn male B6C3F1 mice was also found to be sufficient to induce a high incidence of liver cancer.[x]
• 1’-Hydroxyestragole also induced high incidences of liver tumors when administered by subcutaneous injection to newborn CD-1 mice or via intraperitoneal injection to newborn male CD-1, B6C3F1, CeH/HeJ, or C57B1/6J mice, or in the diet for 12 months to adult female CD-1 mice.[xi]

The carcinogenicity of estragole has not been investigated in the rat, although one subcutaneous

injection study of derivatives of estragole in male rats did not observe any treatment-related increases in tumors.

From this it can be concluded that estragole has demonstrated carcinogenicity in mice and as such is a cancer hazard to mammals. However what is the risk posed to humans?

The same genotoxic mechanism of action was postulated for estragole as for safrole, because both constituents metabolize to 1’hydroxyestragole and 1’-sulphoxy-estragole. Even though both metabolites occur in human metabolism, there are considerable quantitative differences between phenylpropanoid metabolism in humans and. rodents.

The profiles of metabolism, metabolic activation, and covalent binding are dose dependent and the relative importance diminishes markedly at low levels of exposure (i.e. these events are not linear with respect to dose).

In particular, rodent studies show that these events are minimal probably in the dose range of 1-10 mg/kg body weight, which is approximately 100-1000 times the anticipated human exposure to this substance.

For these reasons it is concluded that the present exposure to estragole resulting from consumption of herbal medicinal products (short time use in adults at recommended posology) does not pose a significant cancer risk.

Fennel fruit and Estragole

The issues raised in this article have come to the forefront because of statements made in one of the authoritative guides referred to by nurses and lactation consultants. In the eleventh edition (2004) of Medications and Mothers’ Milk, A manual of Lactational Pharmacology, by Thomas W. Hale Ph.D., the entry for fennel has changed from ‘moderately safe’ to ‘possibly hazardous’.[xii]

The following discussion of the important issues raised is partially based on a paper published in German by Iten and Saller.[xiii] Unfortunately it is not availeble in an English published form.

Fennel seeds have a long history of use, as well as modern use in herbal medicine, as a pleasant and effective carminative and galactagogue. In central Europe there is a tradition of ‘ lactation teas’ based on Apiaceae seeds such as Fennel and Anise. Such lactation teas are sold in German, Swiss and Austrian pharmacies as "Traditionally Used Preparations." They are 'old drugs' already on the market before the German Commission E developed its new standards for herbal drug approval.

Compilations of relevant monographs include the "Standardzulassungen für Fertigarzneimittel"[xiv] (The German Standard Licenses for Finished Drugs), the "Neue Rezeptformularium (NRF)"[xv] (The New German National Formulary), which is published by the "Arzneimittelkommission der Deutschen Apotheker" (Drugs Commission of German Pharmacists), as well as both the Austrian Pharmacopoeia[xvi] (ÕAB) and the Swiss Pharmacopoeia[xvii] (Ph.Helv.).

The characteristic aroma of fennel seed is contributed by the essential oil. This is obtained from the dried, ripe fruit of Foeniculum vulgare var. vulgare Thellung by steam distillation. The primary constituents in the oil are trans-anethole (50-70%), (+)-fenchone (9-22%) and estragole (2-5%) with many minor components.

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Is there a risk posed by fennel fruit because of estragole?

From the previous discussion it is clear that estragole is a potential hazard (especially to mice), but this does not immediately define the nature of the risk posed (if any) to humans. To clarify this the terms hazard and risk must be defined.

Hazard refers to the potential toxicity of a substance in an actual situation; how one deals with the substance in that particular situation determines the risk. Risk differs from hazard in that it cannot usually be determined experimentally. It may be inferred from epidemiological data, or it may be predicted from mathematical models, but rarely can it be measured. Instead, a more qualitative approach to identifying risk must be adopted. The following defined terms are routinely used in risk assessments.

• Hazard is the capability of a substance to cause an adverse effect, although the term can also be applied to physicochemical properties, such as flammability or explosiveness
• Risk is a statistical term that indicates the probability that the hazard will occur under specific exposure conditions
• Risk assessment is the process by which hazard, exposure, and risk are determined
• Risk management is the process of selecting the most appropriate action based on the results of risk assessment and social, economic, and political concerns

In order to determine whether a substance is toxic when present in a large enough amount, several types of information are used. The most conclusive information comes from observation of cases in which humans are exposed to the substance, either in clinical or epidemiological studies. In the absence of information from human studies, inferences are drawn from animal studies, from in vitro studies using living cells, or from comparisons to similar substances that pose known hazards.  As the source of the information moves further from actual human studies, the uncertainty becomes greater.

Can the extrapolation be made from mice to humans? Or even mice to rats?

All the reports concerning estragole toxicity, and hence generalizations concerning herbs that contain it, are based on work with specific laboratory strains of mice. In turn these tests involved feeding very high doses of purified estragole. Dosage ranged between 0.05 to 1,000 mg/kg.

It is well established that considerable differences in sensitivity to toxic substance among different species occurs. For example, mice are more sensitive than rats to the carcinogenic effects of 1,3-butadiene, a chemical used in the production of synthetic rubber and other resins that is one of the 189 hazardous air pollutants identified in the Clean Air Act amendments.[xviii]

Metabolic pathways

Three different metabolic pathways have been identified through which estragole can lead to potentially toxic metabolites which can form DNA adducts. It is believed that the initial step in chemical carcinogenesis is the attachment of the chemical to DNA to produce DNA adducts.

This covalent modification of DNA bases can alter the structure and in turn, the biological processing of the DNA by cellular proteins governing replication, transcription and repair. If not repaired or repaired incorrectly, these modifications may eventually lead to mutations and ultimately cancer, especially if the adduct is located in an oncogene or tumor suppressor gene.

However, even though epoxides of estragole form in vitro DNA adducts, such adducts are not found in humans because of rapid detoxification via epoxide hydrolases and glutathione transferases.[xix]

Dose dependence

Another important difference in estragole metabolism between mice and humans is highlighted by an examination of dose dependency. In this case, the genotoxic metabolite found in urine, 1’-hydroxyestragole, can be used as a indicator of interspecies differences. In mice increasing doses of estragole leads to increasing levels of the metabolite in urine.

• Low doses (0.05-50 mg/kg body weight) led to 1.3-5.4% 1’-hydroxyestragole. 
• High doses (500-1,000 mg/kg body weigh), led to 11.4-13.7%1’-hydroxyestragole.

In humans, the amount of 1’-hydroxyestragole in the urine remained constant at 0.2-0.4% throughout a wide dosage range (1-250 mg estragole or 0.01-5 mg/kg body weight).[xx] A subsequent study on the metabolism of trans-anethole found that it was eliminated by humans 6 to 9 times quicker than by mice.[xxi]

A confounding issue is seeing dosages in mice as having relevance in humans. The dose given to mice amounted to 50 – 100 times the quantities consumed by people normally. It has been estimated by the Scientific Committee on Food of the European Community that the daily exposure to estragole from food in people is in the range of 4.3-8.7mg.  Hager’s Handbook states that 100ml of fennel tea, made from 6g of fennel fruits and 450mL of water, contains only 0.4mg estragole.[xxii]

Iten and Saller make a telling point in that estragole containing plants are not a normal component of the diet of mice. In humans, the exposure to estragole is well established and has developed over evolutionary time. The differences in metabolism suggests that humans have adjusted over the course of time to the naturally occurring amounts of estragole in the context of a detoxification process.

Whole plant v. purified constituent

The next issue is a common conceptual stumbling block. Can the properties of an isolated constituent be assumed from a herb that the chemical is found in. Here is not the place for a detailed exploration of this issue, but consider these points.

• In all the animal studies, isolated, purified estragole was used. Thus the findings give a toxicological profile of this molecule. In humans, however, estragole usually enters the body as a component of fennel tea, or as a food that has been seasoned with an herb that contains is, such as basil or tarragon. In this context estragole occurs in the form of an extremely complex phytochemical mixture.
• If single constituent in vivo data can be used a basis for statements about a herb, then data about other constituents should also be considered. Fennel fruit contains a whole range of antioxidant constituents, which  be considered  protective agents against cancer genesis.[xxiii] For example anethole, the main component of the essential oil, possess anti-inflammatory and anti-carcinogenic actions.[xxiv] Toxicological studies of fennel fruit found no evidence that the complex mixtures obtained by ethanolic extracts had any carcinogenic potential, even at very high single doses (0.5, 1 and 3 g/kg body weight), and followed-up with application of 100 mg extract/kg body weight/day, over a 90 day period.[xxv]

Thus doubt remains that data from animal experiments can be extrapolated to humans, either those concerning desired effects or those concerning undesired effects (e.g. side effects, toxicity).[xxvi] In other words an authoritative risk assessment about fennel necessitates human data. This would include clinical studies, epidemiological and experimental data.

Consideration of these issues (dose, administration form, and differences in metabolism between species) raises doubts about the conclusion that fennel seed can be ‘reasonably anticipated to be a human carcinogen’.

Recognizing these critical issues, the European Agency for the Evaluation of Medicinal Products (EMEA) published a new evaluation of estragole and methyleugenol as constituents of phytomedicines.[xxvii] According to the EMEA, the use of estragole-containing phytopharmaceutical products in typical measured doses and durations of use presents no significant risk of cancer. They recommended that these medicines not be restricted outright for children or for women during pregnancy or breastfeeding, but rather to minimize their use.