ee Propolis

Research-based information about bee propolis its health based propolis. benefits and possible side effects.

Quick Introduction to Bee Propolis

What Is Bee Propolis?
Bee propolis or also refered as bee glue is a beehive product, similar to honey and royal jelly. Basically, it is a mixture of different resins that bees gather from various vegetation around them[1]. Usually, the resin comes from tree buds, or sap flows. During the gathering process, they blend it together with their saliva[2] or are at least, they partially metabolize it[3] What is the use of propolis for bee colonies? Originally, the term itself comes from Greek. It is devised by Aristotle from two main words: pro and polis. Pro ( ) means before while polis () means city. As a complete term, propolis means Defense of The City. This literal definition is the actual function for bee colonies. It is already proven that bee propolis has a very complex chemical composition. There are more than 300 chemical components that have been identified so far most of them have specific biological properties, such as antioxidant, antibacterial, antifungal, and antiviral effect[4] So, in scientific point of view, propolis acts as natural antibiotic agent, protecting the colonies against harmful microbes, especially from Bacillus larvae[7] that cause a fatal disease called American foulbrood. In technical point of view, bees use it to repair and seal-off any fracture or hole that is found in their hive, especially fracture and hole within brood combs Brood comb is one of bee hive structure where the queen bee lays eggs. It is also the place to raise new brood/bee larva. Another function is to decrease the hive entrance capacity. By doing this, the colony get at least two benefits: 1. Bees are purged from harmful microbes. Bees have to creep via a narrow canal that has been coated by propolis every time they want to enter or leave their hive. By doing this, bees can keep themselves hygiene. 2. Seal-off any animal/ insects corpses that are too big to be taken out from their hive. In this case, propolis functioned to suppress the growth of decomposing bacteria from tissues of the corpse, thus, reducing the chance of getting any infection.

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How Does It Looks Like?

Each specific type of bee propolis can have different color, and scent. We can find dark-brown as the most common color. But as outlined by Coggshall and Morse, some samples come with yellow, red, green and even transparent color[6]. Considering that bee propolis has complex and wide variability of chemical composition, then temperature is a factor that can significantly affect its characteristic. Here are some data that describes the correlation between temperatures and bee propolis physical characteristic:

At near freezing temperatures or less than 15C it becomes harden and fragile. At normal temperatures (25C - 45C) it is a lenient, tender and very sticky substance. At 46C - 59C temperatures, it will become stickier. At 60C - 70C most sample will become liquid. In some other samples, the melting point is 100C [2]. However, in one of the most recent research, it is reported that bee propolis from Amaicha del Valle can stay stable even at 120C temperature [7].

I personally believe that the best temperature to keep and consume bee propolis is a room temperature. This is simply because the fact that bees themselves can get the maximum benefits in such temperatures inside their hives.

How Mankind Use Bee Propolis No doubt that propolis has a long history. It serves various purposes, especially when it comes to medicinal concern. The first known usage by mankind is in the age of Ancient Egypt. Archeologists found a numerous pictures on vases and ornaments that show us about the relation between mankind and bees. Some pictures also show us that Egyptian at that time know some benefits from various bee products. In 4th century in Greece, Hippocrates gave prescription to use bee propolis. He uses it to cure external and internal wounds, as well as ulcers. Gaius Plinius Secundus or also known as Pliny the Elder from Roman also talked about this bee product. He wrote a well known encyclopedic work titled Naturalis Historia. In that book, he tells about various resins usages, including bee propolis uses for treating inflammations, relieve pain, and same as Hippocrates to cure wounds.

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Next historical record comes from Europe in 12th century. It is said that bee propolis can be effectively be used to treat oral health problem, such as infections and caries[8]. Then, in the year of 1957, John Gerard told us about how he uses bee propolis in the book titled Generall Historie of Plantes. In his book, John said that this resinous substance works effectively to heal and quicken the recovery process.

Other Uses Aside From Health Concern Aside from its functions in medical and health concern, bee propolis is also used for waterproofed containers, glue, wood preservatives/varnished especially for musical instruments (such as violins or guitar), preparing bow string and for tuning drums[9]. Even in some carpolishing products, it works as a catalyst to convert fats and oils into a quality car wax polishing products[10].

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Health Benefits of Bee Propolis

During this last 4 decades, there are hundreds clinical studies and researches that bring bee propolis as the main subject. One of the hot topics was discussing about the correlation between the benefits and its chemical substances. At the first, experts wanted to know what particular compounds that gives a certain therapeutic effects. However, as more and more researches are performed, it was found that different bee propolis sample (from a different geographic location) contains different active chemical substances. This finding was hypothetically affecting propolis biological activities. Is that a problem for us? Talking about logic, this phenomenon created a hypothesis like this: "Different chemical substances would give different biological activities. Biological activities determine the health benefits that we can get. Thus, each type of bee propolis would give a different health benefits for us." You might find CAPE as an active anti cancer compound in European poplar-based propolis, but you won't likely find it in Brazilian propolis where Baccharian.sp is used as the source.

Explanation Behinds Chemical Diversity of Bee Propolis

What thing that makes the chemical substances different? First of all, we need to keep in mind that propolis is not directly produced like the way bees produce their venom. Bee venom produced directly from their body, while propolis is 'manufactured' from particular vegetation. So, the vegetation source is one of the main factor that directly determine its chemical substances. (For more detailed explanation, you can read about how bee propolis is made in the main page of this blog) So, is that means that each propolis gives a different health benefits for us? Well, the answer to this kind of question was what experts trying to get. One of the very first research that studying this topic was done by Kujumgiev[11]. Kujumgiev examined antimicrobial properties of bee propolis from different geographic location. The result shows that all samples give notable antibiotic effects (antibacterial, antifungal, and antiviral). This fact aligns with the actual function of propolis for bee colonies as the defender against various diseases, (especially American Foulbrood).

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Kujumgievs work was then followed up by more studies. Many of those studies focused on a different biological effect of propolis, such as its anti cancer, hepatoprotective, antioxidant effect, anti-inflammatory, etc. Below are some other notable studies that you might need to know: Study by Popova[12], assess correspondence between biological activity and geographic location of bee propolis samples from Europe, Brazil and Central America by using statistical approach (Analysis of variance/ANOVA). Based on the study, it is found that European and Brazilian propolis have identical activity even though each of them contains different chemical substances. Study by Kumazawa[13], examined the antioxidant effect of bee propolis from numerous geographic location. He used sample from many regions such as Brazil, Uruguay, Argentina, Chile, China, Thailand, New Zealand, South Africa, Ukraine, Bulgaria, Austria, Hungary, United States and Uzbekistan. In this research, Kumazawa performed chemical analysis to identify and measure the result. He found 17 phenolic compounds from 16 types of different propolis sample. Each of bee propolis gives notable antioxidant effect, where significant antioxidant activity is originated from anti oxidative substances such as phenethyl caffeate or kaempferol.

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For a quick review, here is the table[20] that shows us about the main health benefits of bee propolis along with the accountable compounds:

Bee Propolis Type European Brazilian Propolis Propolis Cuban Taiwanese (poplar (Baccharis Propolis Propolis type) type) Flavanones, Prenylated pflavones, Prenylated phenolic coumaric acids, benzophenones Unidentified labdane acids and [17] their esters diterpenes[15]
[14]

Antibacterial

Antiinflammatory

Flavanones, flavones, phenolic Unidentified [15] Unidentified[15] Unidentified acids and their esters
[15]

Prenylated pPrenylated coumaric acids, Prenylated Antitumor clerodane benzophenones flavanones [18] [19] diterpenes, benzofuranes[15] Caffeic Prenylated pacid, ferulic coumaric acis, flavonoids, acids acid, Hepatoprotective Unidentified[15] Unidentified lignans, caffeic acid their caffeoyl quinic esters[15] acids[15] Flavonoids, Prenylated pPrenylated Prenylated phenolic Antioxidant coumaric acis, benzophenones flavanones and their [18] [19] flavonoids[15] esters[21] Caffeic acid phenethyl ester[16]

All of the studies (which bring this particular topic) show us a very clear prove that even though the source and the exact chemical substances are different, bee propolis still gives the same main health benefits for us.

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Standardization, Exact Dosage, and Health Claim Issues

Despite the good news, there is a problem that caused by this wide chemical diversity. Indeed, it doesnt affect the kinds of health benefits that you might get, but it does affect the significance level. For example, in terms of antibacterial effects; it is found that antibacterial activity of Brazilian bee propolis and Europe was significantly higher compared to Central American propolis[1]. While in other comparative study, you can find that bee propolis from Brazil, Peru, Netherlands and China has equally significant hepatoprotective and free radical scavenging activity. However, it is not the same with their cytotoxic activity. The most significant cytotoxic activity belongs to Propolis from Netherland and China, while bee propolis from Peru shows a weaker cytotoxic activity[12] This different significance level is not only assessed for antibacterial and cytotoxic activity. There are many other comparative studies which assess possible therapeutic effects of propolis, such as its antifungal, anti cancer, antiviral and so on. Like it or not, those scientific studies show us undeniable fact that propolis gives different significance level of health benefits due to its chemical diversity; which then, leads to standardization and health claim issues. Until this day, there is no international standard that can ensure consumers to get maximum benefits. This also explains the reason of why propolis dosage is widely varied and cant be strictly determined. Your understanding about the concept of propolis dosage and allergy can be very helpful.

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Antimicrobial Properties of Bee Propolis

Antibacterial Properties
Various studies report that this antibacterial mechanism is not as simple as they thought before. This phenomenon has been confirmed by many researchers who worked on the same topic, such as Scheller[22] and Krol[23]. When they examined it deeper, this antibacterial effect comes to existence due to harmonic works between various flavonoids compounds, aromatic acids and esters[24][25][26], such galangin, pinocembrin and pinostrobin[25], Aside from those, ferulic acid and caffeic acid also contribute to its bactericidal action[26]. In the year of 1994, this antibacterial mechanism was finally explained through Takaisi-Kikuni and Schilchers study. They found that it has these following capabilities[27]: 1) Suppressing bacteria cell development by blocking their cell mitosis and the process of protein synthesis. This makes any kind of bacteria lost its capability to grow and prevent them from doing any reproduction. 2) Directly destructing bacteria cells through: Disarraying their cell cytoplasm,cell membranes, and also their cell walls and triggering partial bacteriolysis (dissolution of bacterias cell).

Antifungal Properties
European poplar-based propolis (in 10% extracts ethanol) has an effective fungistatic effect against 17 fungal pathogens[28]. It also has been demonstrated to work effectively in suppressing the growth of yeasts and fungus which responsible for ringworm and athlete's foot disease[29]. Aside from European type, another study also assesses this therapeutic effect on Brazillian type. As a record, these antifungal properties were tested on patients who suffer for onychomycosis (fungal infection of toenails or fingernails), so basically, we can consider it to be more practical compared to European type. The result shows that the Brazilian bee propolis gives desirable results against 67 yeasts which have been isolated from patients suffering to onychomycosis[30]. This antifungal effect comes to an existence due to some specific compounds. They are flavonoids (pinocembrin, sakuranetin, and pinobanksin) and caffeic acid derivatives (benzyl ester, and pterostilbene)[31]. Based on the study, the effective concentration to achieve such a desirable result for fungus infection treatment is at 0.05mg/ml of flavonoids[30].
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However, please dont forget the fact that each bee propolis type gives different level of significance for a specific treatment. So if you are considering Brazilian bee propolis for treating a fungus infection, you might want to ensure that the product of your choice contains at least 0.05mg/ml of flavonoids.

Does Bee Propolis Works For Candida Infection?

Yes, study shows that it does work effectively for treating candida yeast infection. Candica species are common cause of skin disease and mucosal membranes of the gastrointestinal, genitourinary (genital), and respiratory tracts. Candida albicans is a particular fungus that grows both as yeast and filamentous cells. But basically, it is a common organism that can be found on our body, and it starts to become problem when our immune system is in low condition. By that time, Candida will wildly grow and cause infection that can spread to any part of our body. From one of the most recent research, it is identified that bee propolis has a great capability to work specifically contra various Candida species, especially Candida albicans[32]. To be more specific, it gives a significant result against these species[33]:

Candida albicans Candida tropicalis Candida krusei Candida guilliermondii

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Antiviral Properties
Antiviral properties exists in most samples of bee propolis. The problem relies in the word most, which means, we cant guarantee that every bee propolis type possess antiviral activity (especially for the less popular variants such as Canarian type). But you dont have to be worried because most of products that you can find on your nearest store are most likely to be Brazilian and European types. In addition, both of those types have been proven to show significant antiviral activity. Antimicrobial activity of bee propolis (including its antiviral activity) is highly attributed to the phenolic compounds such as flavonoids[34]. Based on Schnitzler[35] study, the specific substances that gives significant contribution to its antiviral activities are galangin and chrysin. Both of them are specific forms of flavonoids.

Just like any other antiviral drugs, some specific compounds which are contained in bee propolis possess complex capabilities to disrupt and manipulate virus life cycle. Here is the quick and simple explanation to antiviral mechanism of bee propolis which has already been verified and identified by various studies: 1) Preventing virus from entering the host cell[36,37]. 2) Reducing intracellular replication activities[36,37,38,39] . This process contributes to suppress the growth and development of virus. This can be done by the process called reverse transcriptase. This process stops some specific enzymes disabling virus capability to synthesize their RNA or DNA. 3) Stimulating our immune system to fight back against virus infection[39]..

Aside from these findings, it also needs to be remembered that the effectiveness is directly depending on its concentration level. Based on Gekkers in-vitro study, it is found that 85% 98% effectiveness level can be achieved by using 66.6 /ml concentration of bee propolis[37].

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Dosage & Precautions

Safety studies have found it to be non toxic when taken orally, and also appears to be nonirritating when applied to skin[40], unless for people who has hypersensitivity (propolis allergy). In addition, there are very few propolis side effect reactions that have been recorded in the written documents, so, the product is considered generally not to be harmful[41]. Regardless of the claims above, somehow, we just feel the urgency to know the exact figure of its dosage. If bee propolis claimed as a very safe supplement, what is the upper limit? How much that is categorized as too much?

How Much Is Too Much?

Everything in this world always has a toxicity level that our body can tolerate. For example, water can cause water intoxication if it taken in a very large amount, while a very toxic substance such as cobras venom, wont do any harm to us if it is taken in an extremely small amount. In other words, toxicity level of a substance is highly depends on its dosage. The question of how much is too much can be explained by using the concept of toxicology and its relation with dose limitation.

Limit Of Propolis Dosage Based on LD50

Toxicity can be calculated by monitoring the effects on the object (the object itself can be organism, organ, tissue or even cells). However, each individual has different levels of response even for the same propolis dosage. This means a toxicity population-based calculation is needed to determine the precise limit of its dosage. A well known method for measuring toxicity level of a substance is called LD50. LD50 or also known as median lethal dose means a dosage which resulting in 50% of the experiment object population die. Refer to Bardocks study, the LD50 value of bee propolis is more than 7.34 gram/kg body-mass for mice[42]. If we convert that raw number for human, the limit of bee propolis dosage will be 587,200 mg for person with 80 kg weight. This figure is approximately equal to 1,100 capsules consumption at one time where each capsule contains 500 mg of pure propolis.

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Basically, we can have a conclusion that bee propolis is a very safe supplement, unless the consumption is done with an irrationally large dosage[43] (such as over 1000 capsules of 500mg propolis extract at one time).

What Will Possibly Happen if the Limit Exceeded?

In 2011, A. Montoro from Brazil performed a study to assess any possible propolis side effects. He applied a very high concentration of ethanol extract propolis and then analyzed its effect on human peripheral lymphocytes. The result presumed extreme concentration of Ethanol Extract Propolis is possible to cause notable damage to human DNA. Montoros work also confirms previous experiment, where a very high concentration of propolis given can cause DNA damage and/or alteration.

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Propolis Allergy
Considering the number of negative cases in literatures, bee propolis can be claimed as a very safe supplement. The only propolis side effect which taken seriously is allergic reaction. A journal from Italy, titled Surveillance of suspected adversereactions to natural health products: the case of propolis gives us clear example about how bad this side effect can be. It is reported that during 5 years period (2002 2007), there are: 16 reports about allergic reactions in a form of dermatitis and/or respiratory problem, 2 reports regarding digestive tract. From those total 18 cases, there are 6 patients who go to emergency departments, and 2 patients suffer life-threatening side effects. Even though the number of incidents is pretty much low, it is much better that we know the risk. Propolis allergy is caused by some of its constituents. The very first detected chemical substance that is responsible in propolis allergy was LB-1[44]. LB-1 is consistently found in every chemical dissolution process from various bee propolis and poplar bud samples [45]. At the very beginning, LB-1 was initially identified to be entirely composed of 1, 1-dimethylallyl caffeic acid ester [45,46] , but then as it has been shown by the latest study, LB-1 consist of other chemical substance:

3-Methyl-2-butenyl caffeate, methyl-2-butenyl caffeate and 3-methyl-3-butenyl caffeate [44] . Phenylethyl caffeate

Among those chemical substance 3-Methyl-2-butenyl caffeate acts as the most powerful allergen factor[47,48]. It draws out a strong response found in subject experiment who acknowledge suffer to propolis allergy. The same result is also identified with phenylethyl caffeate. Later, it is determined that the main chemical substances which directy cause propolis allergy are 3-methyl-2-butenyl caffeate and phenylethyl caffeate. Aside from those two main allergens, there are also several more that is considered as moderate sensitizer[49]:

Benzyl isoferulate (Based on Hausen experiment, it is considered a noteworthy sensitizer)[48]. Coniferyl benzoate. This substance exists in fresh samples of balsam of Peru, while in propolis it has been detected only once so far [45]. Benzyl salicylate and benzyl cinnamate.

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Many other studies show that people who suffer to propolis allergy dont show any reaction to those sensitizers [48]. However, people who suffer to propolis allergy still should be warned about potential reactions to cosmetics or products containing these substances. Flavonoids and other compounds such as waxes, fatty acids, essential oils, pollen, and other organics and minerals have no capability as allergen[50,51].

Diagnosing Propolis Allergy

Propolis allergy can be diagnosed by performing patch test. In case a person suffers to propolis allergy, a flare as positive patch test allergic reactions will certainly happen[60]. Bee propolis has become a part of European Standard patch test sequence, since 1988[48]. It's availably storebought in 10% petrolatum concentration[52,53]. Nevertheless, in certain nations (just like Italy), patch-testing is performed with 20% concentration[54-59]. Numerous experiments noticed that a 20% concentration is not enough to trigger propolis allergy reaction. Based on particular research conducted by Hausen, it has been observed that the tolerance for bee propolis allergy seemed to be more than 20%, while the tolerance for LB-1 is basically in a range of 3% to 10%[45]. In spite of these experiments outcome, the suggested standard patch-testing concentration for is still at 10% petrolatum concentration.

People Who Should Avoid Bee Propolis Uses

People who suffer to propolis allergy is also equally allergy to bee sting and also bee products. Based on the given statistic, the amount is approximated to be 0.001% 0.002% of total population. That means 1 2 people out of 1,000 people suffered to propolis allergy [62]. However, the amount of propolis allergy cases will probably keep on rising due to the fact that the use of propolis-based products is also increasing. Propolis allergy is also considered as a part that cause an increase in the number of allergic contact reactions, especially for individuals who frequently use products and cosmetics that is formulated with this compound, its constituents and/or sensitizers [47,48]. Based on those clinical studies and experiments, its strongly suggested to avoid any usage if you are included in this following group: 1. Has hypersensitivity with Balsam of Peru (Myroxylon Pereirae), benzyl salicylate and benzyl cinnamate[44,45,48,49]. 2. Suffer for other bee products allergy (including honey, royal jell, bee sting, etc) [19] 3. Pregnancy and breast-feeding women: Not enough data and proven clinical study about propolis use for pregnancy and breast-feeding women.

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4. People who suffer to asthma. Some experts believe that chemical substances contained in bee propolis might worsen asthma attack. Even though some other clinical studies show otherwise (that bee propolis can help to cure asthma), you better avoid it. 5. Paediatric age children [53,54,56,57].

Propolis Allergy Symptoms

1. Dermatitis (skin Inflammation) is the most known propolis allergy symptoms, with approximately 200 occasions documented in literature for last 7 decades period [44]. Usually, dermatitis happen by skin contact with raw propolis, extracts or other products containing caffeic acid and its derivatives[63]. Dermatitis will be relieved by the time the skin is no longer in contact with bee propolis. So, whenever you feel this kind of allergy symptoms, immediately stop the usage. 2. Oral inflammation and ulceration 3. Mouth oedema (swelling) and stomatitis However, these two allergy symptoms (oral inflammation and ulceration also mouth oedema and stomatitis) are rare incidents. They happen as a result of oral chewing of bee propolis [64] 4. Nausea and Stomach upsets. Chewing raw bee propolis with a large quantities and high frequency can trigger the allergic reactions in a form of nausea and stomach upsets [65].

How to Prevent Any Unwanted Propolis Allergy Reactions It is strongly recommended to conduct patch testing, just in case for any propolis allergy symptomp [61]. You can try to consult to dermatologist before deciding to use any product that contains bee propolis. Aside from it, the consumption should begin in a small dose and then it can be steadily increased to the full dose. This kind of procedure is recommended in order to assess the compatibility with propolis allergy. For the same case, stopping bee propolis consumption also needs to be done gradually[65]. For chewing consumption, the recommended dose is maximum at 1 gram for one time in 3 times a day [66]

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Possible Side Effects Aside From Allergy

Regardless of its allergic reaction, systemic toxicity of bee propolis is not something that often reported, and hence, may be underestimated. When I dig deeper about this topic, there are at least three possible side effects that might be caused by propolis consumption: 1. Acute renal failure 2. Mutagenic and Genotoxic 3. Cytotoxic effect

Acute Renal Failure

There are at least two documented cases of acute renal failure that is suspected as a result of propolis side effect: 1. Reported by Li from Hospital of Chang Gung Memorial in Taipei [67] . The first renal failure incident was happening on a 59 years old man who suffers for bile duct cancer. During 2 weeks period, he consumed Brazilian bee propolis to help his cancer treatment. Starting that time, his renal function began to deteriorate. After stopping the consumption, his renal function was improving. However, he then decided to consume bee propolis for the second time, and his renal function got worsened again. After he completely stopped the consumption, his renal function back to normal.

2. Reported by Canadian Adverse Reaction Newsletter. [68] The second case of suspected propolis side effect was happening on a 3 years old boy. He was suffering for gluten enteropathy a disorder in nutrients absorption which caused by gluten allergy. He consumed propolis to prevent infection possibility that might be caused by his disease. The boy himself was diagnosed for suffering acute renal failure after he had consumed bee propolis 2 3 times each week for 4 months periods. The renal failure symptom was shown by his excessive creatinine level. Right after he stopped the consumption, his creatinine level back to normal, and with restricted diet, his gluten enteropathy disease was getting better. Those two cases indicate that acute renal failure might happen as a result of propolis side effects. Bold warning is clearly needed, especially when it is used as a medicine or dietary supplement.

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Mutagenic and Cytotoxic

Speaking about the second possible side effects, there are mutagenic and genotoxic effects. These two possibilities were shown by in-vitro study conducted by Rodrigues C.R. Mutagenic effect can be defined as alteration of genetic material (usually refer to DNA). This kind of effect is considered to be accountable for cancer disease. Mutagenic effect refers to genetic material alteration, while genotoxic specifically refer to chromosomal damage which may result in mutagenicity. These harmful effects are identified by investigating the vegetation source of Brazilian bee propolis which is known as Baccharis dracunculifolia. The study shows that the extract of Baccharis dracunculifolia is capable to cause DNA deterioration in the blood tissues, liver tissues and micronucleus of bone marrow in mice. If the main vegetation source has such a harmful effects, it is assumed that the derivative product (Brazilian bee propolis) can also produce the same negative effects[69].

Cytotoxic Effectsc means a capability of being a toxic to cell. This effect may have variety results. It can cause cell lysis/apoptosis or even mutagenicity. Rodrigues work seems to be followed up recently by study conducted by Montoro. Rather than using mice as an experiment subject, Montoro used human lymphocytes cells and tested the possible propolis side effect effects by using high concentrated ethanolic extract. In conclusion, the study assumes that citotoxicity and genotoxicity on human peripheral lymphocytes might be happen as possible propolis side effects [70].

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Reference:
1. Hill R. that, The Natural Antibiotic. Thorsons, Wellingborough, England, 1977 2. R. Krell, Value Added Products From Beekeping. FAO Agricultural Service Bulltein No. 124, 1996 3. A. Cuellar, Hernandez Rojas, Perez Martinez . 1990. Brand-new anti microbes architecture of bee propolis from Cuba. Revisi Cuba de Phararma cia, 2a (1): 5i-5b 4. GA. Burdock 2005 5. Walker, P. and Crane, E. 1987. Constituents of propolis. Apidologie, 18(4): 327-334 6. Coggshall, W. and Morse, R.A. 1984. Beeswax: production, harvesting, processing and products. Wicwas Press, Ithaca, NY, USA, 192 pp 7. Mlagan, V. and Sulimanovic, D. 1982. Action of bee glue on Bacillus larvae. Apiacta,17:16-20 8. R. Krell, Value Added Products From Beekeping. FAO Agricultural Service Bulltein No. 124, 1996 9. Jolly, V.G. 1978. Bee World, 59 (4): 158-161. 10. History Of Landau Carriage 1743" (website: http://zymol.com/readhistory.aspx) accessed in March 2011 11. Kjumgiev A, Tsvetkova I, Serkedjieva Yu, Bankova V, Christov R, Popov S. Antibacterial, antifungal and antiviral activity of propolis from different geographic origins. J Ethnopharmacol. 1999;64:23540. 12. Popova M, Bankova V, Naydensky Ch, Tsvetkova I, Kujumgiev A. Comparative study of the biological activity of propolis from different geographic origin: a statistical approach. Macedonian Pharm Bull. 2004;50:914 13. Kumazawa Sh, Hamasaka T, Nakayama Ts. Antioxidant activity of propolis of various geographic origins. Food Chem. 2004;84:32939 14. Burdock GA. Review of the biological properties and toxicity of bee propolis (propolis) Food Chem Toxicol. 1998;36:34763. 15. Banskota AH, Tezuka Y, Kadota Sh. Recent progress in pharmacological research of propolis. Phytother Res. 2000;15:56171. 16. Grunberger D, Banerjee R, Eisinger K, et al. Preferential cytotoxicity on tumor cells by caffeic acid phenethyl ester isolated from propolis. Experientia. 1988;44:2302. 17. Hernandez NMR, Cuesta Rubio O, Aviles A, Avellanede DLS. Actividad antimicrobiana de nemorosona aislada de Clusia rosea. Rev Cubana Farm. 2001;35(Suppl Especial):1979. 18. Cuesta Rubio O, Frontana-Uriba BA, Ramirez-Apan T, Cardenas J. Polyisoprenylated benzophenones in Cuban bee propolis; biological activity of nemorosone. Z Naturforsch. 2002;57c:3728.

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34. Viuda-Martos M, Ruiz-Navajas Y, Fernndez-Lpez J, Prez-Alvarez JA. Functional properties of honey, bee glue, and royal jelly.J Food Sci. 2008 Nov;73(9):R117-24. 35. Schnitzler P, Neuner A, Nolkemper S, Zundel C, Nowack H, Sensch KH, Reichling J.Antiviral activity and mode of action from extracst and selected compounds.Phytother Res. 2010 Apr;24(4):632. 36. Bfalo MC, Figueiredo AS, de Sousa JP, Candeias JM, Bastos JK, Sforcin JM.J Appl Microbiol. 2009 Nov;107(5):1669-80. Epub 2009 Apr 21. 37. Gekker G, Hu S, Spivak M, Lokensgard JR, Peterson PK. 2005 Nov 14;102(2):158-63. Epub 2005 Jul 19. 38. Amoros M, et al, Journal of natural products (1994) 57(5):644 7 39. Harish Z, Rubinstein A, Suppression of HIV-1 replication by bee propolis and its immunoregulatory 40. Arvouet-Grand A, Lejeune B, Bastide P, Pourrat A, Privat AM, and Legret P. Bee Propolis extract. I. Acute toxicity and determination of acute primary cutaneous irritation index. J. Pharm. Belg., 48 (3): 165-170, 1993. 41. Schmidt, J.O. and Buchmann, S.L. 1992. Other products of the hive. In: The hive and the honeybee J.M. Graham, ed. Dadant & Sons, Hamilton, Illinois, USA. 927-988 42. Burdock,GA. Bee propolis biological properties and propolis dosage toxicity review. 1997 43. Ghisalberti, E.L. 1979. Bee propolis: a review. Bee World, 60 (2): 59-84 44. Hausen BM, Wollenweber E, Senff H, Post B. Propolis allergy (I). Origin, properties, usage and literature review. Contact Dermatitis 1987;17:16370. 45. Hausen BM, Wollenweber E, Senff H, Post B. Propolis allergy (II). The sensitizing properties of 1,1-dimethylallyl caffeic acid ester. Contact Dermatitis 1987;17:1717 46. Marks JG Jr, Elsner P, DeLeo VA. , Contact and occupational dermatology 3rd ed St. Louis: Mosby; 2002. p. 21247. Hausen BM, Wollenweber E. Propolis allergy. (III). Sensitization studies with minor constituents. Contact Dermatitis 1988; 19(4): 296-303 48. Hausen BM, et al. Propolis allergy (IV). Studies with further sensitizers from bee propolis and constituents common to bee propolis, poplar buds and balsam of Peru. Contact Dermatitis 1992; 26(1):34-44 49. Walgrave SE, Warshaw EM, Glesne LA .Contact dermatitis from propolis allergy. Dermatitis. 2005 Dec;16(4):209-15 50. Schmalle HW, Jarchow OH, Hausen BM, Schulz KH. , ; Aspects of the relationships between chemical structure and sensitizing potency of flavonoids and related compounds. In: Liss AR, editor Plant flavonoids in biology and medicine New York: Alan R. Liss. Inc.; 1986. p. 387-90. 51. Marks JG Jr, Elsner P, DeLeo VA. , Contact and occupational dermatology 3rd ed St. Louis: Mosby; 2002. p. 212-

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52. Chemotechnique Diagnostics Patch Test Products. Chemotechnique Diagnostics, P.O. Box 80 S-230 42 Tygelsjo 53. Malm, Sweden, Giusti F, Miglietta R, Pepe P, Seidenari S. Sensitization to bee propolis in 1255 children undergoing patch testing. Contact Dermatitis 2004;51:255 54. Giusti F, Miglietta R, Pepe P, Seidenari S. Sensitization to bee propolis in 1255 children undergoing patch testing. Contact Dermatitis 2004;51:2558 55. Trevisan G, Kokeli F. Contact dermatitis as propolis allergy: role of gastrointestinal absorption. Contact Dermatitis 1987;16:48 56. Manzini BM, Ferdani G, Simonetti V, et al. Propolis Allergy contact sensitization in children. Contact Dermatitis 1998;15:127 57. Seidenari S, Giusti F, Pepe P, Mantovani L. Propolis Allergy Contact sensitization in 1094 children who conduct patch test for duration of seven years. Pediatr Dermatol 2005 58. Francalanci S, Giorgini S, Ricci L, Sertoli A. Patch testing by additional series of allergens: results of further experiences Am J Contact Dermat 2001;12:2037 59. Francalanci S, Sertoli A, Giorgini S, et al. Multicentre study of allergic contact cheilitis from toothpaste. Contact Dermatitis 2000;43:2162 60. Wohrl S, et al. The significance of fragrance mix, balsam of Peru, colophony and bee propolis as screening tools in the detection of fragrance allergy. Br J Dermatol 2001; 145(2): 268-73 61. Walgrave SE, Warshaw EM, Glesne LA .Allergic contact dermatitis from bee propolis . Dermatitis. 2005 Dec;16(4):209-1 62. Wasp Stings, Bee and Pest Notes, Publication 7449, February 1998, produced by IPM Education and Publications, UC Statewide IPM Project, University of California, Davis, CA 95616-8620;s 63. Hashimoto, T., Tori, M., Asakawa, Y. and Wollenweber, E. 1988. Synthesis of two allergenic constituents of propolis and poplar bud excretion. Zeitschrift flir Naturforschung, C 43: 470-472 64. Hay K. D & Greig D E. (1990) "Propolis Allergy: A Cause Of Oral Mucositis with ulceration." Orak Surg Med Oral Pathol 70, 584-586; & [ ]Wanscher B. (1976) "Contact Dermatitis From Propolis" British journal Of Dermataology 94(4). 451) 65. Donadieu, Y. 1979. La propolis. Editions Maloine, Paris 66. R. Krell, Value Added Products From Beekeping. FAO Agricultural Service Bulltein No. 124, 1996 67. LiYJ.Lin JL.CWYang.CCYuAcute renal failure caused by a Brazilian bee propolis. Kidney Disease. 2005 Dec;46(6):e125-9 68. Canadian Adverse Reaction Newsletter Volume 19 - Issue 1 - January 2009; about suspected propolis side effects 69. RodriguezCR, Dsia5JH, JG Sem3d0. Mutagenic effect and genotoxic effect produced by Baccharis dracunculifolia (D.C.).J Ethanopharmacol. 2009 Jul 15;124(2):321-4. Epub 2009 May

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70. AMont0row. JMSoriano. JFBarquinero. Invitro experiments regarding cytotoxicity and genotoxicity as possible propolis side effects on lymphocytes cell of mankind. Food Chemical Toxicology. 2011 Oct 25.

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