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Safety, quality control and regulational aspects relating to mushroom nutriceuticals.

Mushrooms are devoid of chlorophyll-containing tissues, rendering them incapable of photosynthetic food production. They grow and produce new biomass by relying on organic matter synthesized by green plants, most of which is in the form of forestry and agricultural waste residues. Unlike photosynthetic organisms, mushrooms produce a battery of extracellular enzymes to degrade the complex major macromolecular components (cellulose, hemicellulose, lignin) of the growth substrate. Mushrooms use mainly cellulose and hemicellulose to provide soluble nutrients, which are then absorbed and assimilated for vegetative growth and fruit body formation. However, since the cellulose and hemicellulose in the plant cell wall is normally in the form of lignin-carbohydrate complexes (LCCs), lignin-degrading enzymes are also synthesized in addition to cellulases and hemicellulases in order to gain access to new areas of embedded polysaccharide. This demonstrates a strong biodegradative capability, and an impressive capacity for absorbing from the surroundings all the raw materials, organic and inorganic, required for biosynthesis. Unfortunately, this absorption capability is potentially of major negative significance for mushrooms and mushroom products.

Environmental pollution is now a global problem which affects all aspects of human welfare including the air, water, food and ultimately our health. Consequently, growth substrates and other components of the mushroom growth environment (air, water) may contain harmful compounds that are also taken up and accumulated by the mushrooms. Moreover, there may further possibilities for contamination by environmental pollutants during the transportation and processing (e.g. drying, canning) of fresh fruit bodies, and at different stages involved in the manufacture of mushroom-derived products. When this occurs, the quality of mushrooms and their products is diminished, and there may be serious consequences for human life and health. In this article, we consider the issues affecting the quality and safety of mushrooms and derived products, and some basic regulations that should apply where mushrooms and their derivatives are cultivated and manufactured.

Market Value of Mushroom Nutriceuticals

For the purpose of this article, "mushroom nutriceuticals" (Chang & Buswell, 1996) are defined as "refined/partially defined/unrefined mushroom preparations derived from fruiting bodies, fungal mycelium or the spent culture fluid following mycelium growth in submerged culture that possess nutritional and/or medicinal properties and which are consumed in the form of capsules or tablets as a dietary supplement."

Although there are no recently published data relating to the total world market value of mushroom nutriceuticals, it is useful to review a number of earlier estimates that have been published in different sources. The market value of medicinal mushrooms was estimated in 1991 to be US $1.2 billion (Chang, 1993), US $3.6 billion in 1994 (Chang, 1996) and US $6.0 billion in 1999 (Wasser et al. 2000). Three of the first mushroom nutriceuticals were the [beta]-glucans, krestin, lentinan and schizophyllan extracted from Coriolus versicolor, Lentinula (Lenunus) edodes and Schizophyllum commune, respectively (Reshetnikov et al. 2001). Krestin (PSK) was reported to be the top-selling anticancer drug in Japan during 1987 with annual sales of US $358 million (Chang, 1993), while the 1995 market value of G. lucidum and various products derived from this medicinal mushroom was reported to be US $1,628.4 million (Chang & Buswell, 1999). Before 1995, 99 percent of all sales of medicinal mushrooms and their derivatives were concluded in Asia and Europe, with < 0.1 percent in North America. However, in recent years, both North and South American demands have been increasing between 20 percent and 40 percent annually depending upon the species. More than 10 new companies were established recently in Brazil to promote the sale of different dietary supplements derived from Agaricus blazei (A. brasiliensis). In the year 2000 in China, the major producer and consumer of medicinal mushrooms, more than 100 research units/institutes were engaged on research and development of medicinal mushrooms. Some 30-40 varieties of mushroom products for use as nutriceuticals/herbal medicines were manufactured in more than 200 factories. Furthermore, about 700 mushroom-based health food products, including more than 90 brands of G. lucidum products, were registered and marketed (Lin, 2000). Based on previous data, the current world market value of mushroom nutriceuticals is estimated at US $14 billion.

Sources and Manufacture of Medicinal Mushroom Products

Chang & Miles (2004) reported that about 77 percent of all medicinal mushroom products are derived from fruiting bodies, which have either been cultivated commercially or collected from the wild. Only about 21 percent of all products were reportedly based on extracts from mycelia and approximately 2 percent were derived from culture filtrates. However, mycelial- and culture broth-based products are already assuming greater importance due to demands for increased quality control and for year-round production. The processes involved in submerged mycelial culture can easily be standardized under controlled conditions, and purification and other downstream processing of active components such as polysaccharides released into the culture medium, usually involve relatively simple procedures.

Several types of medicinal mushroom products are currently available on the market, with no systematic scientific verification of which is the preferred method of production. These include:

1. whole fruiting bodies ground into powder and then processed into capsule or tablet form

2. dried and pulverised mycelium harvested from submerged liquid cultures grown in fermentation tanks

3. dried and pulverised combined preparations consisting of substrate, fungal mycelium and mushroom pri-mordia from a semi-solid medium following inoculation with fungal mycelium, and incubation until the appearance of primordia

4. hot water extracts of mycelium harvested from submerged liquid cultures grown in fermentation tanks which have been evaporated to dryness and made into capsule or tablet form

5. hot water and/or alcohol extracts of fruiting bodies (for extraction of the polysaccharide and triterpene components) which have been evaporated to dryness and made into capsules or tablets either separately or integrated together in designated proportions

6. extracts of fruiting bodies, converted to powdered form, obtained by supercritical fluid [CO.sup.2] extraction technology (contain a large spectrum of substances due to the low temperature during processing)

7. pure spore powder in capsular form--this method has been promoted vigorously in recent years but the medicinal benefits of this method remain controversial

8. extract powder from fruiting bodies mixed with an equal portion of mycelium extract powder of the same species

9. binary, triplet, or more complex products consisting of mixtures of different mushrooms (e.g. Ganoderma/Lentinula; Ganoderma/Agaricus brasiliensis, Grifola frondosa/Pleurotus spp/Flammulina velutipes), and even other medicinal herbs (e.g. Spirulina powder, flower pollen grains)

10. treated and ground fruiting body powder, in equal proportions, in a capsule

Enhanced Understanding of the Nature: f Mushroom Nutriceuticals

Past empirical observations relating to the health-promoting effects of mushrooms were often based on the consumption of the intact mushroom or crude potions (e.g. mushroom teas) prepared from the fruit body. More recently, the effectiveness of mushroom nutriceuticals has been confirmed repeatedly by laboratory experiments using in vitro or animal model systems. However, there is a need in virtually all cases to confirm their efficacy in ethically conducted and carefully controlled human trials. Furthermore, exactly how most of these products work is still a matter of conjecture. One approach to understanding the beneficial effects of mushrooms has been to isolate and determine the bioactivity of individual components. The active principle, for example lentinan, is then sold in refined or purified form. Such an approach is certainly valid if the objective is to focus on a single mushroom-derived substance for the treatment of a specific disease condition. However, the overwhelming majority of mushroom-based nutriceutical products currently available

are not single compounds but combinations of several individual components that together contribute to the overall medicinal effects of the product. Thus, the medicinal effects afforded by Ganoderma products may be attributable to several quite different types of compounds present in the mushroom: e.g. polysaccharides, lectins, triterpenoids and fungal immunomodulatory proteins (Wachtel-Galor et al. 2004). These compounds, and possibly others yet to be identified, appear to act in concert in contributing to the documented anticancer, antitumour, antiviral, antibacterial and immunomodulating properties of this mushroom (Chang & Buswell, 2003).

Therefore, it is important that the future development of mushroom nutriceuticals should not be focused solely on the isolation and bioactivity of individual mushroom components, otherwise synergistic effects will be overlooked. In certain cases, it may be more desirable to consider the total medicinal effect(s) of mushroom "extracts" and then to ascertain the contributions made to the overall activity by individual components. The consistency of the "extracts," both in terms of overall chemical composition and in the actual levels of active components between different batches, could be standardized on the basis of one or two of the main active constituents. This is essential for ensuring some degree of uniformity in prescribed dosages. Thus, while the minimum dosage of an active component required to bring about the desired therapeutic effect is often known for similar products; e.g. hypericin in extracts of St. John's Wort, this is generally not the case where mushroom extracts are concerned. This is an area where scientific validation can increase knowledge of the products itself as well as contribute to quality control of the products.

Introduction of a Labeling System for Mushroom Nutriceuticals

During the last two decades, more than 200 substances have been isolated from the fruiting bodies, spores, cultivated mycelium and spent culture broths of medicinal mushrooms, with some established knowledge of their chemical and physical structures. However, many medicinal mushroom products on the market do not list the main ingredients on the product labels. Of 40 mushroom products examined in shops/companies, only two (both Ganoderma products) had labeling that revealed the product was standardized to contain polysaccharides (12.5 percent) and triterpenes (4.5 percent) (S.T. Chang, unpublished).

More commonly, labels on the containers claim only that each capsule contains, for example, only pure natural lingzhi (Ganoderma lucidum) or a mixture of lingzhi and maitake (Grifola frondosa). The labeling may also claim that the product contains no preservatives, artificial colouring or flavoring, and that it was manufactured on licensed premises. No nutritional information is provided and no other ingredients are listed. Although some companies have provided one of us (STC) with validation reports relating to the polysaccharide content, as well as HPLC and HPTLC validation profiles, of powdered Ganoderma fruiting bodies and mycelium, these companies do not disclose the test data on the bottle/packaging containing their products.
Table 1: Comparison of triterpene and polysaccharide contents of 11
commercial lingzhi products currently available on the market.

Nature of product Triterpenes (%) Polysaccharide (%)

A(fruiting body extract) 1.36 4.48
B(fruiting body extract) 2.36 5.32
C(fruiting body extract) 1.88 15.70
D(fruiting body extract) 1.06 10.97
E(fruiting body extract) 0.44 7.51
F(fruiting body extract) 1.78 6.18
G(fruiting body extract) 1.44 13.30
H(fruiting body extract) 0.50 15.80
I(fruiting body extract) 7.82 7.66
J(fruiting body powder) 0.46 1.10
K(mycelium powder) Undetectable 12.78

Note: These data were obtained in one laboratory using the same
equipment and method for each sample. This experiment was conducted in
confidence under the direction of one of the authors (STC).

Mushroom nutriceuticals are mostly upgraded products, which are intermediate between regular food and registered drugs. While they do not qualify for the restrictions imposed on prescription drugs (indeed "nutriceuticals" should be clearly distinguished from drugs, mainly because of their distinctive natural properties and intended use by consumers), they should at least be subject to the same government regulations applicable to simple food products.

They should be properly regulated by the appropriate authority, and should be similarly labeled as food products both in terms of the main ingredients and nutritional data. Although most medicinal mushroom products are compound products containing several bioactive ingredients, selected major active components and nutritional data should be indicated.

The need for disclosure is even more acute when we consider the diversity of products on the market, and is exemplified by the data shown in Table 1. These demonstrate the considerable variation in the two major active components (triterpenes and polysaccharide) of 11 randomly selected samples of lingzhi products (commercial products of 11 different companies). Such variations can arise for several reasons including differences in the species/strains of mushroom used and to different extraction/production methods. In the case of these products, triterpene content ranged from undetectable to 7.8 percent, and polysaccharide content varied from 1.1 percent to 15.8 percent. The polysaccharide content of some lingzhi products available on the Hong Kong market also showed huge variation, ranging from 0.06 percent to 29.7 percent. All these products claimed various beneficial attributes without providing the consumer with any basic quality control data such as that shown in Table 1. Disclosure requirements will serve as a natural monitoring device to ensure consistency between different batches of product and constant quality from one batch to another. They will also promote greater product integrity thereby enhancing consumer confidence in the mushroom nutriceuticals market.

Current Regulations Relating to Mushroom Nutriceuticals

An in-depth coverage of the various regulations that currently apply to the marketing of mushroom nutriceuticals is outside the scope of this article. Suffice to say that the huge global expansion that has recently taken place in the nutriceutical and functional food industries has created major challenges, one of which is the considerable variation in the regulations applicable to the different countries active in the marketplace. Another is the borderline position occupied by mushroom nutriceuticals between food and medicine. The reader is directed to a recent publication (Bagchi, 2008) that examines the regulatory hurdles facing foods and dietaiy supplements in general, and which provides coverage of regulations from South America, Canada, the European Union, Australia, New Zealand, Africa, Japan, Korea, China, India and Southeast Asia as well as the United States.

A Proposed Protocol for Obtaining Quality Mushroom Products

There is no question that medicinal mushroom-based products can serve as superior dietary supplements or "nutriceuticals." The problem is the wide product diversity and the present lack of standard protocols for guaranteeing reproducible, high quality merchandise. Consequently, a number of these products have no enduring public credibility, and there is a serious need for improved quality control, bolstered by scientific validation, in order to maintain and increase consumer confidence, protect public health, and to meet current and future standards set by the regulatory authorities. The following five "G" guidelines have been proposed for adoption as a basis for the manufacture of quality mushroom products from mushroom fruiting bodies (Miles and Chang 1997, Chang 2006). Although these guidelines may be considered too simplistic and/or unrealistic in terms of practical adoption, they are offered as a starting point for future reference.

GLP (Good Laboratory Practice)

The source and nature of the mushroom strain must be clearly documented, and it should be properly maintained and preserved without contamination or degeneration. Mushrooms from many different genera are used in nutriceutical manufacture and often reported under a common name with little or no regard to strain/variety or, in some cases, even to species. The validity of comparing data obtained by different laboratories using the same mushroom species is often questionable due to genetic diversity that often exists among different strains of that species.

GAP (Good Agricultural Practice)

Adherence to recommended standard practices is clearly more difficult to monitor in cases where the mushroom feedstock is collected from the wild. However, in such cases, it should still be possible to introduce a system of random testing of different batches of mushrooms prior to processing. This should be given high priority in view of the propensity of mushrooms to accumulate heavy metals, radionucleides and other potentially harmful contaminants from the growth environment. In the case of commercially cultivated fruit bodies, growth and harvesting conditions must be strictly defined: the growth substrate and, where relevant, ancillary material (e.g. casing) should be free of heavy metals, the levels of various ingredients specified and maintained, the physical growth parameters (e.g. temperature regimes, relative humidity, illumination) stipulated, and good sanitary growth conditions should prevail (e.g. free from contaminated water and polluted air, microbial contamination, insect infestation). Not only are such practices important for the quality and safety of the product, they often affect the yield of the desired bioactive component, For example, log-grown shiitake (L. edodes) contained more high-molecular weight polysaccharides (HMWP) than sawdust-grown mushrooms and, among the log-grown shiitake, both mushroom strain and tree species influenced HMWP content (Brauer et al 2001).

GMP (Good Manufacturing Practice)

Effective, contamination-free downstream processing protocols and parameters (e.g. pre-treatments prior to pulverization, pulverization methods, extraction temperatures, extraction times, solvents, etc.) should be developed, standardized and constantly monitored. Although most mushroom nutriceuticals are heterogeneous in nature, levels of the main active constituents of a particular product should, as far as the nature of that product allows, be determined and disclosed in order to guarantee quality, authenticity and dosage formulation. For example, the quality of some Ganoderma products could be based on the content of the major triterpenoid and/or polysaccharide components as determined by high-pressure liquid chromatography. In the longer term, certified testing centers should be established in order to provide product validation/information to manufacturers, retailers and consumers.

GPP (Good Post-formulation Practice)

Appropriate chemical and microbiological analyses should be undertaken to ensure that all types and levels of chemical (e.g. heavy metals) and microbiological contamination respectively fall within safe limits. Optimum storage conditions and stability data relating to the major active ingredients of all marketed products should be determined in order to determine rates of inactivation/deterioration overtime (shelf-life) and to establish appropriate "sell-by dates." Noteworthy in this context is the exoglucanase-mediated degradation of lentinan reported during the storage of L. edodes fruiting bodies (Minato et al, 1999).

GCP (Good Clinical Practice)

High quality clinical trials, including double-blind studies, should be conducted over the longer term to confirm claims of product bioactivity, and to facilitate product formulation and the determination of an appropriate dosage level for an effective health-promoting outcome.

Concluding Remarks

There is growing experimentally based evidence to suggest that dietary supplements based on bioactive compounds extracted from mushrooms (mushroom nutriceuticals) increase resistance to disease and, in some cases, cause regression of a diseased state. Disease prevention is particularly desirable, not only in having positive financial and social impacts but also in maintaining/improving the quality of life and human dignity. In many cases, these products appear to enhance the host immune response that is often weakened through exposure to increased stress levels caused by present day high-pressure work demands. They have extraordinary low toxicity, even at high doses, are apparently lacking in various side effects that frequently accompany the use of synthetic drugs and, since mushrooms have a long tradition as a food source, mushroom feedstocks are categorised as "generally considered safe."

Increasing interest in mushroom nutriceuticals is likely to continue worldwide in view of the challenges and opportunities they represent, and their economic value may ultimately surpass that of mushrooms currently produced for food. However, consumers nowadays are more demanding and better informed, and apply their knowledge when choosing a particular product. Therefore, it is crucial that mushroom products be of high, reproducible quality and free from potentially harmful substances in order to earn the enduring public credibility essential for future market expansion. Widely accepted procedures relating to feedstock production, downstream processing, product safety and stability, and product efficacy need to be developed and continually improved. Introduction of a registration system for mushroom nutriceuticals based on information obtained using these procedures would achieve the highest level of quality assurance, and provide reputable manufacturers with an effective marketing strategy while helping to eliminate less reliable manufacturers/traders. Moreover, accurate disclosure of this information to the consumer will create an automatic monitoring system, and contribute enormously to the overall integrity of the mushroom nutriceutical industry.


Bagchi D, 2008. Nutraceutical and functional food regulations in the United Slates and around the world. Academic Press, New York, 462pp.

Brauer D, Kimmons T, Phillips M. 2002. Effects of management on the yield and high-molecular-weight polysaccharide content of shiitake (Lentinula edodes) mushrooms. J. Agric. Food Chem., 50, 5333-5337.

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Reshetnikov SV, Wasser SP, Tan KK. 2001. Higher Basidiomycota as a source of antitumor and immunostimulating polysaccharides. Int. J. Med. Mushr. 3, 361-394.

Wachtel-Galor S, Benzie IFF; Tomlinson B, Buswell JA. 2004. Lingzhi (Ganoderma lucidum): Molecular aspects of health effects. In: Herbal Medicines. Packer L, Halliwell B, Ong CN, (Eds). Marcel Dekker Inc., New York, pp. 179-228.

Wasser SP, Nevo E, Sokolov D, Reshetnikov S, Timor-Tismenetsky M. 2000. Dietary supplements from medicinal mushrooms: Diversity of types and variety of regulations. Int. J. Med. Mushr. 2, 1-19.

S.T. Chang

Center for International Services to Mushroom Biotechnology Dept. of Biology The Chinese University of Hong Kong Hong Kong SAR, China


J.A. Buswell

Institute of Edible Fungi Shanghai Academy of Agricultural Sciences Shanghai 201106, Chinn


Reprinted with permission from the Proceedings of the 6th International Conference on Mushroom Biology and Mushroom Products Bonn, Germany Sept 29-Oct. 3, 2008
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Title Annotation:Speciality mushrooms
Author:Chang, S.T.; Buswell, J.A.
Publication:Mushroom News
Article Type:Reprint
Date:Feb 1, 2010
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