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PLANTS-BRACKEN FERN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Bracken fern is a common fern found around the world and ingested by both animals and humans for food.

Specific Substances

    1) Brake
    2) Pasture Braken
    3) Hog Pasture Braken
    4) Pteris aquilina
    5) Pteridium aquilnum
    6) BRACKEN FERN (PLANT)
    7) BRAKEN FERN (PLANT)

Available Forms Sources

    A) SOURCES
    1) The bracken fern is a cosmopolitan plant that covers millions of acres of the earth's land surface. The plant can be found in most countries of the world (e.g. the United States, South America, Europe, Asia, Africa, the Soviet Union, Japan, Australia, New Zealand, Formosa, and Indonesia). It can grow all over the world in piney woodlands above 5000 feet.
    B) USES
    1) It is considered a food delicacy and salad green by humans in Japan, Canada, New Zealand, and the United States (Hirono & Shibuja, 1972; Hirono, 1978; Aoki & Ohno, 1982).
    2) The longterm safety of bracken fern as a potential human carcinogen remains controversial (Alonso-Amelot, 1997; Brown et al, 1999; Wilson, 1999; Bruneton, 1999). However, its been suggested to avoid consumption of the bracken fern (Bruneton, 1999).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Inconsistent data exists regarding the potential longterm effects of bracken fern consumption by humans. It has been suggested as the cause of increased cases of spontaneous urinary bladder cancer in cattle and water buffalo and intestinal and urinary bladder cancer in sheep.
    0.2.8) GASTROINTESTINAL
    A) In epidemiological studies in Japan, carcinoma of the esophagus was 2.7 times more common in people who ate bracken.
    B) Researchers have found a significantly increased risk of gastric cancer among people who spent their childhood in bracken-infested areas.
    0.2.10) GENITOURINARY
    A) Fresh, cooked, or canned bracken have all been implicated as a cause of cancer of the bladder in humans, but recent studies revealed no association between cancer of the urinary tract and the bracken fern.
    0.2.13) HEMATOLOGIC
    A) Some initial studies suggested that the inhalation of bracken spores might be responsible for the slight increase in leukemia mortality, at ages 0 to 2 years in England and Wales. A more recent study showed no indication of an increased risk of leukemia due to bracken fern.
    0.2.17) METABOLISM
    A) There is experimental evidence that bracken ferns, when consumed by human subjects, decrease the availability of thiamine ingested in food.
    0.2.19) IMMUNOLOGIC
    A) Fern spores were found to be the third most common airborne spora in the Bangkok, Thailand atmosphere. As a result of skin tests and nasal provocation tests, researchers concluded that fern spores were potentially allergenic and allergists should be aware that ferns could be an important aeroallergen.
    0.2.20) REPRODUCTIVE
    A) Female rats fed bracken fern as 30% of their diet had reduced fertility and less weight gain during pregnancy. Pups had delayed righting reaction and negative geotaxis, suggesting a reduced neuromuscular function development. General activity was also reduced.
    0.2.21) CARCINOGENICITY
    A) Consumption of bracken fern has been implicated as a cause of intestinal, urinary tract and esophageal cancers in man.

Laboratory Monitoring

    A) No specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise clinically indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Based on no evidence of acute toxicity to humans, treatment such as gastric decontamination or activated charcoal does NOT appear indicated. In many parts of the world, consumption of the bracken fern is considered a delicacy.

Range Of Toxicity

    A) Minimum lethal human exposure is unknown.

Clinical Effects

Summary Of Exposure

    A) Inconsistent data exists regarding the potential longterm effects of bracken fern consumption by humans. It has been suggested as the cause of increased cases of spontaneous urinary bladder cancer in cattle and water buffalo and intestinal and urinary bladder cancer in sheep.

Gastrointestinal

    3.8.1) SUMMARY
    A) In epidemiological studies in Japan, carcinoma of the esophagus was 2.7 times more common in people who ate bracken.
    B) Researchers have found a significantly increased risk of gastric cancer among people who spent their childhood in bracken-infested areas.
    3.8.2) CLINICAL EFFECTS
    A) NEOPLASM OF GASTROINTESTINAL TRACT
    1) Bracken fern can cause gastrointestinal neoplasms in animals, but only isolated reports of increased frequency of gastric neoplasms have been reported in humans following exposure to cow's milk (Alonso-Amelot, 1997). Other authors have suggested that the risk of ptaquiloside ingestion from cow's milk is negligible by blending and dilution processes (Bruneton, 1999).
    B) NEOPLASM OF ESOPHAGUS
    1) In epidemiological studies in Japan, carcinoma of the esophagus was 2.7 times more common in people who ate bracken (Trotter, 1990).
    C) CARCINOMA OF STOMACH
    1) Researchers in North Wales found a significantly increased risk of gastric cancer among people who spent their childhood in bracken-infested areas. The survey suggested that the carcinogen derived from bracken may have been consumed in milk.

Genitourinary

    3.10.1) SUMMARY
    A) Fresh, cooked, or canned bracken have all been implicated as a cause of cancer of the bladder in humans, but recent studies revealed no association between cancer of the urinary tract and the bracken fern.
    3.10.2) CLINICAL EFFECTS
    A) CARCINOMA OF BLADDER
    1) Fresh or cooked or canned bracken have all been implicated as a cause of cancer of the bladder in humans (Evans & Widdop, 1971; Caldwell & Brewer, 1980; Pamukcu & Price, 1970). Recent studies, however, revealed no association between cancer of the urinary tract and the bracken fern (Aoki & Ohno, 1982).
    2) LACK OF EFFECT - A case-control study was conducted to evaluate the risk of bladder cancer among white residents of Vermont and New Hampshire. No increased risk of bladder cancer was found among individuals who consumed fiddlehead greens (bracken fern) (Brown et al, 1999).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEOPLASM UROGENITAL
    a) Bracken fern is known to cause neoplasms in the genitourinary tract of animals, but there are NO adequate data to support that this plant causes neoplasms in humans.

Hematologic

    3.13.1) SUMMARY
    A) Some initial studies suggested that the inhalation of bracken spores might be responsible for the slight increase in leukemia mortality, at ages 0 to 2 years in England and Wales. A more recent study showed no indication of an increased risk of leukemia due to bracken fern.
    3.13.2) CLINICAL EFFECTS
    A) LEUKEMIA
    1) Some initial studies suggested that the inhalation of bracken spores might be responsible for the slight increase in leukemia mortality at ages 0 to 2 years in England and Wales. A more recent study revealed no indication of an increased risk of leukemia due to bracken fern (Cook-Mozaffari & Darby, 1990).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEMOLYSIS
    a) GUINEA PIGS - Tjatur Rasa et al (1999) identified a new toxic substance called hemolysin, which may have a role in the development of vascular hemolysis and hemoglobinuria which have been observed in guinea pigs.

Immunologic

    3.19.1) SUMMARY
    A) Fern spores were found to be the third most common airborne spora in the Bangkok, Thailand atmosphere. As a result of skin tests and nasal provocation tests, researchers concluded that fern spores were potentially allergenic and allergists should be aware that ferns could be an important aeroallergen.
    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) Fern spores were found to be the third most common airborne spora in the Bangkok, Thailand atmosphere. As a result of skin tests and nasal provocation tests, researchers concluded that fern spores were potentially allergenic and allergists should be aware that ferns could be an important aeroallergen.

Reproductive

    3.20.1) SUMMARY
    A) Female rats fed bracken fern as 30% of their diet had reduced fertility and less weight gain during pregnancy. Pups had delayed righting reaction and negative geotaxis, suggesting a reduced neuromuscular function development. General activity was also reduced.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.3) EFFECTS IN PREGNANCY
    A) ANIMAL STUDIES
    1) RATS - Female rats fed bracken fern as 30% of their diet had reduced fertility and less weight gain during pregnancy (Gerenutti et al, 1992).
    a) The quantity of milk remained the same as controls.
    b) Pups had delayed righting reaction and negative geotaxis, suggesting a reduced neuromuscular function development. General activity was also reduced.

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Consumption of bracken fern has been implicated as a cause of intestinal, urinary tract and esophageal cancers in man.
    3.21.3) HUMAN STUDIES
    A) ESOPHAGEAL CARCINOMA
    1) In epidemiological studies in Japan, carcinoma of the esophagus was 2.7 times more common in people who at bracken (Trotter, 1990).
    B) GASTRIC CARCINOMA
    1) Researchers in North Wales found a significantly increased risk of gastric cancer among people who spent their childhood in bracken-infested areas. The survey suggested that the carcinogen derived from bracken may have been consumed in milk.
    2) Consumption of bracken fern has been implicated as a cause of intestinal and urinary tract cancers in man. Other authors suggest that the evidence is insufficient to conclude that bracken is a human carcinogen (Brown et al, 1999; Bruneton, 1999).
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) The major carcinogen responsible for bovine cancer resulting from ingestion of bracken ferns has been identified as ptaquiloside, the sesquiterpenoid carcinogen of Pteridium aquilinum. This norsesquiterpene glucoside can be present in extremely large quantities in the bracken fern, as much as 13000 ppm (Shahin et al, 1999). Experimental work has shown that bracken fern ingestion can cause urinary bladder tumors in guinea pigs and cows; bowel and bladder tumors in rats; intestinal tumors in Japanese quail and cattle; and intestinal and lung tumors and leukemia in mice. Human data remains inconsistent regarding the role of bracken fern ingestion and the development of cancer (Shahin et al, 1999; Bruneton, 1999).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise clinically indicated.

Radiographic Studies

    A) RADIOGRAPHIC-OTHER
    1) None indicated.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) There is a lack of information available regarding the acute effects of human exposure to bracken fern (Hirono, 1986). Admission following acute ingestion should NOT be necessary, and should be based on clinical findings.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Most acute human exposures do NOT require hospitalization.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) None necessary
    6.3.1.4) PATIENT TRANSFER/ORAL
    A) NOT necessary
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) The long-term monitoring for the development of neoplasms of the genitourinary and/or gastrointestinal tract remains unclear. Further epidemiological studies are indicated (Shahin et al, 1999).

Monitoring

    A) No specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise clinically indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS -
    1) Emesis is NOT indicated for acute ingestions.
    B) ACTIVATED CHARCOAL -
    1) Activated charcoal is NOT indicated for acute ingestions.
    6.5.2) PREVENTION OF ABSORPTION
    A) EMESIS
    1) Emesis is NOT indicated for acute ingestions.
    B) ACTIVATED CHARCOAL
    1) Activated charcoal is NOT indicated for acute ingestions.
    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) NO treatment is necessary for acute ingestion of bracken fern as data is lacking regarding the acute effects to humans. Bracken fern should not be used as a food or as an herbal remedy (Hodgson, 1991; Bruneton, 1999).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) NO treatment necessary.
    6.7.2) TREATMENT
    A) GENERAL TREATMENT
    1) There is NO evidence that human exposure to bracken fern can produce acute toxicity in man; asymptomatic patients can be sent home.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) SUMMARY
    1) Methods to enhance elimination are NOT necessary.

Range Of Toxicity

Summary

    A) Minimum lethal human exposure is unknown.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) This plant should NOT be used therapeutically.
    7.2.2) PEDIATRIC
    A) GENERAL
    1) This plant should NOT be used therapeutically.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) There are no data confirming acute lethal toxicity in humans.

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) The maximum tolerated human exposure to this agent has NOT been delineated.

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) No data are available for human subjects.

Pharmacology Toxicology

Pharmacologic Mechanism

    A) There are several active principles in bracken fern (Hopkins, 1986).
    1) Tannin
    2) Quercetin
    3) Shikimic Acid
    4) Prunasin
    5) Ptaquiloside
    6) Qqililide A
    7) Kaemferol

Toxicologic Mechanism

    A) The major carcinogen responsible for bovine cancer resulting from ingestion of bracken ferns has been identified as ptaquiloside, the sesquiterpenoid carcinogen of Pteridum aquilinum (Saito & Nagao, 1990; Hirono, 1986).
    B) Experimental work has shown that bracken fern ingestion can cause urinary bladder tumors in guinea pigs and cows; bowel and bladder tumors in rats; intestinal tumors in Japanese quail and cattle; and intestinal and lung tumors and leukemia in mice (Aoki & Ohno, 1982).
    C) Ptaquiloside produces intestinal, mammary, and urinary bladder tumors in rats.
    D) Tannin, when injected into rats, is carcinogenic but NOT when given orally.
    E) Quercetin - a flavonol. Opinions differ on the carcinogenicity of this chemical (Ambrose & Robbins, 1952).
    F) Shikimic acid - carcinogenic for mice.
    G) Prunasin - contains a cyanogenic glycoside and may be carcinogenic.
    H) Aquilide A - attempts to isolate carcinogenic factor have been unsuccessful.
    I) Kaemferol - a flavonol that is also considered a bracken fern carcinogen.
    J) (REFERENCES - Hopkins, 1986; (Hirono & Fushimi, 1973) Yoshihara et al, 1978; (Wang & Chiu, 1976)

Physicochemical

Physical Characteristics

    A) Acute toxicity and carcinogenicity is greatly reduced or destroyed under alkaline conditions, and is best maintained at an acid pH (Aoki & Ohno, 1982).
    B) Some experiments show that the carcinogen can be removed to some extent by boiling the bracken fern in plain water, and that only weak carcinogenicity is retained if an alkali is added (Aoki & Ohno, 1982).

Molecular Weight

    A) Not applicable

Animal Toxicology

Clinical Effects

    11.1.1) AVIAN/BIRD
    A) Intestinal tumors have occurred in Japanese quail (Evans & Evans, 1965).
    11.1.2) BOVINE/CATTLE
    A) BOVINE ENZOOTIC HEMATURIA - The predominant feature of "bracken poisoning" in cattle is depressed bone marrow activity which gives rise to severe leukopenia, thrombocytopenia, a hemorrhagic syndrome, and hematuria. This disease is very dramatic and NEARLY ALWAYS fatal (Hirono, 1986; Hirono, 1986a; Hirono, 1986b; Rajendran, 1983; Price & Pamukcu, 1968; Hirono & Kono, 1984; Hirono & Shibuya, 1970).
    B) Bracken fern causes upper alimentary track and urinary bladder carcinomas in cattle, water buffalo, and sheep (Aoki & Ohno, 1982; Dawra & Sharma, 1989).
    11.1.3) CANINE/DOG
    A) Urine from cattle that have been fed hay from districts were hematuria in cattle is common, has been introduced into the urinary bladder of dogs. This has produced change similar to hemangioma (Evans & Evans, 1965).
    11.1.5) EQUINE/HORSE
    A) Ingestion of bracken fern by horses, leads to a thiamine deficiency that can be remedied by administering thiamine. This deficiency develops because the fern contains the enzyme thiaminase, which can cleave the thiamine molecule, thus inactivating it (Hirono, 1986).
    11.1.9) OVINE/SHEEP
    A) Carcinoma is seen in sheep who graze on this material (Smith et al, 1989).
    11.1.12) RODENT
    A) Experimental evidence in rats, mice, hamsters, and guinea pigs, confirms the carcinogenicity of bracken fern. Rat target organs are ileum, cecum, urinary bladder, and breast.
    1) NEOPLASMS - Adenoma, adenocarcinoma, and sarcoma of intestine. Papilloma and carcinoma of the urinary bladder are also seen as mammary carcinoma in Sprague-Dawley rats (Pamukcu & Price, 1969).
    2) MICE TARGET ORGANS - Lung (lung adenoma), jejunum (jejunal adenocarcinoma), spleen and bone marrow (lymphatic leukemia).
    3) HAMSTER TARGET ORGANS - Intestine, adenocarcinoma of caecum and ileum.
    4) GUINEA PIG TARGET ORGANS - Small intestine (adenoma and adenocarcinoma of the small intestine) and urinary bladder (carcinoma of the urinary bladder) (Hirono, 1986).
    a) Tjatur Rasa et al (1999) have identified a bracken extract known as hemolysin, which may contribute to the acute hemolysis that has been observed in guinea pigs exposed to the plant.
    11.1.13) OTHER
    A) OTHER
    1) Strong carcinogenic activity from the bracken fern has been identified in many animals. The target organs vary with the species and include stomach, small intestine, cecum, colon, lung, bladder, and reticuloendothelial system. In some cases single oral or intraperitoneal doses of purified extract are sufficient to produce changes (Evans & Osman, 1974; Pamukcu & Goksoy, 1967; Pamukcu & Olson, 1966).

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) SPECIFIC TOXIN
    1) In some cases, experimental, single, oral, or intraperitoneal doses can be carcinogenic (Evans & Osman, 1974).

Sources

    A) SPECIFIC TOXIN
    1) The bracken fern (synonyms: Pteridium aquilnum, brake, pasture bracken, hog pasture bracken, Pteris aquilina) is a member of the Polypodiaceae. It is the commonest fern in the United States. The plant is coarse and strong, and often grows in large colonies of over knee high, wavy, dark green, almost horizontal leaves. The leaves are distinctly stemmed and cut into leaflets and subleaflets.

References

General Bibliography

    1) Alonso-Amelot ME: The link between bracken fern and stomach cancer: milk (editorial). Nutrition 1997; 13:694-696.
    2) Ambrose AM & Robbins DJ: Comparative toxicity of quercetin and quercitrin. J Am Pharm Assoc 1952; 41:119-122.
    3) Angier B: Bracken Fern, Field Guide to Edible Wild Plants, Stackpole Books, Harrisburg, PA, 1974, pp 158-159.
    4) Aoki K & Ohno Y: Bracken fern, phenacetin and cancer of the urinary tract. Natl Cancer Inst Monograph 1982; 62:191-195.
    5) Bailey LH & Bailey EZ: Hortus Third, MacMillan Publishing Co, Inc, New York, NY, 1976.
    6) Brown LM, Zahm SH, & Hoover RN: Bracken fern consumption and human bladder cancer (letter). J Epidemiol Commun Health 1999; 53:653.
    7) Bruneton J: Toxic Plants: Dangerous to Humans and Animals, Intercept Ltd, Hampshire, UK, 1999, pp 52-56.
    8) Caldwell Me & Brewer WR: Possible hazards of eating bracken fern. N Engl J Med 1980; 303:164.
    9) Cook-Mozaffari P & Darby S: Bracken spores and leukaemia. Lancet 1990; 335:736.
    10) Dawra RK & Sharma OP: Erythrocyte glutathione and its metabolizing enzymes in bovine bladder. Cancer 1989; 48:143-146.
    11) Evans IA & Osman MA: Carcinogenicity of bracken and shikimic acid. Nature 1974; 250:348-349.
    12) Evans IA & Widdop B: The possible human hazard of the naturally occurring bracken carcinogen. Biochem J 1971; 124:28-29.
    13) Evans IA, Jones RS, & Mainwaring-Burton R: Passage of bracken fern toxicity into milk. Nature 1972; 237:107-108.
    14) Evans WC & Evans IA: Carcinogenic activity of bracken. Nature 1965; 208:913-914.
    15) Gerenutti M, Spinosa H, & Bernardi M: Effects of bracken fern (Pteridium aquilinum L Kuhn) feeding during the development of female rats and their offspring. Vet Hum Toxicol 1992; 34:307-310.
    16) Hirono I & Fushimi K: Comparative study of carcinogenic activity in each part of bracken. J Natl Cancer Inst 1973; 50:1367-1371.
    17) Hirono I & Kono K: Reproduction of acute bracken poisoning in a calf with ptaquiloside. Vet Rec 1984; 115:375-378.
    18) Hirono I & Shibuja C: Carcinogenic activity of processed bracken used as human food. J Natl Cancer Inst 1972; 48:1245-1250.
    19) Hirono I & Shibuya C: Studies on carcinogenic properties of bracken, Pteridium aquilinum. J Natl Cancer Inst 1970; 45:179-188.
    20) Hirono I: Carcinogenic principles isolated from the bracken fern. Crit Rev Toxicol 1986a; 17:1-22.
    21) Hirono I: Carcinogenicity of boiling water extract of bracken, Pteridium aquilinum. Gann 1978; 69:383-388.
    22) Hirono I: Carcinogenicity of plant constituents: pyrrolizidine, alkaloids, flavonoids, bracken fern. Prog Clin Biol Res 1986b; 45:45-53.
    23) Hirono I: Human carcinogenic risk in the use of the bracken fern diet. Nutrition and Cancer, Japan Sci Soc Press, Tokyo, Japan, 1986, pp 139-145.
    24) Hodgson ES: Is bracken a health hazard (letter)?. Lancet 1991; 337:493.
    25) Hopkins NCG: Aetiology of enzootic hematuria. Vet Rec 1986; 118:715-717.
    26) Pamukcu AM & Goksoy SK: Urinary bladder neoplasms induced by feeding bracken fern to cows. Cancer Res 1967; 27(Part I):917-924.
    27) Pamukcu AM & Olson C: Assay of fractions of bovine urine for carcinogenic activity after feeding bracken fern. Cancer Res 1966; 26(Part I):1745-1753.
    28) Pamukcu AM & Price JM: Assay of fractions of bracken fern for carcinogenic activity. Cancer Res 1970; 30:902-905.
    29) Pamukcu AM & Price JM: Induction of intestinal and urinary bladder cancer in rats. J Natl Cancer Inst 1969; 43:275-281.
    30) Price & Pamukcu AM: The induction of the urinary bladder of the cow and the small intestine of the rat by feeding bracken fern. Cancer Res 1968; 28:2247-2251.
    31) Rajendran MP: Experimental production of enzootic bovine haematuria with bracken fern (abstract). Indian Vet J 1983; 60:173-178.
    32) Saito K & Nagao T: The sesquiterpenoid carcinogen of bracken fern and some analogues, from the pteridaceae. Phytochemistry 1990; 29:1475-1479.
    33) Shahin M, Smith BL, & Prakash AS: Bracken carcinogens in the human diet. Mutation Res 1999; 443:69-79.
    34) Smith BL, Embling PP, & Lauren DR: Carcinogen in rock fern (Chielanthes sieberi) from New Zealand and Australia. Aust Vet J 1989; 66:230-231.
    35) Trotter WR: Is bracken a health hazard?. Lancet 1990; 336:1563-1564.
    36) Wang CY & Chiu CW: Identification of carcinogenic tannin isolated from bracken fern. J Natl Cancer Inst 1976; 56:33-36.
    37) Wilson D: Brackne fern consumption and human bladder cancer (Reply). J Epidemiol Commun Health 1999; 53:653.