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OCR for page 234
12 Naturally Occumng Carcinogens
The production of toxic compounds by living cells has long been
recognized. Some of these chemicals, especially those produced by
microbes and plant cells, have carcinogenic activity. Although some
of these compounds are integral components of foods that are relatively
common in the diet of humans, many of them have been found either in
unusual food sources or in foods contaminated by microorganisms or
unwanted plant materials. The potential hazards to human health posed
by these components or contaminants of foods range from slight to very
great. For example, very low levels of exposure to chemicals with
relatively weak carcinogenic activity in laboratory animals may pose
little risk to human populations. On the other hand, the presence of
aflatoxin B1 in foods is a matter of great concern, since aflatoxin
B1 is a potent carcinogen for a number of species and epidemiological
data suggest that this carcinogen may play a role in the development of
cancer in humans living in some parts of Africa and in the Far East
(Peers et al., 1976; van Rensburg et al., 1974~.
Much of the literature on the carcinogenic products of living cells
has been collected and evaluated by working groups of the International
Agency for Research on Cancer (1976) and by the National Research Coun-
cil (National Academy of Sciences, 1973~. Accordingly, these compre-
hensive reviews are often cited in this chapter instead of the primary
literature. In addition, several recent reviews on naturally occurring
carcinogens include exhaustive lists of primary references pertaining
to these carcinogens. The overviews also cite literature on certain
aspects of these carcinogens not covered in this chapter, such as their
metabolic activation and deactivation, the reactions of electrophilic
derivatives with cellular macromolecules, and the biochemical and
biological consequences of the latter reactions (Hirono, 1981; Miller
and Miller, 1979; Miller et al., 1979; Schoental, 1976~.
MYCOTOXINS
By definition, mycotoxins are toxic secondary products resulting
from the metabolism of molds. In this chapter, the committee has
reviewed only those toxic metabolites of mold that occur as natural
contaminants of food or feed or that demonstrate some evidence of car-
cinogenicity in mammals when administered orally. Although at least
45 mycotoxins have been identified as eliciting some type of carcino-
genic or mutagenic response, only 17 of them have been reported to
occur naturally in food or feed (Stoloff, in press) (or only 13, if
the aflatoxin group is considered as a single compound).
234
12-1
OCR for page 235
Naturally Occu~nng Carcinogens 235
The selection of the mycotoxins discussed in this section was
based on the extent of their occurrence in food and/or the data demon-
strating their carcinogenicity. These compounds include: aflatoxins,
sterigmatocystin, ochratoxin A, zearalenone, T-2 toxin, patulin, pen-
icillic acid, griseofulvin, luteoskyrin, cyclochlorotine, and ergot.
Aflatoxins
A very extensive effort has gone into the study of this group of
mycotoxins, especially to examine its most potent member, aflatoxin
B1. Much more is known about the occurrence and toxicity of the
aflatoxins than about any other mycotoxin and, probably, most other
natural contaminants.
The scattered data pertaining to worldwide occurrence of aflatoxins
in food were compiled for a conference on mycotoxins, which was spon-
sored by the Food and Agriculture Organization, the United Nations
Environment Program, and the World Health Organization (1977~. More
recently, Stoloff (in press) compiled data on the occurrence of afla-
toxins in the United States.
The aflatoxin-producing molds Aspergillus flavus and A. parasiti-
cus are ubiquitous. They are frequently encountered as outgrowths on
stored commodities under conditions prevailing in many tropical areas.
In the United States, aflatoxin contamination is generally restricted
to those crops invaded by the aflatoxin-producing molds before harvest
most frequently peanuts, corn, and cottonseed, and to a much lesser
extent tree nuts, including almonds, walnuts, pecans, and pistachios.
The extent of contamination is greater in the southeastern United
States.
In the United States, humans are exposed to aflatoxin mostly from
corn and peanuts (U.S. Food and Drug Administration, 1979~. Other
direct dietary sources, such as tree nuts, are of minor significance,
either because contamination is infrequent or because only small
quantities are consumed.
It is unlikely that secondary exposures result from the ingestion
of aflatoxin residues in tissues of animals fed aflatoxin-contaminated
feed (Stoloff, 1979), except for aflatoxin M1, a metabolite that
appears in the milk of lactating mammals exposed to aflatoxins. But,
although large amounts of milk are consumed, this exposure is negligi-
ble compared to the direct exposure from peanuts and corn.
Aflatoxins are classified as unavoidable contaminants. In the
United States, the maximum allowable limit of total aflatoxins in
consumer peanut products is currently 20 ~g/kg (U.S. Food and Drug
Administration, 1980b'
12-2
OCR for page 236
236 DIET, NUTRITION, AND CANCER
Epidemiological Evidence. Oettle (1965) was the first investi-
gator to draw serious attention to the hypothesis that aflatoxin
ingestion might cause liver cancer. He suggested that the geographic
distribution of liver cancer in Africa could be explained by differing
levels of exposure to aflatoxin in the diet. Keen and Martin (1971)
reported an apparent association between the consumption of groundnuts
contaminated with aflatoxin and the occurrence of liver cancer in
different areas of Swaziland. Alpert _ al. (1971) made a similar
correlation of contaminated foodstuffs and incidence of hepatoma by
tribe and by province or district in Uganda. In a later study in
Swaziland, Peers et al. (1976) analyzed aflatoxin levels in foods
consumed by a representative sample of the population in 11 geographic
areas. He reported a significant correlation between aflatoxin contam-
ination and incidence of primary liver cancer among adult males. A
similar study in the Murang'a district of Kenya (Peers and Linsell,
1973) indicated that there was a correlation between aflatoxin levels
in dietary staples of three district subdivisions and the incidence of
liver cancer. Mozambique has particularly high rates of liver cancer,
perhaps the highest in the world, and studies of aflatoxin contamina-
tion of foods indicated that the estimated daily intake of aflatoxin in
that country was higher than that reported for any other country (van
Rensburg et al., 1974~. One problem recognized by the researchers in
all of these studies is the inadequacy of the data on liver cancer
incidence, since cancer registration is not well established in these
areas.
Detailed studies of aflatoxin contamination of ingested foodstuffs
have also been conducted in Thailand, where there was an overall corre-
lation between estimated aflatoxin intakes in two regions and liver
cancer incidence (Shank et al., 1972a,b; Wogan, 1975~. The frequency
with which aflatoxin was detected in foods has also been correlated
with liver cancer mortality in Guangxi province in China (Armstrong,
1980~. In Taiwan, where liver cancer mortality rates are high, Tung
and Ling (1968) reported that dietary staples (e.g., peanuts and peanut
oil, which is widely used in cooking) are frequently contaminated with
aflatoxin.
Linsell and Peers (1977) observed a strong correlation between
estimated levels of aflatoxin ingested and liver cancer incidence from
various studies conducted in Africa and Asia. They further noted that
there were no areas where high levels of aflatoxin ingestion have been
associated with low rates of liver cancer.
Although the studies described above suggest that aflatoxin causes
primary hepatocellular carcinoma (PHC), numerous other reports have
also documented a high correlation between PHC and exposure to hepati-
tis B virus (Chien et al., 1981; Prince et al., 1975; Simons et al.,
1972; Tong et al., l9lr; Vogel et al., lY7057 These studies BE not
indicate whether present or past exposure to this virus is more closely
associated with the development of PHC. However, Kew et al. (1979)
12-3
OCR for page 237
Naturally Occurring Carcinogens 237
reported that active hepatitis B viral infection is present in approxi-
mately 80% to 90% of the patients with PHC. Approximately 5% to 10% of
the victims of hepatitis B infection actually develop chronic active
hepatitis with persistent liver damage. The liver cells of these indi-
viduals are believed to regenerate more rapidly, thereby increasing the
likelihood that a biochemical lesion that initiates neoplasia will
become fixed in the genes of the subsequent cell population.
The worldwide occurrence of hepatitis B viral infection is similar
to that of primary hepatocellular carcinoma. However, it is possible
that the influences of aflatoxin and hepatitis B virus on the risk for
PHC are not completely independent. Van Rensburg (1977) reviewed the
evidence for both risk factors and concluded that preexisting viral in-
fection is probably a prerequisite for malignant transformation by afla-
toxin.
The possibility that aflatoxin may also be involved in the etiology
of esophageal cancer is suggested by the correlation between mortality
from esophageal cancer and the consumption of large amounts of pickled
vegetables and other fermented or moldy food in Linxian county of Henan
province in northern China (Yang, 1980~. Although Aspergillus flavus
has been isolated from some products, it is difficult to determine the
role of aflatoxin in the etiology of this disease because these foods
also contain other fungal species, mutagens, and carcinogens, including
_-nitroso compounds.
Epidemiological studies have not been undertaken in Western coun-
tries, but there have been reports indicating the presence of aflatoxin
B1 in autopsy samples from liver cancer patients in Czechoslovakia
(Dvoratkova _ al., 1977), New Zealand (Becroft and Webster, 1972), and
the United States (Sire; et al., 1981). Siraj et al. (1981) detected
aflatoxin B1 in four of the six liver samples obtained from patients
with PHC in the United States. The significance of these findings is
not yet known.
Experimental Evidence: Carcinogenicity. Aflatoxin B1 is the
most potent hepatocarcinogen known, being about 1,000 times more
powerful than butter yellow (p-dimethylaminoazobenzene) in rats. The
carcinogenicity of aflatoxins has been examined in several studies in
variety of species and strains of laboratory animals, including mice,
marmosets, tree shrews, trout, ducks, rhesus monkeys, hamsters, and
several strains of rats (Wogan, 1973~. Of the various species tested,
the male Fischer 344 rat was the most sensitive to aflatoxin-induced
carcinogenesis (Wogan, 1973~.
Aflatoxin B1 induced mainly hepatocellular carcinomas in rats.
However, other studies in rats have indicated that it may also induce a
very low incidence of carcinomas of the glandular stomach (Butler and
Barnes, 1966), cancers of the colon (Newberne and Rogers, 1973; Wogan
and Newberne, 1967), renal epithelial neoplasia (Epstein et al., 1969),
12-4
OCR for page 238
238 DIET, NUTRITION, AND CANCER
and lung adenomas (Newberne et al., 1967~. Within a susceptible
species and strain, males are much more susceptible than females to
challenge with aflatoxin (Wogan and Newberne, 1967~.
Mice are resistant to aflatoxin-induced carcinogenesis under con-
ditions that result in 100% tumor incidence in Fischer rats. However,
hepatomas were induced in 82 of 105 inbred (C57BL X C3H)F1 mice in-
jected intraperitoneally during the first 7 days after birth with doses
of aflatoxin B1 as low as 1.25 Agog body weight (bw) and killed 82
weeks later (Vesselinovitch et al., 1972~.
In comparison to Fischer rats, nonhuman primates (170 animals in 12
different investigations) were relatively resistant to aflatoxin-induced
carcinogenesis (Stoloff and Friedman, 1976~. Liver tumors do not occur
spontaneously in monkeys (O'Gara and Adamson, 1972), but a female rhesus
monkey developed a primary liver carcinoma after ingesting approximately
500 mg of aflatoxin B1 over a 6-year period (Adamson et al., 1973~. In
another study, one of nine marmosets developed liver tumors after 50 weeks
on a diet (5 days a week) containing aflatoxin B1 at 2 Agog (tin et al.,
1974~. However, the authors also observed liver cirrhosis,which is not a
symptom of aflatoxicosis in rats. Reddy _ al. (1976) reported that 9 of
18 tree shrews intermittently fed aflatoxin B1 at 2 Agog diet developed
liver cancers after 74 to 172 weeks of treatment.
Experimental Evidence: Mutagenicity. Aflatoxin B1 was shown to be
mutagenic to Salmonella typhimurium strains TA98 and TA100 with and with-
out S9 fraction (Ueno et al., 1978~. It was positive in the Bacillus
subtilis rec assay (Ueno and Kubota, 1976~. In FM3A mouse cells, afla-
toxin induced 8-azaguanine-resistant mutants as well as chromosome aber-
rations (Umeda et al., 1977~. Aflatoxin M1, the metabolite of aflatoxin
B1, was mutagenic in the Ames test (Won" and Hsieh, 1976), but inactive
in B. subtilis rec assay (Ueno and Kubota, 1976~.
Other Mycotoxins
Table 12-1 summarizes the data on the occurrence, carcinogenicity,
and mutagenicity of mycotoxins other than aflatoxins that may be found
in food. Although most of these mycotoxins are mutagenic in bacterial
systems and other short-term tests and/or are carcinogenic in laboratory
animals, there are no epidemiological studies pertaining to their role
in neoplasia in humans.
Summary and Conclusions: M l~to~ns amd Othec ~ycocu~i``s
A consistent body of evidence, all based on correlational data,
associates the contamination of foods by aflatoxin with a high incidence
of liver cancer in parts of Africa and Asia, but there is no epidemiologi-
cal evidence that aflatoxin contamination of foodstuffs is related to
12-5
OCR for page 239
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OCR for page 240
240 DIET, NUTRITION, AND CANCER
cancer risk in the United States. Epidemiological studies have also
indicated a high correlation between primary hepatocellular carcinoma
and exposure to hepatitis B viral infection. Aflatoxin is carcinogenic
in several species of animals, including rats, mice, trout, ducks,
monkeys, and marmosets, and there is evidence of dose response. It
induces mainly tumors of the liver and, to a lesser extent, tumors in
the kidney, lung, stomach, and colon, more readily in males and in the
young. The carcinogenicity of aflatoxin is paralleled by its
mutagenicity in various systems.
There is no reliable information about the role of other mycotoxins
· · · .
In carc~nogenes~s In humans.
HYDRAZINES IN MUSHROOMS
Epidemiological Evidence. No epidemiological studies have been
conducted to determine the effects of hydrazines on carcinogenesis in
humans.
Agaricus bisporus
Agaricus bisporus is a commonly eaten cultivated mushroom in
Europe, North America, and other parts of the world. The exact
consumption figures for Agaricus bisporus are unknown, but the U.S.
Department of Agriculture (1981) has estimated that approximately 213
million kilograms of this mushroom were available for consumption
(production and imports) in the United States during 1980.
Agaricus bisporus contains agaritine -- 6-N-~-L(+~-glutamyl]-4-
hydroxymethylphenylhydrazine (Toth et al., 1978) -- and 4-(hydroxy-
methyl~benzenediazonium ion (Levenberg, 1962~. 4-Hydroxymethylphenyl-
hydrazine and 4-methylphenylhydrazine, which are breakdown products of
agaritine, have also been found in A. bisporus (Levenberg, 1964~.
Experimental Evidence: Carcinogenicity. N'-Acetyl-4-(hydroxy-
methyl~phenylhydrazine as a 0.0625% solution in drinking water admin-
istered continuously to Swiss mice from 6 weeks of age to the end of
their lives induced lung and blood vessel tumors (Toth et al., 1978~.
4-(Hydroxymethyl~benzenediazonium tetrafluoroborate administered
to Swiss mice in 26 weekly subcutaneous injections at 50 ~g/g bw
resulted in an increased incidence of tumors of the subcutis and skin
(Toth _ al., 1981~.
4-Methylphenylhydrazine hydrochloride administered to Swiss mice in
7 weekly intragastric instillations of 250 ~g/g bw induced lung and
blood vessel tumors (Toth et al., 1977~.
12-7
OCR for page 241
Naturally Occulting Carcinogens 241
Experimental Evidence: Mutagenicity. N'-Acetyl-4-(hydroxy-
methyl~phenylhydrazine was most mutagenic in S. typhimurium TA1537
without metabolic activation, and it exhibited marginal DNA-modifying
activity only when the S9 fraction was included (Rogan et al., in
press).
4-(Hydroxymethyl~benzenediazonium tetrafluoroborate was weakly
mutagenic in TA1535 and strongly mutagenic in TA1537, exhibiting tox-
icity in both strains (Rogan et al., in press).
Agaritine produced equivocal results in both in vitro assays. There
was a slight enhancement of mutagenicity in S. typhimurium TA1537 with-
out metabolic activation, and marginal DNA-modifying activity in the
presence of S9 fraction (Rogan et al., in press).
4-Methylphenylhydrazine hydrochloride was also found to be mutagenic
with and without S9 fraction in S. typhimurium TA98 and TA100 (Shimizu
et al., 1978~. ~
GYromitra esculenta
Each year, approximately 1 million people throughout the world eat
the mushroom Gyromitra esculenta (Simons, 1971~; 100,000 of these
people reside in the United States (S. Miller, personal communication).
The literature contains more than 500 reports of poisonings resulting
from the ingestion of this mushroom. Some of these incidents were
fatal (Franke et al., 1967~.
Experimental Evidence: Carcinogenicity. Eleven hydrazines and
hydrazones have been identified in G. esculenta. Studies have been
conducted to determine the carcinogenicity of many of these compounds.
Continuous administration of 0.0078% N-methyl-N-formylhydrazine
(MFH) in drinking water to 6-week-old outbred Swiss mice for life pro-
duced tumors of the liver, lung, gallbladder, and bile duct. A higher
dose (0.0156% MFH) given under identical conditions had no tumorigenic
effect, since it proved too toxic for the animals (Toth and Nagel,
1978~. Subsequently, the carcinogenicity of MFH was confirmed in mice
(Toth and Patil, 1980, 1981) and in Syrian hamsters (Toth and Patil,
1979~.
Acetaldehyde methylformylhydrazone, the main ingredient of G. escu-
lenta, was administered to Swiss mice in propylene glycol in 52 weekly
intragastric instillations at 100 ~g/g bw (Toth et al., 1981~. The
treatment induced tumors of the lungs, preputial glands, forestomach,
and clitoral glands.
Drinking water solutions of 0.001% hydrazine, 0.01% methylhydrazine,
and 0.001% methylhydrazine sulfate were administered continuously to 5-
and 6-week-old randomly bred Swiss mice for their lifetimes. Hydrazine
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A.
242 DIET, NUTRITION, AND CANCER
and methylhydrazine sulfate significantly increased the incidence of
lung tumors in Swiss mice, whereas methylhydrazine enhanced the
development of this neoplasm by shortening its latent period (Toth,
1972).
A 0.01% solution of methylhydrazine was administered daily in the
drinking water of 6-week-old randomly bred Syrian golden hamsters for
the remainder of their lifetimes. The treatment produced malignant
histiocytomas of the liver and tumors of the cecum (Toth and Shimizu
1973).
Experimental Evidence: Mutagenicity. _-Methyl-N-formylhydrazine,
which is present in G. esculenta, was mutagenic only in S. typhimurium
TA1537 without activation and had no DNA-modifying activity (Rogan et
al., in press).
Methylhydrazine was mutagenic in S. typhimurium TA1535 and TA1537.
The addition of S9 fraction activating system enhanced the mutagenicity
in both strains (Rogan et al., in press). The DNA modifying activity
was observed earlier by van Wright et al. (1977~.
Summary and Conclusions: Hydrazines
Studies have shown that some chemical constituents of the Agaricus
bisporus mushroom are carcinogenic in mice and mutagenic in bacterial
systems. One constituent has also been shown to be carcinogenic in ham-
sters. But the findings of these studies are not sufficient for conclu-
sions to be drawn concerning the risk to humans.
Some derivatives of hydrazines in the fungus Gyromitra esculenta
have proven carcinogenic in a number of organs and tissues of mice and
hamsters. Two of them were mutagenic in bacterial systems. There are
no epidemiological studies concerning the carcinogenicity of these
mushrooms in humans.
PLANT CONST ITUENTS AND METABOLITES
Pyrrolizidine Alkaloids
Pyrrolizidine alkaloids occur in many nonedible plant species,
including the genera Senecio (ragworts), Crotalaria (rattleboxes), and
Heliotropium (heliotropes), in amounts ranging from trace amounts to as
much as 5% of the dry weight. In general, members of this group that
contain a nuclear double bond alpha to an esterified carbinol are very
potent toxins in the liver and lung of rodents and certain farm live-
stock (Hirono, 1981; Hirono et al., 1979; International Agency for
Research on Cancer, 1976~.
Experimental Evidence: Carcinogenicity. Monocrotaline, retrorsine,
lasiocarpine, heliotrine, senkirkine, symphytine, and petasitenine, all
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Naturally Occurring Carcinogens 243
of which are a, S-unsaturated esters, are carcinogenic when administered
to rats orally or parenterally under conditions that permit long-term
survivals. Most frequently, tumor induction has involved multiple doses
of the alkaloids at moderate levels (e.g., a 0.01% solution of petasite-
nine in drinking water for 480 days) (Hirono et al., 1979), but low in-
cidences of tumors after long latent periods have apparently resulted
from only one or a few doses. Tumors have also been induced in rats
after the administration of plants, such as coltsfoot (Tussilago far-
fare) or comfrey (Symphytum sp.), which contain high levels of pyrrol-
izidine alkaloids. The tumors occur most frequently in the liver, but
some have developed in other tissues, including the skin and lungs.
Plants containing the pyrrolizidine alkaloids may contaminate
forages and food grains. Such contamination has resulted in acute and
chronic poisoning of livestock in some parts of the world (Schoental,
1976~. Humans may also be exposed by consuming such alkaloid-containing
plants as drugs or foods. For example, one species of comfrey (Sym-
phytum officinale) is consumed as a green vegetable in Japan (Hirono et
al., 1979)e The carcinogenic potency of some pyrrolizidine alkaloids
and their widespread occurrence have led to the suggestion that these
a,5-unsaturated esters may play a role in the induction of hepatic
cancer in humans in some parts of the world; however, there are no
reliable data to support this hypothesis.
Experimental Evidence: Mutagenicity. Retrorsine, lasiocarpine,
heliotrine, senkirkine, symphytine, and petasitenine, but not monocrota-
line, have been shown to be mutagenic in the Salmonella/microsome assay
(Hirono et al., 1979; Wehner et al., 1979; Yamanaka et al., 1979~.
Allylic and Propenylic Benzene Derivatives
Numerous allylic and propenylic benzene derivatives are present in
the essential oils of a wide variety of plants (Guenther, 1948-1952;
Guenther and Althausen, 1949), and some of these plants or their ex-
tracts are used as flavoring agents for human foods or as medicines
consumed by humans. Of the known naturally occurring allylic benzene
derivatives, safrole (l-allyl-3,4-methylenedioxybenzene), which is a
major component of oil of sassafras, and estragole (l-allyl-4-methoxy-
benzene), which is present in tarragon and anise, have been the most
comprehensively studied.
Experimental Evidence: Carcinogenicity. Safrole has induced low-
to-moderate incidences of hepatic tumors in adult rats fed at levels of
0.5% or more of the diet for as long as 2 years (International Agency
for Research on Cancer, 1976~. Both safrole and estragole induced
hepatic tumors and subcutaneous angiosarcomas within 18 months after
they were fed to adult female CD-1 mice at levels of 0.25%-0.5% for ap-
proximately 1 year (Miller _ al., 1979~. Administration of less than
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244 DIET, NUTRITION,AND CANCER
1 mg of either compound or of methyl eugenol to CD-1 or (C57BL/6 x
C3H/He)F1 male mice prior to weaning resulted in a high incidence of
hepatomas by the age of 12 months (Miller et al., 1979~.
Experimental Evidence: Mutagenicity. Safrole was mutagenic _
vitro and in the host mediated assay (Green and Savage, 1978~. However,
McCann et al. (1975), Swanson et al. (1979), and Wislocki et al. (1977)
reported that it was not mutagenic in the Ames test. It was positive
in Bacillus subtilis rec assay (Rosenkranz and Poirier, 1979) and in
Saccharomyces cerevisiae D3 (Simmon, 1979~.
Estragole was mutagenic to S. typhimurium TA100 (Swanson et al.,
1979~. Eugenol was not mutagenic to Ames Salmonella strains in vitro
and in the host-mediated assay (Green and Savage, 1978; Swanson et al.,
1979~.
Bracken Fern Toxin~s)
Bracken fern (Pteridium aquilinum) occurs widely in nature and is
consumed by humans in several parts of the world, especially in Japan
(Hirono, 1981~. For at least 30 years, it has been known that consump-
tion of this plant causes damage to the bone marrow and intestinal
mucosa of cattle, but the precise compounds) responsible for these
toxic effects have not been identified.
Epidemiological Evidence: Carcinogenicity. In a prospective cohort
study in Japan, Hirayama (1979) found a significantly higher risk of
esophageal carcinoma associated with the daily intake of hot gruel or
bracken fern every day, especially in people who ate both foods daily.
However, Howe et al. (1980) found no association between bladder cancer
and consumption of fiddlehead greens (related to bracken fern) in a
case-control study in Canada.
Experimental Evidence: Carcinogenicity. The carcinogenicity of
bracken fern was first suspected by Pamukcu in 1960, who found polyps
in the urinary bladder mucosa of cattle fed large amounts of bracken
fern for long periods (Pamukcu and Bryan, 1979~. Since that time,
ingestion of high levels of bracken fern (25% to 40% of the diet) has
been found to result in the formation of urinary bladder carcinomas in
cattle, urinary bladder carcinomas and intestinal adenocarcinomas in
rats, urinary bladder tumors in guinea pigs, pulmonary adenomas in
mice, and intestinal adenocarcinomas in Japanese quail (Evans, 1976~.
Hirono (1981) reported that the greatest concentration of the
toxin~s) is present in young plants before the fronds have uncurled,
and the carcinogenic activity of the rhizome is greater than that of
the stalk or fronds. The toxicity of the fern is reduced, but not
eliminated, by cooking.
12-11
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266 DIET, NUTRITION, AND CANCER
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Naturally Occurring Carcinogens 267
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Representative terms from entire chapter:
occurring carcinogens
