CURRENT AWARENESS DOCUMENT
TRICHOTHECENE-TYPE, LYSERGIC ACID RELATED AND OTHER MICROB10AL
CARCINOGENS OF DIVERSE CHEMICAL STRUCTURES
CARCINOGENICITY AND STRUCTURE ACTIVITY
RELATIONSHIPS. OTHER BIOLOGICAL PROPERTIES,
METABOLISM. ENVIRONMENTAL SIGNIFICANCE.
Prepared by:
David Y. Lai, Ph.D.
Yin-Tak Woo, Ph.D., D.A.B.T,
JRB Associates/
Science Applications
International Corporation
8400 Westpark Drive
McLean, Virginia 22102
EPA Contract No. 68-02-3948
JRB Project No. 2-813-07-409
EPA Project Officer and Scientific Editor
Joseph C. Arcos, D.Sc.
Extradivisional Scientific Editor
Mary F. Argus, Ph.D.
March 1985
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5.3.1.4 Trichothecene-type, Lysergic Acid Related and Other Microbial
Carcinogens of Diverse Chemical Structures.
5.3.1.4.1 Fusarium Toxins.
Various species of Fusarium are, among other fungi, commonly found in
moldy cereal grains and are associated with numerous outbreaks of mycotoxi-
cosis in humans and livestock throughout the globe. The natural occurrence,
chemistry, toxicity and biological effects of several metabolites elaborated
by Fusarium and related fungi have been extensively studied and reviewed
(1-5).
Chemically, T-2 toxin (T2-trichothecene; fusariotoxine T2; isariotoxin)
and fusarenon X (3,7,15-trihydroxy-4-acetoxy-8-oxo-l2,13-epoxy- 4^-tricho-
thecene) (see Table XXIV), two of the Fusarium toxins which have been tested
for carcinogenicity, belong to the group trichothecenes. The trichothecenes
are a complex group of sesquiterpenoids containing the tricyclic trichothecane
skeleton. More than forty trichothecenes have been isolated as metabolites of
various fungi. All of these naturally occurring compounds contain an olefinic
double bond at the 9,10 position and an epoxy group at the 12,13 position of
the trichothecene nucleus. They are generally colorless, crystalline,
optically active and soluble in polar organic solvents. The esters of the
compounds are saponified in alkali solutions; in strong mineral acids the
12,13 epoxide is opened. Zearalenone (also known as F-2 toxin), a resorcvclio
acid lactone (see Table XXIV) is another Fusarium toxin that has been assayed
for carcinogenicity. Some physicochemical properties of T-2 toxin, fusarenon
X and zearalenone are compiled in Table XXV.
Toxicity. Like many other trichothecenes, T-2 toxin and fusarenon X are
highly toxic to mammals. The characteristic pathological changes are "radio-
mimetic" type lesions to actively dividing cells of the gastrointestinal
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Table XXIV
Fusarium Toxins Which Have Been Tested for Carcinogenic Activity
3 Q-C-CH3
CH-, 0-C-CH-,
Fusarenon X
1-2 Toxin
OH 0 CH
Zearalenone
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Table XXV
Physicochemical Properties of Some Fusariurn Toxins3
Toxin
T-2 toxin
Physical form
Colorless needles
m.p. Optical rotation
151-152°C [<*-ln6 = +15°
Solubility
Soluble in acetone, aceto-
Fusarenon X
Zearalenone
Colorless bi- 91-92°C
pyramide crystals
Colorless crystals 164-165°C
= -
nitrile, chloroform, diethyl
ether, ethyl acetate and
dichloromethane
Soluble in chloroform, ethyl
acetate, methanol and water;
insoluble in ji_-hexane and
n-pentane
At 25 C, soluble in acetone,
slightly soluble in ethanol,
methanol and dichloromethane;
sparingly soluble in aceto-
nitrile, benzene, n-hexane
and water
Summarized from IARC Monographs, Vol. 31, 1983.
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tract, spleen, bone marrow, lymph nodes, thymus, ovary and testes (6, 7).
Common symptoms in the trichothecene poisoning of humans and farm animals are
skin irritation, nausea, vomiting, neural disturbance, leukopenia and anemia
(2, 8-10). Table XXVI summarizes the I^Q values of T-2 toxin and fusarenon X
in the rat, mouse and guinea pig. Structure-activity studies showed that
reductive or hydrolytic opening of the 12,13-epoxide group results in loss of
the toxicity and biological activities of these compounds; hydrogenation of
the 9,10 double bond also lead to decreased toxicity in HeLa cells and hamster
kidney cells (4). Zearalenone is a non-steroidal estrogenic compound exhibit-
ing physiological and biochemical activities similar to the known carcinogen,
diethylstilbestrol. In experimental and field animals, zearalenone causes
atrophy of the seminal vesicles and testes, uterine wall edema and epithelial
metaplasia in the cervix and vagina (cited in ref. 11).
Mutagenicity. The mutagenic and related genotoxic potential of T-2
toxin, fusarenon X and zearalenone have been investigated in a few assay
systems (Table XXVII). Several investigators (12-14, 16-18) found no muta-
genic activity of these three Fusarium toxins in various strains of Salmonella
typhimurium with or without microsomal activation. T-2 toxin and fusarenon X
were also negative in a rec assay using mutant and parent strains of Bacillus
subtilis (19). Similarly, T-2 toxin and zearalenone did not cause higher
frequencies of mitotic crossing-over to the ade 2 locus of Saccharomyces
cerevisiae strain D3 (13). However, Nagao and coworkers (15) have reported
positive mutagenic effects of fusarenon X on strains TA100 and TA98 of S.
typhimurium in the absence of S-9 mix. This toxin also induced "petite"
mutations in the yeast assay (20) and caused clastogenic damage in mouse
lymphocytes (23), Chinese hamster V79-E cells (21) and HeLa cells (24).
Similarly, T-2 toxin has been demonstrated to induce high incidences of
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Table XXVI
Acute Toxicity of Some Fusarium Toxins
Toxin3 Species and route
T-2 toxin Rat, oral
Mouse, oral
i.p.
Guinea pig, oral
Fusarenon X Rat , oral
Mouse, oral
s .c .
i.p.
i.v.
Guinea pig, oral
i.p.
LDjjQ (mg/kg)
5.2
10.5
5.2
3.0
4.4
4.5
4.2
3.4
3.4
4.4
< 0.5
Reference
(2)
(2)
(2)
(8)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
aSee Table XXIV for structural formulas.
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Table XXVII
Mutagenic and Related Genotoxic Effects of Some Fusarium Toxins3
Toxinb
T-2 toxin
Fusarenon X
Zearalenone
Salmonella
typhimurium
- (12-14)
- (12)
+ (15)
- (12-14,
16-18)
Bacillus
subt ilis
- (19)
- (19)
+ (16,19)
Saccharomyces
cerevisiae
- (13)
+ (20)
- (13)
Chromosomal
aberration
+ (21,22)
+ (21,23,24)
n. t .
Unscheduled
DNA synthesis
+ (25)
n.t .
n.t.
a"+" = positive; "-" = negative; n.t. = not tested; numbers in parentheses are
references.
bSee Table XXIV for structural formulas.
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chromatic! aberrations in V79-E cells (21) and bone marrow cells (22) of the
Chinese hamster. Treatment of human fibroblasts with T-2 toxin was reported
to result in increased unscheduled DNA synthesis (25). In the _B. subt ilis rec
assay, zearalenone exhibited a positive effect (16, 19).
Teratogenicity. T-2 toxin is teratogenic in the mouse. Gross malforma-
tions involving the tail, limbs, ribs and vertebrae, exencephaly, open eyes
and retarded jaws were found in fetuses from female mice intraperitoneally
injected with 0.5, 1.0 or 1.5 mg/kg T-2 toxin on day 9, 10 or 11 of gestation
(26, 27). Fusarenon X, on the other hand, showed no teratogenic effects in
DDD mice when the animals were treated with the toxin at doses of 0.6-1.6
mg/kg or 10-20 ppm during pregnancy (28). Ruddick and associates (29) treated
groups of 10 pregnant rats with 1, 5, or 10 mg/kg zearalenone by gavage on
days 6 through 15 of gestation; various skeletal abnormalities, in a dose-
dependent fashion, were observed in the offspring. Infertility, fetal resorp-
tion, reduced litter size, and fetal malformations have also been reported in
pigs fed zearalenone in the diet (30).
Carcinogenic ity. Table XXVIII summarizes the carcinogenicity studies on
T-2 toxin, fusarenon X and zearalenone.
In 1972, a Japanese group led by Saito were the first to note in rats and
mice chronically fed rice moldy with Fusarium nivale and _F_. graminearum
several unusual tumors not seen in control animals (cited in ref. 32). How-
ever, subsequent bioassay studies with T-2 toxin did not reveal any neoplasms
in Wistar rats given the toxin in the feed at levels of 10 or 15 ppm for 12
months (32). Similarly, Marasas et al. (31) failed to detect tumors in
Holtzman rats or rainbow trout fed low doses (5 or 15 ppm to the rats and 200
or 400 ppb for the trout) of T-2 toxin for 8-12 months. Also, topical appli-
189
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Table XXVIII
Carcinogenicity of Some Fusarium Toxins
Toxin3
Species and strain
Principal organs
affected
and route
Reference
T-2 toxin Trout , rainbow
Rat, Holtzman
Rat, Wistar
Rat, Wistar-Porton
None; oral
None; oral
None; oral
Pancreas, gastro-
(31)
(31)
(32)
(33)
Rat, unspecified
Mouse, unspecified
Mouse, DDD
Fusarenon X Rat, Donryu
Mouse, DDD
Zearalenone Rat, Fischer 344/N
Mouse, B6C3FJ
intestinal tract,
brain and mammary
gland; oral
Hematopoiet ic
tissues; topical
None; topical
Multiple sites ; oral
Liver, lung ; s.c.
Liver ; oral
Cited in ref. 23
(31)
(32)
(34)
(34)
Multiple sitesc'd; oral (32, 35)
Hematopoiet ic
tissue ; s.c.
None; oral
Liver, pituitary; oral
(34)
(11)
(11)
a
See Table XXIV for structural formulas.
Low tumor incidence. Not considered by the authors to be a significant car-
cinogenic effect.
Tumor incidence not significantly higher than that of controls.
High mortality of the treated animals.
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cation of T-2 toxin to mouse skin did not initiate tumorigenesis (31).
Ohtsubo and Saito (32) administered to groups of 16 to 22 female DDD mice 0,
10 or 15 ppm T-2 toxin in the feed for 12 months. One animal with adenocar-
cinoma of the glandular stomach, one animal with angiosarcoma of the uterus,
one animal with thymoma and two animals with hepatocellular carcinoma were
found among the 10 treated mice surviving for 15 months. Although such neo-
plasms were not seen in the controls, the findings were not considered by the
authors (32) to be attributable to the compounds, because of the low
incidences.
The first indication for the carcinogenicity of T-2 toxin came from the
studies of Schoental _et_ al. (33) in 1979. These authors noted the carcino-
genic effects of T-2 toxin in groups of Wistar-Porton rats that survived for
12 to 27.5 months following the first of 3-8 monthly doses of the toxin (0.2-4
mg/kg body weight), given intragastrically; significant incidences of benign
and malignant tumors of the pancreas, stomach, duodenum, brain and mammary
gland were found in the treated animals. The results have suggested to
Schoental and coworkers (33) that the T-2 toxin is a "versatile carcinogen"
for the rat. Unpublished data of Lafarge-Frayssinet et al. (23) also indicate
that this fungal metabolite is carcinogenic toward the rat , inducing leukemia
in animals painted with the toxin on the skin of the back for an extented
period of time. Moreover, Lindenfelser _et_ _al_. (36) observed a weak promoting
effect of T-2 toxin in skin tumorigenesis by 7,12-dimethylbenz[a]anthracene in
CD-I mice.
The carcinogenic potential of fusarenon X has been tested in rats and
mice by Saito and associates (32, 34, 35). In one experiment, a group of 20
male Donryu rats was administered fusarenon X (0.4 mg/kg body weight) by
gavage weekly for 50 weeks. One of the 16 animals that survived 50 weeks bore
190
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a hepatoraa; no tumors were seen in 10 controls. In another experiment, 18
rats of the same strain were given weekly s.c. injections of fusarenon X (0.4
mg/kg body weight) for 22 weeks. Of 14 treated animals surviving for more
than 52 weeks, one developed a hepatoma and one had an epidennoid tumor of the
lung. Again, none of the 10 controls bore any neoplasms (32, 34). In a more
recent study.which involved feeding groups of 25-52 Donryu rats with 3.5 or
7.0 ppm fusarenon X in the diet for 1 or 2 years, tumors of various organs
were observed. However, the tumor incidences were not significantly higher
than those of the controls. The high mortality of the treated animals in the
study renders it difficult to evaluate the carcinogenicity of this toxin (32,
35). When two groups of 16 or 18 male DDD mice were given weekly s.c. injec-
tions of fusarenon X (2.5 mg/kg body weight) for 10 or 20 weeks, one case of
leukemia (not seen in 25 controls) occurred in 13 of the mice that survived
the treatment. Again, because of the low tumor incidence and low survival
rate of the treated animals, it was uncertain to the authors (34) whether the
neoplasms were indeed induced by fusarenon X.
Schoental (37) has suspected that zearalenone may be the dietary compo-
nent that contributes to the high incidence of spontaneous tumors in some
laboratory animals in the United States. Under the bioassay conditions of the
U.S. National Toxicology Program, zearalenone is indeed carcinogenic in B6C3Fj
mice but not carcinogenic for F344/N rats (11). Groups of 50 F344/N rats and
50 B6C3Fi mice of each sex were given either a control diet or a diet contain-
ing low dose (25 ppm for rats; 50 ppm for mice) or high dose (50 ppm for rats,
100 ppm for mice) of zearalenone for 103 weeks. No chemical-related increase
in tumor incidence was found in the rats killed 1-3 weeks after the last
treatment. However, increased incidences of hepatocellular adenomas were seen
in female low-dose mice (2/49) and female high-dose mice (7/49) as compared
191
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with the controls (0/50). Moreover, the incidences of pituitary adenomas in
high-dose mice (6/44 for males; 13/42 for females) were significantly higher
than those of the controls (0/40 for males; 3/46 for females).
Metabolism and Mechanism of Action. In vivo (38) and in vitro (39-41)
metabolic studies in mammals have shown that T-2 toxin is deacetylated at the
C-4 position to give HT-2 toxin which is then converted to 4-deacetylneo-
solaniol, after hydrolytic removal of the isovaleric acid moiety at the C-8
position. Further deacetylation at the C-6 methylol side chain yields T-2
tetraol. A microsomal esterase responsible for the deacetylation has been
found in the liver and brain of rats and in the liver, kidney, brain and
spleen of rabbits (40). Deacetylation of fusarenon X at the C-4 position by
liver esterase of rats and rabbits leads to nivalenol (42). Pharmacokinetic
studies indicate that T-2 toxin (38) and fusarenon X (20) are rapidly metab-
olized and cleared from the body with short retention in the tissues and body
fluids. Zearalenone is reduced to 0{- and ff-isomers of zearalenol by hepatic
3 ^(-hydroxysteroid dehydrogenase (43, 44). Both free and conjugated (gluc-
uronic and sulfate) forms of the parent compound and the metabolites are
excreted in the urine and feces; the extent of formation and excretion of the
metabolites varies with the animal species. In humans, the predominant
metabolites in the urine are glucuronide conjugates of zearalenone and
oC-zearalenol (43). The metabolic half-life of zearalenone in the rat is
reduced by increased dietary protein (45).
The mechanism of carcinogenic action of Fusarium toxins is not known. It
is generally believed, however, that T-2 toxin and fusarenon X probably do not
require metabolic activation to exert their biological effects (see refs. 4,
23, 33). Owing to the presence of an epoxide grouping in their molecules,
they react readily with physiologically important thiol-containing enzymes,
192
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such as creatine phosphokinase, and lactate and alcohol dehydrogenases. Like
many other trichothecenes, T-2 toxin and fusarenon X bind to and disaggregate
polyribosomes, and are potent inhibitors of protein and DNA synthesis in
eukaryotes (see ref. A). T-2 toxin has been reported to induce single strand
breaks in DNA of lymphoid cells but not of liver cells of mice (23). The fact
that T-2 toxin is reactive toward thiol groups and that liver cytosol contains
glutathione transferase capable of catalyzing the conjugation of the tricho-
thecene was suggested as the reason for the absence of effect of T-2 toxin in
hepatic tissue. Fusarenon X affects membrane function and the uptake of
phosphate in Tetrahymena (46). Zearalenone mimics the physiological and
molecular action of the known carcinogen, diethylstilbestrol. It has been
shown to promote cellular proliferation and enhance the rate of protein, DNA
and RNA synthesis in uterus of mice and rats. Zearalenone, as well as its
metabolites, 3\- and K -zearalenol, compete with estradiol for cytoplasraic and
nuclear estrogen receptor sites in uterus tissue. It is possible that this
estrogenic mycotoxin might act as an epigenetic carcinogen, perturbing gene
expression by interacting with nuclear estrogen receptors.
Environmental Significance. T-2 toxin, fusarenon X and Zearalenone are
produced by a large number of Fusarium species (see Table XXIX) which infect
various agricultural commodities such as corn, wheat, oat, barley, sorghum,
straw, hay and mixed feed. These fungi occur most commonly in the midwestern
United States, Canada, Russia, eastern Europe, Finland and northern Japan,
where temperatures are low and moisture contents are high during harvest and
storage seasons. Sporadic outbreaks of mycotoxicosis in humans and farm
animals attributed to moldy food contaminated by Fusarium species have been
recorded worldwide. There is evidence showing that T-2 toxin is responsible
for the "Alimentary Toxic Aleukia (ATA)" syndrome, a fatal epidemic which
193
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Table XXIX
Some Fusarium Toxins and the Fungi of Origin
Compound
Fungi of origin
T-2 toxin
Fusarenon X
Zearalenone
Fusarium tricinctum; _F_- poae ; _F_. roseum; JR. solani ; _F_.
semi tec turn; F. laterit ium; _F. rigidosum; _F. equiset i ;
Trichothecium viride; _T_. lignorum
Fusarium nivale; F. episphaeria; F. oxysporum ;
GibbereTla zeae CF. roseum graminearum)
Gibberella zeae (Fusarium roseum graminearum); _F.
culmorum; F. equiseti ; F. gibbosum ; Jj\ laterit ium ; F.
moniliforme ; F. tricinctum; _F_. avenaceum; _F. roseum
aSummarized from IARC Monographs, Vol. 31, 1983.
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affected over 10% of the population in Orenburg, USSR, between 1942 and
1947. This fungal metabolite has also been implicated in the moldy corn
poisoning of poultry, pigs and cattle in the United States and Canada (see
refs. 1, 4). Organisms such as _F_- solani which produce T-2 toxin were
detected in moldy bean hulls that caused poisoning of horses in northern Japan
for the past several decades. Fusarenon X and nivalenol isolated from F.
nivals are believed to be associated with "red mold disease" which affected
humans, horses and sheep in Japan (see ref. 4). Apparently unaware of the
carcinogenic potential of Fusarium graminearum, which contains fusarenon X and
zearalenone and has been implicated to be carcinogenic itself (see
"Carcinogenicity" Section), two British food manufacturers have recently
planned to produce various "myco-protein" foods from this fungus (47).
5.3.1.4.2 Ergot Alkaloids.
Ergot is the sclerotium of the fungus Claviceps purpurea which grows on
many grasses and some grains, particularly rye. It contains many alkaloids
belonging chemically to various amides of lysergic acid (see Table XXX). The
most prominent constituents of ergot alkaloids are ergotamine, ergocristine,
ergokryptine, ergocornine, ergosine, ergometrine and their respective isomers
ergotaminine, ergocristinine, ergokryptinine, ergocorninine , ergosinine and
ergometrinine. Dihydroergotoxine is a mixture (1:1:1) of the dihydrogenated
derivatives (saturation of the double bond between C-9 and C-10) of ergocris-
tine, ergokryptine and ergocornine.
Ergot alkaloids are known to cause contraction of smooth muscle, parti-
cularly of the blood vessels and the uterus. Therefore, many of them or their
dihydrogenated derivatives (less toxic and having fewer side effects) have
been used in obstetrics as a uterine stimulant and for the relief of migraine
194
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Table XXX
Cheniccl Formulas and Cytogenetic Effects of Some Ergot Alkaloids and Derivatives
R
0
°W*'
Compound R R1 Cytogenetic effect
Compound
R1
Cytogenetic effectb
Lysergic acid -H -OH
Ergotamine
-H -CH2-C6H5
+ (49, 50)
Lysergide (LDS) -H -N-(C2H5)2 + (48)
Ergocristinea -CHo -CHo-C^Hc
Methysergide
-CH-j -N-CHCH2OH
H
+ (49-51) Ergokryptine3 -CH3 -CH2CH(CH3)2
Ergonetrine* -H
-N-CHCH2OH
H
+ (48)
Ergocornine3 -CH3 -CH(CH3)2
Ergosine3 -H -CH2CH(CH3)2
Dihydroergo-
toxinec
+ (49-51)
a Ergot alkaloids derived from Claviceps purpurea.
Symbol: "+" = positive effect; numbers in parentheses are references.
c Representing a 1:1:1 mixture of the dihydro derivatives (saturation of the double bonds between C-9 and C-10) of
ergocristine, ergokryptine and ergocornine.
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headache. Acute toxic effects of ergot poisoning include diarrhea, thirst,
tachycardia, confusion and coma. "Ergotism," the poisoning by chronic inges-
tion of rye contaminated with ergot, is characterized by CNS symptoms, gastro-
intestinal disturbances and necrosis of the extremities due to constriction of
the musculature of arterioles.
The cytogenetic effects of ergot derivatives have been studied in several
assay systems. Negative findings were reported for dihydroergotoxine, ergot-
araine and methysergide in the micronucleus test in the bone marrow of mice and
Chinese hamsters (52). Chromosome damage was not detected either in bone
marrow cells of mice or of hamsters exposed to the three compounds (53, 54).
However, Roberts and Rand (49) found that, at high doses, dihydroergotoxine,
ergotamine and methysergide induce chromosomal aberrations in human lymphocyte
cultures in vitro. Albeit to a lesser extent, these ergot derivatives also
produce chromosome damage in bone marrow cells of mice in vivo (50). Di-
hydroergotoxine and methysergide, but not ergotamine, exhibit weak dominant
lethal effects in the mouse (51). Similarly, ergometrine and lysergide cause
chromosomal abnormalities in human lymphocytes in vitro (48). The structures
of ergot derivatives which display chromosome damaging properties are shown in
Table XXX.
The teratogenic and carcinogenic activities of ergot alkaloids have not
been evaluated. However, one of the ergot derivatives, lysergide, has been
suspected to be a teratogen and carcinogen toward humans (55). In 1942,
Nelson and coworkers (56) fed crude ergot to groups of Osborne-Mendel rats for
2 years and observed multiple tumors on the ears in 24% (9/38) of rats at a 2%
dosage, and in 61% (23/28) of rats at a 5% dosage. The tumors were histologi-
cally identified as neurofibromas. There has been no other reports on the
carcinogenicity of ergot alkaloids since; the exact component(s) of the crude
ergot responsible for the tumor induction is still unknown.
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5.3.1.4.3 Other Microbial Toxins.
Although only a small number of microbial products have so far been
discovered to be carcinogenic, it is doubtless that many more natural carcino-
gens among microbial metabolites will come to light if more of them are tested
in proper bioassay systems for carcinogenicity. In fact, the genotoxic activ-
ity of a considerable number of mycotoxins has been shown in several short-
term assays. Many of these mutagenic (and/or teratogenic) mycotoxins are
structurally related to the aflatoxins, to rugulosin, luteoskyrin, fusarium X,
T-2 toxin and other known carcinogens (see refs. 57-61). Recently, teleo-
cidin, a product isolated from Streptomyces, and its hydrogenated derivative
dihydroteleocidin B, have been demonstrated to be potent promoters of mouse
skin carcinogenesis (62-64). Like many other tumorigenesis promoters,
teleocidin blocks intercellular communication between Chinese hamster V79
cells (65). Rifampicin, a semi-synthetic derivative of rifamycin antibiotics
produced by the fermentation of Streptomyces mediterranei, increases signi-
ficantly the incidence of hepatomas in C3Hf female mice after oral administra-
tion (66). A single i.v. dose of 15 mg/kg marcellomycin, a new anthracycline
antitumor antibiotic extracted from Actinosporangium sp. and structurally
similar to adriamycin and daunomycin, induces mammary tumors in 9 of 20 female
Sprague-Dawley rats (67). The structures of teleocidin, rifampicin and mar-
cellomycin are shown in Table XXXI.
In 1965 Blank and coworkers (68) tested a series of fungal extracts for
carcinogenic activity. Extracts of several species of fungi pathogenic for
humans showed carcinogenic activity in Swiss Webster mice by subcutaneous
injection. Increased incidences of sarcomas, leukemia and lung tumors were
observed in mice that survived for 6 months following 3 weekly injections (for
4 weeks) of extracts of Candida albicans, Candida parapasilosis,
196
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Table XXXI
Structural Formulas of Teleocidin, Rifampicin and Marcellotnycin.
CH = CH2
Teleocidin
HO
CH3COO
N-CH3
Rifampicin
COO.CH-
H,C
HO
^~7 ^o-,
Z^jr-^/
I OH
0
OH
Marcellomycin
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Scopulariopsis brevicaulis, Epidermophyton floccosum, Microsporum (3 species)
or Trichophyton (6 species). The chemical nature of the extracts, however,
has not been established.
As discussed in Section 5.2.1.3 of Volume IIIA, several hydrazo compounds
present in the edible mushrooms Agaricus bisporus and Gyromitra esculenta are
carcinogenic in rodents. Recent research has shown that A-(hydroxymethyl)-
benzenediazonium ion (tetrafluoroborate) present in Agaricus bisporus is also
carcinogenic (69, 70), using mice as the test species.
Ethionine, the ethyl analog of the amino acid, methionine, is produced by
Escherichia coli and by several other bacterial and fungal species (71). The
hepatocarcinogenicity of ethionine was a topic in a previous volume of this
series (see Section 5.2.1.5, Vol. IIIA).
197
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REFERENCES TO SECTION 5.3.1.4
1. Ueno, Y.: Trichothecenes: Overview Address. In: "Mycotoxins in
Human and Animal Health" (J.V. Rodericks, C.W. Hesseltine, and M.A.
Mehlman, eds.), Pathotox, Park Forest South, Illinois, 1977, p. 189.
2. Sato, N. and Ueno, Y.: Comparative Toxicities of Trichothecenes.
In: "Mycotoxins in Human and Animal Health" (J.V. Rodericks, C.W.
Hesseltine, and M.A. Mehlman, eds.), Pathotox, Park Forest South,
Illinois, 1977, p. 295.
3. Tamm, C.: Chemistry and Biosynthesis of Trichothecenes. In: "Myco-
toxins in Human and Animal Health" (J.V. Rodericks, C.W. Hesselt'ine,
and M.A. Mehlman, eds.), Pathotox, Park Forest South, Illinois, 1977,
p. 209.
4. Busby, W.F. and Wogan, G.N.: Trichothecenes. In: "Mycotoxins and
N-Nitroso Compounds: Environmental Risks" (R.C. Shank, ed.), Vol. II,
CRC Press, Boca Raton, Florida, 1981, p. 30.
5. IARC: "Some Food Additives, Feed Additives and Naturally Occurring
Substances," IARC Monographs on the Evaluation of the Carcinogenic Risk
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