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







                                      187

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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
                                      188

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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.






                                      195

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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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