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    PATULIN

    1.  EXPLANATION

         Patulin has not been previously evaluated by the Joint FAO/WHO
    Expert Committee on Food Additives.

         Patulin is a mycotoxin produced by fungi belonging to several
    genera including  Penicillium, Aspergillus and  Byssochlamys. 
    Although patulin can occur in many molding fruits, grains and other
    foods, the major source of patulin contamination is in apples with
    brown rot, and in apple cider or apple juice.  Patulin is stable in an
    acid environment, and is not destroyed during thermal processing
    (Pohland & Allen, 1970; Scott & Somers, 1968).  Patulin toxicosis has
    been described in cattle and poultry (Camguilhem  et al., 1976;
    Schultz  et al., 1969; Lovett, 1972).

         Many of the older studies on patulin levels in fruit and fruit
    products employed methodology that lacked sufficient sensitivity.  In
    addition, positive identification of patulin has not always been
    confirmed. Based on the results of more recent surveys conducted in
    several countries, the mean patulin content of apple juice/beverage is
    estimated to be less than 10-15 g/l (based on the values of the
    positive samples and assuming that patulin is at the detection limit
    in the non-detected samples) with an overall range of less than 1 to
    250 g/l patulin and a contamination range of 7-52% in the retail
    product.  (Mortimer  et al., 1985; Anderson & Josephson, 1979).  The
    dietary intake of patulin from apple juice containing 10-15 g/l is
    estimated to range from less than 0.03 to 0.26 g/kg bw/day (less than
    l.9-3.9 g/day) for different age groups in the population, including
    children.  Because of the limited number of countries upon which these
    estimates are based they cannot automatically be applied worldwide.

         Patulin has been reviewed by IARC (1976 & 1986).

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution and excretion

         A single oral dose of 3 mg/kg bw of [14C] (0.133 mCi/mmol)
    patulin in 1mM citrate buffer was given to 17 male and 12 female
    Sprague Dawley rats that had been exposed for 41-66 weeks after birth
    to levels of 0 or 1.5 mg/kg bw of patulin in 1 mM citrate buffer.  All
    animals were fasted for 24 hours before the administration of labelled
    patulin.  Animals were placed in metabolic cages and feces, urine and
    CO2 were collected.  One or two animals of each sex from each group
    (untreated or pretreated with patulin) were sacrificed at 4, 24, 48,
    or 72 hours or 7 days after blood was collected.  Concentrations of
    patulin in erythrocytes were calculated from the difference between
    radioactivity of whole blood and serum.  Within 7 days approximately
    49% of administered radioactivity was recovered from feces, and 36%
    from urine.  Most of the excretion of label occurred within the first
    24 hours.  Approximately 1-2% of the label was recovered as 14CO2. 
    At the end of 7 days, 2-3% of the radioactivity was recovered in soft
    tissues and blood.  The major retention sites of patulin were
    erythrocytes and blood-rich organs (spleen, kidney, lung and liver)
    (Dailey  et al., 1977a).

    2.1.2  Effects on enzymes and other biochemical parameters

         Oxygen uptake stimulated by Krebs-cycle intermediates was
    reported in an abstract to be inhibited in tissue extracts from mice,
    rat and golden hamster.  Inhibition of oxygen uptake in liver
    homogenates was observed at levels of patulin as low as 0.033 mM. 
    Inhibition of oxygen uptake in heart and muscle homogenates was
    greater than in liver homogenates.  Patulin competitively inhibited
    succinate dehydrogenase in mouse liver homogenates.  The P/O ratio was
    not affected by the toxin.  In comparative studies, the golden hamster
    was more susceptible, and the rat less susceptible to patulin
    inhibition than the mouse (Hayes, 1977).

         Kidney explants from male Osborne-Mendel rats, when incubated for
    18 hours in medium containing 0.5, 0.75, or 1.0 mM of patulin
     in vitro, lost their respiratory ability as measured by conversion
    of [14C] glucose to 14 CO2.  During measurement of respiration,
    patulin was not present in the reaction mixture.  At 0.1 mM of
    patulin, respiration was increased.  Leakage of protein into the
    medium at a concentration of 1.0 mM patulin may indicate increased
    cell membrane permeability (Braunberg  et al., 1982).

         Absorption of radiolabelled glycine, alanine and lysine was
    reduced in perfused intestines of rats that had received 100 g of
    patulin intraperitoneally on alternate days for 1 month (dose
    aproximately 1.6 mg/kg bw/day).  The authors attributed this effect to

    reduced total ATPase, NaK ATPase, and alkaline phosphatase activities
    which were studied in a satellite group of rats (Devaraj  et al.,
    1982a).

         Forty-eight hours after i.p. injection of 5.0 or 7.5 mg/kg bw of
    patulin into male ICR mice, NaKATPase and MgATPase of liver, kidney
    and brain preparations were significantly inhibited.  Injection of 2.5
    mg/kg bw of patulin had no significant effect on enzyme activity.  The
    same effects were demonstrated in  in vitro studies with
    mitochondrial and microsomal fractions of liver, kidney and brain of
    ICR mice (Phillips & Hayes, 1977).

         Patulin inhibited the  in vitro activity of NaKATPase in
    microsomes prepared from mouse brain.  Activity was partially restored
    by washing.  Preincubation of patulin with dithiothreitol or
    glutathione prevented the inhibition (Phillips & Hayes, 1978).

         Patulin inhibited acetylcholinesterase and NaKATPase in cerebral
    hemisphere, cerebellum and medulla oblongata in rats treated for 1
    month with approximately 1.6 mg/kg bw/day of patulin injected
    intraperitoneally.  Concomitantly, acetylcholine levels were raised in
    these brain segments (Devaraj  et al., 1982b).

         A non-competitive and irreversible inhibition of the activity of
    alcohol dehydrogenase derived from yeast was attributed by the authors
    to patulin's ability to bind to SH-groups; the Ki was found to be
    5.0 x 10-5 M (Ashoor & Chu, 1973a).

         Non-competitive inhibition was demonstrated when patulin was
    inclubated with rabbit-muscle aldolase; the ki was 1.3 x 10-5 M.  The
    cysteine adduct of patulin was a less effective inhibitor (Ashoor &
    Chu, 1973b).

         Patulin, at a level of 4.348 mol/ml, was reported to inhibit
     in vitrothe activity of DNA-dependent RNA polymerases I and II
    prepared from rat liver nuclei by 29% and 84%, respectively (Tashiro
     et al., 1979).

         Patulin at a level of 200 g/ml inhibited  in vitro the chain
    initiation stage of RNA synthesis in rat liver nuclei (Moule & Hatey,
    1977).

         Inhibition of yeast-derived aminoacyl-tRNA synthetase by patulin
    occurs mainly by modification of sulfhydryl groups on the enzyme
    (Arafat,  et al., 1985).

         Ribonuclease H, prepared from rat liver nuclei, was inhibited by
    patulin  in vitro by 62% at a concentration of 0.324 mol/mol, and by
    47% at a concentration of 1.071 mol/ml (Tashiro  et al., 1979).

         Acid RNAse in human placental microsome and mitochondria-rich
    fractions was increased up to 1.5 times when incubated with 0.5 - 3
    mg/g placenta of patulin  in vitro (Fuks-Holmberg, 1980).

         Patulin caused a competitive inhibition of lactate dehydrogenase
    from rabbit muscle (Ki = 7.2 x 10-5 M). The presence of cysteine
    reversed the inhibitory effect of patulin on lactate dehydrogenase
    (Ashoor & Chu, 1973a).

         Liver lactate dehydrogenase was increased in 4 pregnant Sprague
    Dawley rats after exposure to 3 mg/kg bw/day of patulin in tris-
    acetate buffer, by gavage, from days 1-19 of gestation (Fuks-Holmberg,
    1980).

         Malate dehydrogenase in human placental microsome- and
    mitochondria-rich fractions was increased up to 15 times when
    incubated with 0.5 - 3 mg/g placenta of patulin  in vitro
    (Fuks-Holmberg, 1980).

         Placental GPT was depressed in 4 pregnant Sprague Dawley rats
    after exposure to 3 mg/kg bw/day of patulin in tris-acetate buffer, by
    gavage, from days 1-19 of gestation (Fuks-Holmberg, 1980).

         When white male albino mice were injected with 10 doses of 0.1 mg
    of patulin in propylene glycol on alternate days, glycogen
    phosphorylase in the liver was activated, and blood glucose levels
    increased by 60%.  These results were confirmed by studies  in vitro
    (Madiyalakan & Shanmugasundaram, 1978).

         Groups of 10 rats were fed either regular diet, diet infected
    with  Penicillium patulum, or were injected intraperitoneally with
    purified patulin (1 mg/kg bw  on alternate days) for 3 months. Fasting
    blood glucose levels were elevated and a glucose tolerance test
    revealed an elevated glucose curve and reduced insulin production. The
    authors concluded that patulin is diabetogenic (Devaraj  et al.,
    1986).

         Four days after a single intraperitoneal dose of 0, 0.5, 5.0, or
    10.0 mg/kg bw of patulin to male Fischer 344 rats, liver mixed
    function oxidases and cytochrome P450 activity were determined.
    Oxidative cleavage of phosphonothioate EPN and aryl hydrocarbon
    hydroxylase were elevated at 10 mg/kg bw.  No effect was observed on
    p-nitroanisole O-demethylase or on cytochrome P450 (Kangsadalampai
     et al., 1981).

         Patulin was reported in an abstract to induce mixed function
    oxidase in male ICR mice treated with 0.5, 1.0 or 2.0 mg/kg bw of
    patulin intraperitoneally (Siraj & Hayes, 1978).

    
    2.2  Toxicological studies

    2.2.1  Acute toxicity

                                                                                     

                                          LD50
    Species      Sex        Route       (mg/kg bw)     Reference
                                                                                     

    Mouse         M         oral        29-48          Escoula  et al., 1977
                                                       Lindroth & von Wright, 1978
                                                       McKinley & Carlton, 1980a
                  F                     46.31          Escoula  et al., 1977
                 M&F                    17             Hayes  et al., 1979
                  ?                     25             Katzman  et al., 1944

                  M         i.p.        5.7-8.17       Ciegler  et al., 1976
                                                       Escoula  et al., 1977
                                                       McKinley & Carlton, 1980a
                  F                     10.85          Escoula  et al., 1977
                 M&F                    7.6            Hayes  et al., 1979
                  ?                     4-5.7          Katzman  et al., 1944
                                                       Ciegler  et al., 1976

                  M         i.v.        8.57           Escoula  et al., 1977
                  F                     8.57           Escoula  et al., 1977

                  ?         s.c.        8-10           Katzman  et al., 1944
                  M                     10             McKinley & Carlton, 1980a

    Rat           M         oral        30.53-55.0     Escoula  et al., 1977
                                                       McKinley  et al., 1982
                  F                     27.79          Escoula  et al., 1977
                  ?                     32.5           Dailey  et al., 1977b
                 M&F                    108-118        Hayes  et al., 1979
                                                                                     

                                                                                     

                                          LD50
    Species      Sex        Route       (mg/kg bw)     Reference
                                                                                     

                  M         i.p.        4.59-10.0      Escoula  et al., 1977
                                                       McKinley  et al., 1982
    (neonate)     F                     5.70           Escoula  et al., 1977
                 M&F                    6.8            Hayes  et al., 1979
    (weanling)   M&F                    5.9            Hayes  et al., 1979
                  M         i.v.        8.57           Escoula  et al., 1977
                  M         s.c.        11.0           McKinley  et al., 1982
                  ?                     25             Katzman  et al., 1944

    Hamster       M         oral        31.5           McKinley & Carlton, 1980b
                            i.p.        10             McKinley & Carlton, 1980b
                            s.c.        23             McKinley & Carlton, 1980b
                                                                                     
    
         Acute toxicity of i.p.-administered patulin was reported to be
    reduced by simultaneous administration of another mycotoxin,
    rubratoxin B (Kangsadalampai  et al., 1981).  Toxic signs
    consistently reported in all studies were agitation, in some cases
    convulsions, dyspnea, pulmonary congestion and edema, and ulcerations,
    hyperemia and distension of the gastro-intestinal tract.  When a
    patulin/cysteine adduct was administered to mice intraperitoneally, no
    acute toxicity was observed at levels up to  150 g of patulin/mouse
    (Ciegler  et al., 1976).

    2.2.2  Short-term Studies

    2.2.2.1  Mice

         When patulin was administered by gavage in citrate buffer to
    groups of 10 male Swiss ICR mice at doses of 0, 24 or 36 mg/kg bw,
    daily or on alternate days for 14 days, body weight was depressed and
    mortality was increased in a dose dependent manner.  Histopathological
    lesions were found in the gastro-intestinal tract, which included
    epithelial degeneration, hemorrhage, and ulceration of gastric mucosa,
    and exudation and epithelial desquamation in the duodenum (McKinley &
    Carlton, 1980a).

    2.2.2.2  Rats

         When patulin was administered by gavage to groups of 10 male
    Sprague Dawley rats at doses of 28 or 41 mg/kg bw, daily or on
    alternate days for 14 days, initial loss of body weight was observed;
    animals recovered after day 4.  Mortality was increased in all treated
    groups, but no dose dependency was observed. Gross lesions were found
    in the stomach and small intestine; the gastric mucosa was reddened
    and the stomach was distended. The duodenum and jejunum were distended
    by fluid. Histopathological lesions were found in the stomach which
    consisted of ulceration of the mucosa, epithelial degeneration,
    hemorrhage, and neutrophil and mononuclear cell infiltration (McKinley
     et al., 1982).

         Drinking water containing 0, 24, 84, or 295 mg/l of patulin in
    1 mM citrate buffer was given to groups of 6 SPF RIVM:Tox (Wistar
    derived) rats for 4 weeks. Food and liquid intake were recorded three
    times per week.  Body weights were determined at the start of the
    experiment and at termination.  Urinalysis, including urine volume,
    bilirubin, and urinary protein were determined in the last week. 
    Creatinine clearance was calculated from serum and urine levels of
    creatinine.  At termination, the animals were examined
    macroscopically, and the liver, spleen, thyroid glands, brain,
    kidneys, heart, mesenteric lymph nodes, adrenal glands, thymus, testes
    and ovaries were weighed.  Histopathological examination was carried
    out on all organs and tissues of the high-dose and the control groups.
    Food and liquid intake were reduced in the mid- and high-dose animals. 
    Body weights at the high dose level were decreased. Creatinine

    clearance was lower in the high-dose animals, but no morphological
    glomerular damage was observed. In the high-dose group, fundic ulcers
    in the stomach were observed in combination with enlarged and active
    pancreatico-duodenal lymph nodes, while villous hyperemia of the
    duodenum was observed at the mid- and high-dose levels. The authors
    suggested, based on normal appearance of the adrenal glands, that the
    observed effects in the gastrointestinal tract were a direct effect of
    patulin on the tissue, which was not mediated through adrenal gland
    stimulation (stress) (Speijers  et al., 1988).

    2.2.2.3  Hamsters

         When patulin was administered by gavage to groups of 10 male
    Syrian golden hamsters at doses of 0, 16 or 24 mg/kg bw, daily or on
    alternate days for 14 days, loss of body weight was observed and
    mortality was increased in all treated groups, but no dose dependency
    was observed. Gross lesions were found in the stomach and duodenum.
    Histopathological lesions were found in the gastro-intestinal tract
    that included epithelial degeneration, hemorrhage and ulceration
    (McKinley & Carlton, 1980b).

    2.2.2.4  Monkeys

         Groups of 1 male and 1 female pigtail monkeys  (Macaca nemestrina)
    received daily doses of 0, 5, 50, or 500 g/kg bw/day of patulin for
    4 weeks. Monkeys of the highest dose group received 5 mg/kg bw/day
    patulin for 2 additional weeks.  Weekly determinations were made of
    SGOT, SAP, BUN, cholesterol, sodium and potassium as well as
    hematological parameters.  Plasma protein electrophoresis was
    performed and glucose and lipoprotein levels were determined. No signs
    of toxicity were noted, except that the monkeys receiving 5 mg/kg
    bw/day of patulin started to reject their food during the last 3 days
    of the experiment. No statistically significant differences were
    observed in any of the parameters studied (Garza  et al., 1977).

    2.2.3  Long-term/carcinogenicity studies

    2.2.3.1  Mice

         Twelve pregnant Swiss mice received 2 mg/kg bw/day of patulin in
    water containing 0.05% lactic acid twice daily by gavage for 6 days
    starting 14 days after mating. The 12 control mice received 0.05%
    lactic acid by gavage.  Mean survival time was significantly reduced
    in the patulin-treated dams, while 2 of 12 control animals and 5 of 12
    experimental animals developed tumours. Of the offspring, 8 of 43 male
    and 11 of 52 female suckling mice died in the first 6 days of life,
    with hyperemia and bleeding in the brain, lungs and skin. When these
    early deaths were excluded from the calculations, patulin did not
    affect survival time in the animals exposed in utero. No evidence of
    carcinogenicity was observed in the offspring that had been exposed
    only to patulin  in utero, (Osswald  et al., 1978).

    2.2.3.2  Rats

         Subcutaneous injections of 0.2 mg of patulin in 0.5 ml of arachis
    oil administered biweekly for 61 or 64 weeks to 2 groups of 5 male
    Wistar rats weighing 100 g at the start of the experiment was reported
    to produce local (fibro)sarcomas at the injection site in 4 of 4 and
    2 of 4 rats surviving at the time when the first tumour was observed.
    No metastases were observed, and of 3 tumours tested, only one was
    transplantable in 3 of 12 recipient rats. Control animals receiving
    arachis oil did not develop local tumours (Dickens & Jones, 1961).

         When patulin in water containing 0.05% lactic acid, was
    administered by gavage twice weekly to 50 female SPF Sprague Dawley
    rats at a dose of 1 mg/kg bw for 4 weeks, and 2.5 mg/kg bw for the
    following 70 weeks (total dose: 358 mg/kg bw of patulin), no effects
    were observed on weight gain or on survival.  No significant
    differences were observed in tumour incidence.  The occurrence of 4
    forestomach papillomas and 2 glandular stomach adenomas, as compared
    to none in the control animals, is noteworthy. The Committee noted a
    discrepancy between the reported duration of the study (64 weeks) and
    the reported duration of administration (74 weeks) (Osswald  et al.,
    1978).

         Groups of 70 FDRL Wistar rats of each sex were exposed to 0, 0.1,
    0.5, and 1.5 mg/kg bw/day of patulin in citrate buffer by gavage 3
    times per week for 24 months. The rats were derived from the F1
    generation of a 1-generation reproduction study. Mortality was
    increased in both sexes in the highest dose:  all males had died by 19
    months; 19% of females survived until termination at 24 months. Body
    weights of males were reduced in the mid- and high-dose, but for
    females body weights were comparable in all groups. No difference in
    tumour incidence was observed (Becci  et al., 1981).

    2.2.4  Reproduction studies

    2.2.4.1  Rats

         Groups of 30 Sprague-Dawley rats of each sex received doses of 0,
    1.5, 7.5, and 15.0 mg/kg bw/day of patulin in citrate buffer by gavage
    5 times per week for 7 weeks before mating. The pregnant dams were
    gavaged daily at the same levels during gestation. Half the dams were
    sacrificed on day 20 of gestation, and used for teratological
    evaluation. The remaining dams were allowed to produce the F1
    generation. Some of the F0 and F1 males were used for a dominant
    lethal experiment. Twenty-three controls and 15 low-dose animals per
    sex were continued to produce an F2 generation. One-half of the
    latter generation were again used for teratological evaluation.
    Hematology and blood chemistry examinations were performed on 10 males
    and 10 females of the F1 generation 23 days after weaning.  The only
    lesion found at necropsy of parent animals was gaseous distension of
    the gastrointestinal tract.  All treated males of the F0 generation

    had a dose-related reduction in weight gain. High mortality occurred
    at 7.5 and 15.0 mg/kg bw/day in both males and dams. Although litter
    size at 7.5 mg/kg bw/day was comparable to controls, survival of male
    progeny was severely impaired. At the 1.5 mg/kg bw/day level, pup
    growth of both sexes was reduced, and there was increased mortality
    among the F2 females. No significant alterations were found in the
    hematology and blood chemistry levels in selected animals of the F1
    generation (Dailey  et al., 1977b).

         Groups of 50 FDRL Wistar rats of each sex were exposed to 0, 0.1,
    0.5, and 1.5 mg/kg bw/day of patulin in citrate buffer by gavage for
    4 weeks before mating, and pregnant females were dosed through
    gestation and lactation. The parent generation was sacrificed after
    weaning. Body weight gain was comparable among groups. In the high
    dose group, 10 females died.  Reproductive parameters such as mating
    success, litter size, fertility, gestation, viability, and lactation
    indices, and pup weight at birth, 4 days and at weaning, were not
    statistically different among experimental groups.  Histopathological
    evaluation of grossly abnormal tissues of the F0 generation did not
    show any effects of patulin treatment. The F1 generation was used for
    a 2-year toxicity/carcinogenicity study (see section 2.2.3.2) (Becci
     et al., 1981).


        2.2.5  Special studies on genotoxicity

    Results of genotoxicity assays on Patulin

                                                                                               

                                           Concentration
    Test System        Test Object         of Patulin           Results      Reference

                                                                                               

    DNA synthesis      T.pyriformis        3.2 g/ml            Positive     Burger  et al.
    retardation                                                              1988

    DNA synthesis      AWRF cells          1,2,4&8 g/ml        Positive     Stetina &
    retardation        CHO cells           0.25, 0.5, l,2,4                  Votava, 1986
                                           g/ml

    DNA breakage       ColE1 plasmid       0.25, 0.5, 1.0       Negative     Lee &
     in vitro          DNA                 & 5.0 mM             (1)          Roeschenthaler,
                       Lambda DNA          0.5, 1, 5, 10                     1986
                                           & 14 mM

    DNA breakage       E.coli              10, 20, 25 & 50      Positive     Lee &
     in vivo             D110 polA           g/ml                             Roeschenthaler,
                                                                             1986

    DNA breakage       FM3A mouse          1.0, 3.2, 10         Positive     Umeda  et al.,
                       mammary carcinoma   g/ml                             1977
                       cells

    DNA breakage       AWRF cells          2 & 10 g/ml         Positive     Stetina &
                       CHO cells           2, 8 & 10                         Votava, 1986
                                           g/ml
                                                                                               

                                                                                               

                                           Concentration
    Test System        Test Object         of Patulin           Results      Reference

                                                                                               

    Prophage           E. coli             5, 10, 25 & 50       Positive     Lee &
    induction          X8011(lambda)       g/ml                             Roeschenthaler,
                                                                             1986

    Spot test          E. coli             1 - 10 g/           Positive     Auffray &
                       K12                 assay                (2)          Boutibonnes,
                                                                             1986

    Chromotest (3)     E. coli             0.01, 0.02 &         Positive     Auffray &
                       K12 PQ37            0.05 g/ml           (No S-9)     Boutibonnes,
                                                                Negative     1987
                                                                (with S-9)

    Chromotest (2)     E. coli             0.001 - 30           Negative     Krivobok  et
                       PQ37                g/ml                              al., 1987

    Recombinogenesis   B. subtilis         20 & 100 g/         Positive     Ueno &
                       H17/M45             disc                              Kubota, 1976

    Ames test          E. coli             1 g/ml (to          Positive     Burger  et
                       M13am6H1            phage) &/or                        al., 1988.
                       phage               5 g/ml (to
                                           bacteria)

    Ames test (3,4)    S.typhimurium       0.01, 0.1, 1,        Negative     Ueno  et al., 
                       TA-98               10, 100 & 500                     1978
                       TA-100              g/plate
                                                                                               

                                                                                               

                                           Concentration
    Test System        Test Object         of Patulin           Results      Reference

                                                                                               

    Ames test (3)      S.typhimurium       0.25, 2.5, 25 &      Negative     Wehner  et
                       TA-98               250 g/plate                       al., 1978
                       TA-100
                       TA-1535
                       TA-1537

    Ames test (3)      S.typhimurium       0.1, 1, 10 & 100     Negative     Kuczuk  et
                       TA-1535             g/plate                           al., 1978
                       TA-1537
                       TA-1538

    Ames test (5)      S.typhimurium       5, 10, 20 & 30       Negative     von Wright &
                       TA-98               g/plate                          Lindroth, 1978
                       TA-100

    Ames test (3,5)    S.typhimurium       <0.0065 umoles/      Negative     Bartsch  et
                       TA-100              plate                              al., 1980
                       TA-1538

    Host mediated      S.typhimurium       3x <500 g           Negative     Gabridge &
    assay in           G46                 i.m.                              Legator, 1969
    Swiss albino
    mice

    Host mediated      S.typhimurium       10 & 20 mg/kg        Negative     von Wright &
    assay in           TA-1950             bw, gavage                        Lindroth, 1978
    male NMRI mice     TA-1951

    Reverse            S. cerevisiae       50 (No S-9) &        Negative     Kuczuk  et
    mutagenesis (3)    D-3                 100 (with S-9)                     al., 1978
                                           g/plate

                                                                                               

                                                                                               

                                           Concentration
    Test System        Test Object         of Patulin           Results      Reference

                                                                                               

    Forward            S. cerevisiae       10, 25, 50 & 75      Positive     Mayer &
    mutagenesis        (haploid)           g/ml                             Legator, 1969

    Forward            FM3A mouse          0.032, 0.1 &         Positive     Umeda  et al.,
    mutagenesis        mammary carcinoma   0.32 g/ml                        1977
    (8-azoquanine      cells
    resistance)

    Unscheduled        Primary ACI rat     60 & 600 M          Negative     Mori  et al.,
    DNA synthesis      hepatocytes                                           1984
    induction           in vitro
                       Primary C3H         65 & 650 M          Negative     Mori  et al.,
                       mouse hepatocytes                                     1984
                        in vitro

    Chromosome         FM3A mouse          0.032, 0.1 &         Positive     Mori  et al.,
    aberration         mammary carcinoma   0.32 g/ml                        1984
    induction          cells

    Chromosome         Chinese hamster     1, 2.5, 5 & 10       Positive     Thust  et al.,
    aberration         V79-E cells         M                   (no S-9)     1982
    induction (3)       in vitro                                  Negative
                                                                (with S-9)

    Chromosome         Human               3.5 M               Positive     Withers,
    aberration         leucocytes                                            1966
    induction           in vitro
                                                                                               

                                                                                               

                                           Concentration
    Test System        Test Object         of Patulin           Results      Reference

                                                                                               

    Sister chromatid   Chinese hamster     1, 2.5, 5 & 10       Negative     Thust  et al.,
    exchange           V79-E cells         M                                1982
    induction (3)       in vitro

    Sister chromatid   Primary Chinese     0.5,1 & 2            Positive     Kubiak &
    exchange           hamster cells       g/ml                             Kosz-Vnencha k,
    induction           in vitro                                               1983

    Sister chromatid   Human peripheral    0.075, 0.10,         Weakly       Cooray  et
    exchange           blood               0.20 & 0.30          positive      al., 1982
    induction          lymphocytes         g/ml                at 0.10 &
                        in vitro                                  0.20 g/ml

    Cell cycle         Primary Chinese     0.5, 1 & 2           Positive     Kubiak &
    retardation        hamster cells       g/ml                             Kosz-Vnenchak,
                        in vitro                                                1983

    Cell cycle         Human peripheral    0.075 & 0.30         Positive     Cooray  et
    retardation        blood lymphocytes   g/ml                at 0.30       al., 1982
                        in vitro                                  g/ml

    Chromosome         Chinese hamster     2 x 20 mg/kg         Positive     Korte  et
    aberration         bone marrow         bw gavage            (6)           al., 1979
    induction          cells  in vivo

    Chromosome         Chinese hamster     2 x 1, 10 &          Positive     Korte, 1980
    aberration         bone marrow         20 mg/kg bw          >10 mg/kg
    induction          cells  in vivo        gavage
                                                                                               

                                                                                               

                                           Concentration
    Test System        Test Object         of Patulin           Results      Reference

                                                                                               

    Chromosome         Chinese hamster     2 x 10 & 20          Positive     Korte &
    aberration         bone marrow         mg/kg bw             dose         Ruckert, 1980
    induction          cells  in vivo                             response

    Sister chromatid   Chinese hamster     2 x 1, 10 &          Negative     Korte, 1980
    exchange           bone marrow         20 mg/kg bw
    induction          cells  in vivo        gavage

    Cell cycle         Human peripheral    0.075 & 0.30         Positive     Cooray  et
    retardation        blood lymphocytes   g/ml                              al., 1982
                        in vitro

    Dominant           ICR/Ha Swiss        0.1 & 0.3 mg/kg      Negative     Epstein  et
    lethal assay       Mice                bw, i.p.                           al., 1972

    Dominant           Sprague-Dawley      1.5  mg/kg bw        Negative     Dailey  et
    lethal assay       rats                5x/wk x 10-11                      al., 1977b
                                           wk gavage

    Dominant           Texas ICR x         3.0 mg/kg bw,        Negative     Reddy  et
    lethal assay       Sprague Dawley      i.p.                               al., 1978
                       Sch:Ars(CF1)f
                                                                                               

    (1)  Positive when CuCl2 & NADPH were added
    (2)  Both with and without S-9 fraction (source not specified)
    (3)  Both with and without rat liver S-9 fraction
    (4)  Both with regular plate and preincubation methods
    (5)  Both with and without mouse liver S-9 fraction
    (6)  Effect negated if animals first given ethanol as only liquid for 9 wk prior to exposure
    

    2.2.6  Special studies on neurotoxicity

    2.2.6.1  Rats

         Groups of 25 albino rats (sex not specified) weighing 25 - 30 g
    received 0 or 100 g of patulin in propylene glycol intraperitoneally
    on alternate days (dose approximately 1.6 mg/kg bw/day) for 1 month.
    The patulin treated animals showed convulsions, tremors, impaired
    locomotion, stiffness of hindlimbs, and wagging of the head. Patulin
    inhibited acetylcholinesterase and NaKATPase in the cerebral
    hemisphere, cerebellum and medulla oblongata.  Concomitantly,
    acetylcholine levels were raised in these brain segments (Devaraj
     et al., 1982a).

    2.2.7  Special studies on teratogenicity

    2.2.7.1  Rats

         As part of a 2-generation reproduction study (see section
    2.2.4.1), offspring of 15 Sprague Dawley dams of the F1 and F2
    generation exposed by gavage to 0 or 1.5 mg/kg bw/day of patulin in
    citrate buffer were evaluated for teratological abnormalities. Patulin
    caused an increase in resorptions in the F1 litters, but this effect
    was not observed in the F2 generation. The average weight of male
    fetuses of the F2 generation was significantly less than controls. No
    increases in skeletal or soft tissue abnormalities were observed
    (Dailey  et al., 1977b).

         However, when patulin was administered i.p. to groups of 10 - 17
    pregnant Charles River CD1 rats at doses of 1.5 or 2.0 mg/kg bw/day,
    a significant decrease in average fetal body weight was observed at
    the lower dose, and at 2.0 mg/kg bw/day all implanted embryos were
    resorbed (Reddy,  et al., 1978).

         Patulin was injected into the air cell of chick eggs. It was
    reported to be embryotoxic at levels of 2.35-68.7 g/egg depending on
    the age of the embryo, and teratogenic at levels of 1-2 g/egg.
    Patulin/cysteine adducts exhibited the same toxic effects, but at much
    higher doses: 15-150 g of patulin equivalents (Ciegler  et al.,
    1976).

    2.3  Observations in man

         Patulin has been tested as an antibiotic for treatment of the
    common cold in humans. Application was through the nasal route
    (1:10,000 or 1:20,000 solutions, every 4 hours). Most of the
    information is anecdotal (Gye, 1943).  A report on a controlled trial
    failed to identify the number of patients tested, and was unclear as
    to which clinical tests were performed to support the author's
    assertion that no ill effects were observed (Hopkins, 1943).

    3.  COMMENTS

         The Commitee reviewed studies on the biochemistry and toxicology
    of patulin as well as very limited information pertaining to
    observations in humans when patulin was tested as an antibiotic for
    treatment of the common cold in humans.

         In rats, most of the administered dose was eliminated within 48
    hours in feces and urine.  Less than 2% was expired as CO2.  No other
    metabolites have been identified.  About 2% of the administered dose
    was present after 7 days, primarily associated with erythrocytes.

         Patulin has a strong affinity to sulfhydryl groups.  Patulin
    adducts formed with cysteine are less toxic than the unmodified
    compound in acute toxicity, teratogenicity, and mutagenicity studies. 
    Its affinity for SH-groups explains its inhibitory activity on many
    enzymes.

         In acute and short-term studies, patulin caused gastrointestinal
    hyperemia, distension, hemorrhage and ulceration.  Pigtail monkeys
    tolerated patulin consumption of up to 0.5 mg per kg of body weight
    per day for 4 weeks without adverse effects.

         Two reproduction studies in rats were available.  No reproductive
    or teratogenic effects were noted at levels of up to 1.5 mg/kg of
    bw/day, but there was an increase of resorptions at that level.

         An oral carcinogenicity study in rats was negative.  Short-term
     in vitro genotoxicity studies indicate that patulin is not
    mutagenic, but that it has clastogenic activity in some test systems.

         A provisional tolerable weekly intake (PTWI) for patulin of 7
    g/kg bw was set based on a no-effect level of 0.1 mg/kg bw in a
    combined reproduction/long-term/carcinogenicity study.  An additional
    long-term carcinogenicity study in a rodent species other than the rat
    is recommended for further evaluation of the toxicity of patulin.

         Data on patulin levels in apple juice, a food that is often
    consumed by children, were available.  In this group of the population
    and based on surveys in limited areas of the world a maximum intake of
    0.26 g/kg bw/day has been estimated.  However, occasional samples of
    apple juice can be heavily contaminated and therefore efforts should
    be made to avoid unnecessary exposure to this mycotoxin by adherence
    to good manufacturing practices in which rotted or mouldy fruit are
    not used.  This should reduce dietary exposure to levels below the
    PTWI.  The Committee urged the application of such practices.

    4.  EVALUATION

    Level causing no toxicological effect

         Rat: 0.1 mg/kg bw/day

    Estimate of Provisional Tolerable Weekly Intake

         7 g/kg bw

    Further work or information desirable

         A long-term/carcinogenicity study in a rodent species other than
    the rat.

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    See Also:
       Toxicological Abbreviations
       Patulin (WHO Food Additives Series 35)
       PATULIN (JECFA Evaluation)
       Patulin (IARC Summary & Evaluation, Volume 10, 1976)
       Patulin (IARC Summary & Evaluation, Volume 40, 1986)