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    OCHRATOXIN A

    First draft prepared by
    Dr Preben Olsen
    Institute of Toxicology
    National Food Agency, Ministry of Health, Soborg, Denmark

    Explanation
    Biological data
         Biochemical aspects
         Absorption, distribution, and excretion
         Effects on enzymes and other biochemical parameters
    Toxicological studies
         Short-term toxicity studies
         Long-term toxicity/carcinogenicity studies
         Special studies on the mate reproductive system
         Special studies on embryotoxicity/teratogenicity
         Special studies on genotoxicity
         Special studies on immune response
         Observations in humans
    Comments
    Evaluation
    References

    1.  EXPLANATION

         Ochratoxin A is a mycotoxin produced by a variety of species of
    the genera  Aspergillus and  Penicillium. It is found mainly in
    cereal and cereal products, some pulses, coffee, cocoa, figs, nuts and
    coconut products, but can also occur in meat and dairy products
    derived from animals exposed to ochratoxin A-contaminated feedstuffs.

         Ochratoxin A was first evaluated at the thirty-seventh meeting of
    the Committee (Annex 1, reference 94), when a provisional tolerable
    weekly intake (PTWI) of 112 ng per kg of body weight was established.
    The assessment was based on the deterioration of renal function in
    pigs, for which the lowest-observed-effect level was 0.008 mg/kg/
    bw/day (a no-effect level was not observed). A safety factor of 500
    was used in deriving the tolerable intake of ochratoxin A. At that
    time the Committee recommended that efforts should be made to
    highlight the need tor ensuring proper storage conditions for grain
    and grain products. Furthermore, appropriate ochratoxin A residues
    should be monitored to obtain better estimates of dietary exposure and
    to identify populations at greater risk with a view to implementing
    preventive measures. The Committee also encouraged further studies
    aimed at elucidating the role of ochratoxin A and other mycotoxins in
    nephropathy in pigs and humans, the mechanism of induction of tumours,
    and the role of phenylalanine in antagonizing the adverse effects of
    ochratoxin A.

         In view of the increasing number of reports on the occurrence of
    ochratoxin A in food commodities in several countries, the Committee
    was asked to re-evaluate this substance. Ochratoxin A has been
    evaluated by the IPCS (1990) and IARC (1993).

         Since the last review additional data have become available and
    are summarized and discussed in the following monograph addendum.

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution, and excretion

         Inhibition of the microorganisms in the lower GI tract by
    neomycin caused reduced hydrolysis of ochratoxin A to the non-toxic
    ochratoxin alpha, and increased blood levels of ochratoxin A of rats
    (Madhystha  et al., 1992).

         Whole body autoradiography using intravenous injection of
    14C-ochratoxin A to rats resulted in the following distribution
    after 24 h (in decreasing order of concentration): lung, adrenal
    medulla, skin, liver, myocardium, kidney, salivary gland, adrenal
    cortex, muscle, gastric mucosa, and bone marrow (Breitholtz-
    Emanuelsson  et al., 1992).

         In feeding studies in hens, ochratoxin A was not found in eggs
    (Krogh  et al., 1976). In another study, it was found in eggs when
    hens were fed large amount of ochratoxin A (10 mg/kg bw) (Juszkiewicz
     et al., 1982). A study on tissue distribution of 14C-ochratoxin A
    in laying Japanese quail, demonstrated specific retention of
    unidentified radioactivity as a ring-shaped deposition in eggs,
    indicating that the toxin could be deposited over a short time period
    (Fuchs  et al., 1988).

         Egg-laying Japanese quail were given single oral doses of 0, 1, 5
    or 20 mg/kg bw ochratoxin A. Six hours following administration, the
    concentrations of ochratoxin A were 13 and 34 g/kg in abdominal yolks
    of birds given 5 and 20 mg/kg bw ochratoxin A, respectively.
    Ochratoxin A was still found in abdominal yolks on day 4 after
    ochratoxin A administration, and the mean ochratoxin A concentration
    in abdominal yolks was 10-fold higher than in whole eggs. No
    ochratoxin A was found in eggs of birds given 1 mg/kg bw ochratoxin A
    (Piskorska-Pliszczynska & Juszkiewicz, 1990).

         Lactating rats, treated orally with single doses of up to
    250 g/kg bw ochratoxin A, excreted ochratoxin A in the milk. The
    milk/blood concentration ratios of ochratoxin A at 24 h and 72 h were
    0.4 and 0.7, respectively. A linear relationship was found between the
    concentration of ochratoxin A in the dam's milk and that in the blood
    and kidneys of the pups at 72 h. The pups blood/milk concentration
    ratio of ochratoxin A was approximately 6. At 72 h, the sucklings had
    higher levels of ochratoxin A than their dams in both blood and
    kidneys (Breitholtz-Emanuelsson  et al., 1993a).

    2.1.2  Effects on enzymes and other biochemical parameters

         When ochratoxin A was added to isolated rat renal proximal
    tubules in suspension, mitochondrial dysfunction was seen as an early
    event in the process of nephrotoxicity. Mitochondrial impairment
    apparently occurred at sites I and II of the respiratory chain.
    Although lipid oxidation occurred before cell death, it did not seem
    to be responsible for the toxic effect (Also  et al., 1991).

         Calcium homeostasis was studied in rats treated intraperitoneally
    with a single dose of 10 mg/kg bw ochratoxin A or multiple doses of
    0.5 to 2 mg/kg bw ochratoxin A. An increase in renal endoplasmic
    reticulum calcium pump activity was observed, suggesting an
    association with ochratoxin A-induced renal cytotoxicity (Rahimtula &
    Chong, 1991).

          In vitro studies using pig renal cortical explants indicated
    that ochratoxin A inhibition of macromolecule biosynthesis (protein,
    RNA and DNA) possibly was not due to impairment of cellular
    respiration (Braunberg  et al., 1992).

         The effect of ochratoxin A on phenylalanine metabolism was
    studied in isolated hepatocytes and in liver homogenates from male
    rats treated  in vivo. Both the hydroxylation of phenylalanine to
    tyrosine and the subsequent metabolism of tyrosine, as measured by
    homogenate oxidation, were inhibited when ochratoxin A, at a
    concentration of 0.12 to 1.4 mM, was incubated with isolated
    hepatocytes (Creppy  et al., 1990).

         Ochratoxin A enhanced NADPH or ascorbate-dependent lipid
    peroxidation in rat liver microsomes and NADPH-dependent lipid
    peroxidation in kidney microsomes  in vitro, as measured by
    malondialdehyde formation or oxygen uptake. It was suggested that
    ochratoxin A stimulates lipid peroxidation by complexing Fe3+ and
    facilitating its reduction. Subsequent to oxygen binding, an
    iron-oxygen complex initiates lipid peroxidation. Cytochrome P-450,
    free active oxygen species and free hydroxy radicals do not appear to
    be involved in Fe3+-ochratoxin A stimulated lipid peroxidation.
    Peroral administration of 6 mg/kg bw ochratoxin A to rats appeared to
    increase  in vivo lipid peroxidation, causing a 7-fold increase in
    ethane exhalation (Rahimtula  et al., 1988, Omar  et al., 1990).

         In  in vitro studies using pig renal cortical tissue, ochratoxin
    A and citrinin added singly or in combination at concentrations of
    10-6 or 10-3 M, did not elicit consistent or strong synergistic
    effects as measured by transport of tetraethylammonium and
    paraaminohippurate ions or protein synthesis using 3H-leucine
    (Braunberg  et al., 1994).

         The effects of the enzymes superoxide dismutase and catalase on
    ochratoxin A-induced nephrotoxicity were studied. Superoxide removes
    oxygen by converting it to hydrogen peroxide; this enzyme works in
    conjunction with catalase which removes hydrogen peroxide within
    cells. Rats were given by subcutaneous injection 20 mg/kg bw of each
    enzyme, every 48 h, 1 h before gavage with ochratoxin A (289 g/kg bw
    every 48 h), for 3 weeks. Superoxide dismutase and catalase prevented
    most of the nephrotoxic effects induced by ochratoxin A, observed as
    enzymuria, proteinuria, creatinemia and increased urinary excretion of
    ochratoxin A. The results indicated that superoxide radicals and
    hydrogen peroxide were likely to be involved in the nephrotoxic
    effects of ochratoxin A  in vivo. The authors suggested that use of
    superoxide dismutase and catalase might be considered for prevention
    of renal lesions in cases of ochratoxicosis (Baudrimont  et al.,
    1994).

         Subchronic administration of ochratoxin A to rats indicated that
    the renal proximal tubule was not the main target of ochratoxin A
    nephrotoxicity, although decreased capacity to eliminate ochratoxin A
    may possibly result in a self-enhancing effect (Gekle & Silbernagl,
    1994). The main renal effect of ochratoxin A in rats was found in the
    "postproximal" nephron as measured by reduced glomerular filtration
    rate, increased fractional water, Na+, K+ and Cl- excretion and
    an increased dependence of the osmol clearance on urine flow. In
    addition, ochratoxin A was able to block membrane anion conductance in
    canine kidney cells  in vitro (Gekle  et al., 1993).

    2.2  Toxicological studies

    2.2.1  Short-term toxicity studies

    2.2.1.1  Chickens

         Groups of 10 broiler chicken given ochratoxin A at a dietary
    concentration of 4 mg/kg for 2 months resulted in a mortality
    rate of 42.5%. When the feed was supplemented with 0.8 or 2.4%
    L-phenylalanine, the mortality rate decreased to 12.5 and 15%,
    respectively (Gibson,  et al., 1990).

    2.2.1.2  Pigs

         A total of 533 blood samples from slaughter pigs, each
    representing one herd, contained more than 2 g/ml ochratoxin A (mean
    9.4 ng/ml) in 35% of the samples analyzed. The pigs were raised on
    barley from the unusually wet crop of 1987 in Sweden. The study did
    not attempt to correlate the ochratoxin A content in feed and blood
    (Holmberg  et al., 1990).

         Blood samples obtained from 279 herds of pigs slaughtered at 9
    slaughterhouses in Sweden were analyzed for ochratoxin A. In total,
    14% of the pigs had levels of ochratoxin A > 2 ng/ml blood. The
    highest level found was 215 ng/ml blood (Hult  et al., 1992).

    2.2.2  Long-term toxicity/carcinogenicity studies

    2.2.2.1  Rats

         Groups of Fischer F344/N rats (80/sex/group) were administered
    ochratoxin A by gavage in corn oil at 0, 21, 70 or 210 g/kg bw/day, 5
    days/week for 103 weeks. Renal carcinomas were found in 16/51 male
    rats dosed with 70 g/kg bw/day and in 30/50 dosed with 210 g/kg
    bw/day; no carcinomas were found in the lower dose groups. In female
    rats, renal carcinomas were less common with 0/50, 1/50 and 3/50
    animals showing carcinomas at low, mid and high dose. Renal adenomas
    were found in all groups of male rats, increasing in frequency with
    increasing doses. In the female rats, renal adenomas were only found
    in the two highest dose groups. Fibroadenomas in the mammary gland
    were found in 45-56% of treated female rats, a significantly higher
    percentage than in the control group (NTP, 1989; Annex 1, reference
    94).

    2.2.3  Special studies on the male reproductive system

         An  in vitro study using isolated testis interstitial cells of
    gerbils indicated that ochratoxin A inhibited testosterone secretion
    (Fenske & Fink-Gremmels, 1990).

         Male rats treated by gavage with 289 g/kg bw ochratoxin A every
    second day for up to 8 weeks, showed a two-fold increase in testicular
    content of testosterone, and an accumulation of premeiotic germinal
    cells as measured by increases in alpha-amylase, ALP and gamma-GT
    enzyme activities in testis homogenate. All of these effects were
    indicative of a disturbance of the spermiogenesis (Gharbi  et al.,
    1993).

    2.2.4  Special studies on embryotoxicity/teratogenicity

         Quantitative assessment of neurons and synapses was performed in
    ochratoxin A-induced microcephalic mice at 6 weeks of age. The mice
    were derived from pregnant females treated intraperitoneally with 3 mg
    ochratoxin A/kg bw on day 10 of gestation. The somatosensory cortices
    of treated mice had fewer synapses per neuron compared to controls
    indicating reduced dendritic growth (Fukui  et al., 1992).

         Prechondrogenic mesenchymal cells from the limb buds of 4-day
    chick embryos were cultured together with ochratoxin A for 6 days.
    Ochratoxin A inhibited the accumulation of cartilage proteoglycans and
    general protein synthesis in a dose-related manner (Wiger & Stormer,
    1990).

         Rat embryos explanted on day 10 of gestation were cultured in a
    medium containing ochratoxin A at concentrations of up to 300 g/ml.
    Dose-dependent reductions in protein and DNA content of embryos were
    seen.

         Induced malformations included hypoplasia of telencephalon,
    stunted limb bud development and decreased size of mandibular and
    maxillary bones. Cellular necrosis of mesodermal and neuroectodermal
    structures was observed (Mayura  et al., 1989).

    2.2.5  Special studies on genotoxicity

         Treatment of mice with oral doses of 0.6, 1.2 or 2.5 mg/kg bw
    ochratoxin A caused formation of DNA adducts in the kidney and to a
    less extent in the liver and spleen. The adducts were measured after
    24, 48, and 72 h by use of a modified 32P-postlabelling method
    (Pfohl-Leszkowicz  et al., 1991).

         The frequency of SCE was increased in human peripheral
    lymphocytes, and mutagenic effect was induced in  Salmonella TA1535,
    TA1537, TA1538, TA98, and TA100 that had been incubated in the
    presence of conditioned medium derived from hepatocytes exposed to
    ochratoxin A (Hennig  et al., 1991).

         Significantly increased number of chromosomal aberrations in
    lymphocytes of patients with Balkan endemic nephropathy were found in
    comparison to healthy human subjects. Similar numerical and structural
    aberrations were seen in chromosomes of lymphocyte cultures from
    healthy donors that had been incubated  in vitro with ochratoxin A.
    Aberrations of the X chromosome were significantly more frequently
    involved than any single autosome in lymphocytes from patients with
    Balkan endemic nephropathy and in lymphocytes treated  in vitro with
    ochratoxin A. The authors concluded that the observation of sex-linked
    chromosome aberration of the X chromosome, and never the Y chromosome,
    may be associated with the often observed prevalence of females among
    Balkan endemic nephropathy patients in endemic regions (Manolov
     et al., 1991).

         Several DNA adducts with the same RF values as those obtained
    from mouse kidney after treatment with ochratoxin A were detected in
    tumorous tissue from three kidneys and five bladders of Bulgarian
    patients. In comparison, no DNA adducts were detected in 3
    non-malignant kidney collected from 3 French human subjects
    (Pfohl-Leszkowicz  et al., 1993).

         The SOS-DNA repair-inducing activity of ochratoxin A and of
    structurally related compounds in  E. coli strains suggested an
    ochratoxin A-derived free radical rather than reduced oxygen species
    as the genotoxic intermediate(s) in bacteria (Malaveille  et al.,
    1991).

         Ochratoxin A, administered orally to mice for 45 days at dietary
    doses of 1 g/kg bw/day, induced chromosome abnormalities and a
    decrease in the number of spermatocytes. Dietary supplementation with
    vitamin C at a concentration equivalent to the human therapeutic dose
    (10 mg/kg bw/day), significantly minimized the adverse effects of
    ochratoxin A (Bose & Sinha, 1994).

         Similar adverse effects were observed when ochratoxin A was
    administered to mice at an oral dose of 1 g/kg bw/day for 14 days.
    The genotoxic effects were substantially reduced by concurrent oral
    administration of 132 IU vitamin A/kg bw/day (Kumari & Sinha, 1994).

         Ochratoxin A, ochratoxin a and seven structurally related
    substances were assayed for SOS-DNA repair inducing activity in
     E. coli strain PQ37. The results indicated that the presence of
    chlorine at C-5 appeared to be one determinant of genotoxicity.
    Furthermore, the results again implicated an ochratoxin A-derived free
    radical rather than reduced oxygen species as the genotoxic
    intermediate(s) in bacteria (Malaveille  et al., 1994).

    2.2.6.  Special studies on immune response

         Immunosuppression was observed in chicken fed diets containing
    0.5 or 2 mg ochratoxin A/kg of feed for 21 days. Compared to controls,
    treated animals had reduced total serum protein, lymphocyte counts,
    weights of thymus, bursa of Fabricius and spleen (Singh  et al.,
    1990).

    2.3  Observations in humans

         The clinical picture of Balkan endemic nephropathy was
    characterized by progressive hypercreatininaemia, uraemia,
    normochromic anaemia, hypertension and edema (Radovanovic, 1991;
    Tanchev & Dorossiev, 1991). Pathologically, the disease was described
    as a bilateral, non-inflammatory, chronic nephropathy, in which the
    kidneys were much reduced in size and weight. Diffuse cortical
    fibrosis extending into the corticomedullary junction, hyalinized
    glomeruli and severely degenerated tubules were seen (Vukelic  et al.,
    1991).

         Mycotoxic nephropathy in pigs (Krogh, 1978) was not apparent in
    Balkan nephropathy endemic areas in Yugoslavia, raising questions
    about the role of ochratoxin A in the etiology of Balkan nephropathy
    (Mantle  et al., 1991).

         An unidentified nephrotoxin produced by  Penicillium
    aurantiogriseum, which causes persistent renal histopathological
    changes in rats, has been suspected of playing an important role in
    Balkan endemic nephropathy (Mantle  et al., 1991).

         Serum samples collected in Yugoslavia during 1979 from
    inhabitants of villages affected by Balkan endemic nephropathy more
    frequently contained ochratoxin A (1-100 ng/ml, one sample with
    1800 ng/ml) than those from control villages (1-5 ng/ml). Of the 1553
    samples of foodstuffs locally produced in the endemic area during
    1972-1978, 10.3% contained ochratoxin A at levels of 2-140 g/kg.
    (Plestina  et al., 1990).

         Thirty-eight out of 297 human subjects from three districts in
    Sweden showed content of ochratoxin A in plasma varying from 0.3 ng/ml
    to 6.7 ng/ml, the highest level being observed in one district. Based
    on data on the average concentrations of ochratoxin A in human plasma
    combined with data on the plasma clearance for ochratoxin A in
    different animal species, a calculated daily intake of ochratoxin A in
    the range of 0.03 to 0.35 ng/kg bw in humans was suggested.
    (Breitholtz  et al., 1991).

         A survey in Sweden showed that 23/40 human milk samples contained
    ochratoxin A at concentrations of 10-40 ng/litre. Thirty-nine blood
    samples from identical milk donors were all positive for ochratoxin A
    at levels of 90-940 ng/litre. The study did not include a correlation
    between levels of ochratoxin A in milk and diet (Breitholtz-Emanuelsson
     et al., 1993b).

         Nine out of 50 samples of human milk collected from different
    areas in Italy during 1989-90 contained ochratoxin A at concentrations
    of 1.7-6.6 ng/ml. The survey did not include estimates of ochratoxin A
    in the diets (Micco  et al., 1991).

         A total of 152 urine samples collected from patients with Balkan
    endemic nephropathy or urinary tract tumours and from control families
    were analyzed. Ochratoxin A (5-604 ng/l) was detected in about 33% of
    samples, more often in endemic villages than in non-endemic ones. The
    highest levels were detected in patients with Balkan endemic
    nephropathy or urinary tract tumours. 4-Hydroxyochratoxin A, a
    regularly observed metabolite of ochratoxin A in rats, was not
    detected (Castegnaro  et al., 1991).

         The mean concentration of ochratoxin in human serum samples from
    65 healthy subjects in Italy was 0.5 ng/ml, in comparison to 1.4 ng/ml
    in serum from 28 hospitalized patients treated by dialysis for
    impaired kidney function. The difference was statistically significant
    (Breitholtz-Emanuelsson  et al., 1994).

         Surveys conducted in 1986, 1989 and 1990 in Bulgaria showed
    that ochratoxin A was found, more frequently and at higher levels,
    in blood from patients with urinary tract tumours and/or Balkan
    endemic nephropathy than in blood samples from unaffected subjects
    (Petkova-Bocharova & Castegnaro, 1991).

         A survey in Yugoslavia during 1986-1990 showed that the frequency
    of urinary tract tumours was higher among inhabitants of Balkan
    nephropathy endemic areas (population, 10346) compared to non-endemic
    areas (population, 98 713) (Ceovic  et al., 1991).

         Results from a case-control study in patients with Balkan endemic
    nephropathy or urinary tract tumours and healthy human subjects from
    endemic and non-endemic areas, indicated a genetic predisposition to
    develop Balkan endemic nephropathy, as the ability of patients to
    metabolize ochratoxin A correlated to human phenotypes of debrisoquine
    metabolism (Nikolov  et al., 1991).

    3.  COMMENTS

         Since the last review a number of toxicological studies have been
    conducted on ochratoxin A, including investigations on epidemiology,
    genotoxicity and nephrotoxicity. Although the results of these studies
    are important for understanding the biological effects of ochratoxin
    A, the Committee did not consider that they justified any change in
    the basis on which the previous assessment of the tolerable intake of
    ochratoxin A was made. In addition, the Committee confirmed that
    nephrotoxicity was the most sensitive effect of ochratoxin A and that
    the increased incidence of both benign and malignant tumours seen in
    the rat occurred at higher doses.

    4.  EVALUATION

         The Committee reconfirmed the PTWI established at the
    thirty-seventh meeting, rounded it off to 0.1 g/kg bw, and
    reiterated its request for further studies on ochratoxin A.

         Grain should be stored under suitable conditions to keep
    levels of ochratoxin A to a minimum.

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    See Also:
       Toxicological Abbreviations