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OCHRATOXINS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) The ochratoxins are fungal toxins derived primarily from Aspergillus ochraceus and Penicillium viridicatum. Ochratoxin A is commonly found on grains and corn, ochratoxin C is seldom found in these products. Ochratoxin A is the most toxic.
    B) Ochratoxin A has been found in human food and blood, as well as animal feed. There is great variation on the content in food, depending on environmental factors.

Specific Substances

    A) OCHRATOXIN A
    1) Molecular Formula: C20-H18-CL-N-06
    2) NCI-c 56586
    3) NIOSH/RTECS AY 4375000
    4) CAS 303-47-9
    OCHRATOXIN B (Dechloro Derivative of Ochratoxin A)
    1) Molecular Formula: C20-H19-N-06
    2) NIOSH/RTECS AY 6825000
    3) WISWESSER NOTATION: T66 BVOT&J D1 IVMYVQ1R& JQ
    4) CAS 4825-86-9
    OCHRATOXIN C (Ethyl Ester of Ochratoxin A)
    1) Ochratoxin A ethyl ester
    2) Molecular Formula: C22-H22-CL-N-06
    3) CAS 4865-85-4

Available Forms Sources

    A) FORMS
    1) MANUFACTURING: Not produced commercially in the US (HSDB , 1993).
    B) SOURCES
    1) ORGANISMS RESPONSIBLE: The ochratoxins are fungal toxins derived primarily from Aspergillus ochraceus and Penicillium viridicatum (Scott et al, 1972; Van Walbeek et al, 1969; Lai et al, 1970).
    a) Penicillium strains appear to be responsible for ochratoxin A formation in colder climates such as northern Europe and Canada, while the A ochraceous group are found in more tropical or subtropical areas (IARC, 1972; Chu, 1974):
    1) Aspergillus alliaceus
    2) Aspergillus melleus
    3) Aspergillus ochraceus
    4) Aspergillus ostianus
    5) Aspergillus petrakii
    6) Aspergillus sclerotiorum
    7) Aspergillus sulphureus
    8) Penicillium commune
    9) Penicillium cyclopium
    10) Penicillium palitans
    11) Pencillium purpurescens
    12) Pencillium variabile
    13) Penicillium viridicatum
    2) FOOD SOURCES: Some toxins have been found as contaminants on corn, peanuts, storage grains (beans, barley, wheat, rye), cottonseed, peppers, other decaying plant material, and some meats like dry fish, fermented sausage, and ham (Krogh et al, 1977; Pavlovic et al, 1979; Budavari, 1989a; Chu, 1974). Ochratoxin A is commonly found on grains and corn; ochratoxin C is seldom found in these products (Fuchs et al, 1984). Ochratoxin A is the most toxic (Keeler & Tu, 1983).
    a) CORN: 2.6% of corn in France was found to be contaminated with ochratoxin A in 1974 (Krogh et al, 1977).
    b) WHEAT: Up to 2.8% of wheat in the United States was found to contain ochratoxin A in the test period 1970 to 1973.
    c) Grain (Balkan Area): From 5 to 90 mcg/kg (Krogh et al, 1977).
    d) Pork (Balkan Area): A level of 5 mcg/kg was found in about 8% of pork samples collected in one study (Krogh et al, 1977).
    3) Ochratoxin A has also been found in blood (Hult et al, 1982), as well as animal feed (Hult et al, 1984).
    4) Purity may be determined by visual exam of fluorescence on chromatograms under UV light. Microgram quantities can be determined under optimum conditions (IARC, 1972).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) DESCRIPTION: Ochratoxins are fungal toxins derived primarily from Aspergillus ochraceus and Penicillium viridicatum. Ochratoxin A is commonly found on grains and corn, but ochratoxin C is seldom found in these products. There is great variation on the content in food, depending on environmental factors. Ochratoxin A has also been found in blood.
    B) TOXICOLOGY: Ochratoxins cause an early accumulation of glycogen in the cytoplasm of rat liver cells, which decreases rapidly (within 4 hours of an administered dose). It also causes an inhibition (site unknown) of the phosphorylase enzyme system. Ochratoxin A is the most toxic. Toxicity of ochratoxins is related to the acid dissociation constant of the phenolic hydroxyl group.
    C) EPIDEMIOLOGY: Exposure is rare.
    D) WITH POISONING/EXPOSURE
    1) Ochratoxin A is a nephrotoxic agent associated with acute tubular necrosis and Balkan endemic nephropathy in humans. In animal studies, it also caused adverse renal and liver effects and enteritis. In one study, respiratory distress developed in 2 individuals following 8 hours of exposure to moldy wheat in an enclosed granary. Ochratoxin A and an ochratoxin producing mold, Aspergillus ochraceus, were isolated from the wheat. Because of the presence of other factors (eg, dust, other microbes/toxins, rodent urine), a causal relationship could not be established. In animal studies, adverse pulmonary effects due to ochratoxin A exposure have been reported.
    0.2.20) REPRODUCTIVE
    A) HUMAN data are lacking, mostly because human exposures to significant amounts are unusual. Exposures may occur via contaminated breads or cereals. Ochratoxin may be transferred in maternal milk to the nursing infant.
    B) ANIMAL experiments have shown ochratoxin to delay sexual maturation. It may be transferred to nursing offspring following maternal ingestion of the toxin, and is both embryotoxic and teratogenic.
    C) Ochratoxin A has been implicated in fetal death in laboratory and domestic animals, including rats, cattle, quail, mice, and hamsters.
    0.2.21) CARCINOGENICITY
    A) There is inadequate human evidence, but there is some limited evidence in animals. Overall, this agent is not classifiable as to its carcinogenicity to humans.

Laboratory Monitoring

    A) Monitor serum electrolytes in patients with severe enteritis.
    B) Monitor renal function and liver enzymes in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF TOXICITY
    1) Treatment is symptomatic and supportive. Limited human data related to exposure. Treat possible enteritis, kidney damage, and liver toxicity as appropriate. Monitor fluids and electrolytes in cases of severe enteritis. Replacement should be based on individual laboratory values.
    B) DECONTAMINATION
    1) Decontamination methods are likely to be unnecessary or not useful. Acute ingestions of small quantities of products containing ochratoxins are unlikely to be toxic, while large amounts are not likely to be eaten. Chronic ingestion may result in toxicity, but in these cases decontamination is not helpful.
    C) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary following an ochratoxin exposure.
    D) ANTIDOTE
    1) None.
    E) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    F) PITFALLS
    1) Missing an ingestion of another toxin/chemical or other possible etiologies for a patient’s symptoms. History of exposure may be difficult to obtain in some settings.
    G) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause nephropathy, hepatotoxicity, or enteritis.

Range Of Toxicity

    A) TOXICITY: Ochratoxin A is the major ochratoxin component and is the most toxic. Ochratoxin C is almost equal in toxicity while ochratoxin B is about 1/10th as toxic. Human toxicity/sensitivity is unknown. A rough estimation of toxicity based on a very sensitive species (beagles) was done. Assuming beagle sensitivity, and a safety factor of 50, an infant could eat 10 kg of a foodstuff contaminated with 20 ppb without significant adverse effects.

Clinical Effects

Summary Of Exposure

    A) DESCRIPTION: Ochratoxins are fungal toxins derived primarily from Aspergillus ochraceus and Penicillium viridicatum. Ochratoxin A is commonly found on grains and corn, but ochratoxin C is seldom found in these products. There is great variation on the content in food, depending on environmental factors. Ochratoxin A has also been found in blood.
    B) TOXICOLOGY: Ochratoxins cause an early accumulation of glycogen in the cytoplasm of rat liver cells, which decreases rapidly (within 4 hours of an administered dose). It also causes an inhibition (site unknown) of the phosphorylase enzyme system. Ochratoxin A is the most toxic. Toxicity of ochratoxins is related to the acid dissociation constant of the phenolic hydroxyl group.
    C) EPIDEMIOLOGY: Exposure is rare.
    D) WITH POISONING/EXPOSURE
    1) Ochratoxin A is a nephrotoxic agent associated with acute tubular necrosis and Balkan endemic nephropathy in humans. In animal studies, it also caused adverse renal and liver effects and enteritis. In one study, respiratory distress developed in 2 individuals following 8 hours of exposure to moldy wheat in an enclosed granary. Ochratoxin A and an ochratoxin producing mold, Aspergillus ochraceus, were isolated from the wheat. Because of the presence of other factors (eg, dust, other microbes/toxins, rodent urine), a causal relationship could not be established. In animal studies, adverse pulmonary effects due to ochratoxin A exposure have been reported.

Heent

    3.4.3) EYES
    A) ANIMAL STUDIES: CONJUNCTIVITIS: Purulent conjunctivitis was seen in male beagle dogs given ochratoxin A 0.2 to 3.0 mg/kg orally for 14 days (Szczech et al, 1973).
    3.4.6) THROAT
    A) ANIMAL STUDIES: TONSILLITIS: Was seen in male beagle dogs given ochratoxin A 0.2 to 3.0 mg/kg orally for 14 days (Szczech et al, 1973).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) IRRITATION SYMPTOM
    1) WITH POISONING/EXPOSURE
    a) A case study reported immediate respiratory irritation, with the delayed development of retrosternal burning and respiratory difficulty in 2 individuals following 8 hours of exposure to moldy wheat in an enclosed granary. Ochratoxin A and an ochratoxin producing mold, Aspergillus ochraceus, were isolated from the wheat (Di Paolo et al, 1993).
    1) A clear association of the respiratory complaints with ochratoxin is difficult to determine from the case report, due to the possible presence of other factors (eg, dust, other microbes/toxins, rodent urine) which may have contributed to the adverse effects.
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PULMONARY EDEMA
    a) Rabbits exposed to ochratoxin A developed pulmonary edema and lymphocytic infiltration of the lung parenchyma (Di Paolo et al, 1993).
    b) Pulmonary edema in 1 rabbit and lymphocytic infiltration in the lung parenchyma of 2 rabbits were noted. The conditions of animal exposure were limited. There were no controls or dose-response information.
    2) RESPIRATORY DISORDER
    a) A limited animal study demonstrated possible adverse pulmonary effects due to ochratoxin A exposure (Di Paolo et al, 1993). Four guinea pigs and 4 rabbits were exposed (together in one housing unit) for 8 hours to moldy wheat from which Aspergillus ochraceus and ochratoxin A had been isolated. Two rabbits and 1 guinea pig died within 34 hours. The remaining animals were killed and examined 5 days after exposure.

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL SYMPTOM
    1) LACK OF INFORMATION: Human effects are uncertain. In animals, vomiting, anorexia, tenesmus, weight loss, and enteritis are seen after ingestion.
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ENTERITIS
    a) Enteritis is a common effect seen in animals and birds (Peckham et al, 1971; Peckham et al, 1971; Szczech et al, 1973; Kanisawa et al, 1977).
    b) CHICKENS: Enteritis was seen in chickens fed ochratoxin A (Peckham et al, 1971).
    c) COCKERELS: Sublethal doses of ochratoxin A given to 1-day-old babcock B-300 cockerels produced enteritis (Peckham et al, 1971).
    d) DOGS: Ochratoxin A (0.2 to 3.0 mg/kg orally for 14 days) produced anorexia, emesis, tenesmus, and blood-stained mucous from the rectum in male beagle dogs (Szczech et al, 1973).
    e) RATS: Single or multiple doses of ochratoxin A in rats produced severe catarrhal and erosive enteritis of the duodenum and jejunum within four hours of a dose (Kanisawa et al, 1977).
    2) WEIGHT DECREASE
    a) Weight loss is reported with chronic ingestion in animals (Szczech et al, 1973; Berndt & Hayes, 1979).
    b) DOGS: Beagle dogs given 0.2 to 3.0 mg/kg for up to 14 days experienced anorexia and weight loss (Szczech et al, 1973).
    c) RATS: Daily administration of ochratoxin to rats in doses of 0.75 and 2.0 mg/kg caused weight loss (Berndt & Hayes, 1979).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH POISONING/EXPOSURE
    a) LACK OF EFFECT: Human effects have not been reported. Animals experience changes in liver glycogen, liver lipids, and focal hepatic necrosis.
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) Hepatic degeneration has not been reported in humans. Focal necrosis has been seen in some bird species. Other hepatic effects have been noted in animals (Kanisawa et al, 1977; Di Paolo et al, 1993; RTECS , 1993; Peckham et al, 1971).
    b) RATS: When ochratoxin A was administered to rats in either single or several doses, hepatic glycogen was depleted (Kanisawa et al, 1977).
    c) RABBITS, GUINEA PIGS: A limited animal study demonstrated possible adverse hepatic effects due to ochratoxin A inhalation. Four guinea pigs and 4 rabbits were exposed (together in 1 housing unit) for 8 hours to moldy wheat from which Aspergillus ochraceus and ochratoxin A had been isolated. Two rabbits and 1 guinea pig died within 34 hours. The remaining animals were killed and examined 5 days after exposure. Five out of 8 animals had evidence of adverse liver effects. The rabbits which died within 34 hours exhibited macroscopic liver injury and fatty liver degeneration. Liver degeneration was noted in the guinea pig which died within 34 hours. Liver degeneration was noted in a rabbit and guinea pig which had survived to day 5. The conditions of animal exposure were limited. There were no controls or dose-response information (Di Paolo et al, 1993).
    d) CHICKENS: Broiler chicks given ochratoxin A until 3 weeks old developed significantly altered size of liver, spleen, and pancreas. Liver lipids were also changed (Huff & Doerr, 1981). Focal hepatic necrosis has also been reported (RTECS , 1993).
    e) COCKERELS: Sublethal doses of ochratoxin A given to 1-day-old babcock B-300 cockerels produced hepatic degeneration or focal necrosis (Peckham et al, 1971).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) TOXIC NEPHROPATHY
    1) SUMMARY: Ochratoxins are suspected human nephrotoxic agents and are a definite cause of nephropathy in animals.
    2) HUMANS: Ochratoxin A is a nephrotoxic agent (Chu, 1974; Krogh et al, 1974) associated with, but not proven to be the cause of Balkan endemic nephropathy in humans (Hult et al, 1982; Krogh et al, 1977). One case report associates the inhalation of ochratoxins with the development of acute tubular necrosis (Di Paolo et al, 1993).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEPHROPATHY TOXIC
    a) Ochratoxin A induced nephropathy has been shown in experiments on pigs, dogs, rats, chickens, ducks, and trout (Kanisawa et al, 1977; Berndt & Hayes, 1979; Meisner & Selanik, 1979; Di Paolo et al, 1993; Szczech et al, 1973). Ochratoxin A has also been suspected as a cause of renal damage in a study involving rabbits. Field cases of nephropathy in pigs and poultry are thought to be due to ochratoxin A (IARC, 1972; Peckham et al, 1971; Rutqvist et al, 1978; Hult et al, 1982).
    b) RATS: Rats given several daily doses of ochratoxin A developed massive acidophilic degeneration, necrosis, and desquamation of the epithelium in the proximal tubules (Kanisawa et al, 1977).
    1) Daily administration of ochratoxin to rats in doses of 0.75 and 2.0 mg/kg caused persistent urinary hypoosmolality and excessive glucose and protein excretion (Berndt & Hayes, 1979).
    2) Slices of kidney cortex taken from rats given 2 mg/kg/day of ochratoxin A for 2 days showed gluconeogenesis from pyruvate was decreased by 26%, and renal phosphoenolypyruvate carboxykinase activity was also lowered by nearly 55% (Meisner & Selanik, 1979).
    c) RABBITS/GUINEA PIGS: Renal tubule necrosis in 2 out of 4 rabbits was associated with exposure to ochratoxin A (Di Paolo et al, 1993). Four guinea pigs and 4 rabbits were exposed (together in 1 housing unit) for 8 hours to moldy wheat from which Aspergillus ochraceus and ochratoxin A had been isolated. Adverse renal effects were not reported in the guinea pigs. The experimental conditions were limited. There were no controls or dose-response information.
    d) DOGS: Granular casts, low urinary specific gravity, and necrotic renal epithelium were seen in male beagle dogs given ochratoxin A 0.2 to 3.0 mg/kg orally for 14 days (Szczech et al, 1973).
    e) COCKERELS: Sublethal doses of ochratoxin A given to 1-day-old babcock B-300 cockerels produced acute nephritis (Peckham et al, 1971).
    2) SEXUAL FUNCTION ABNORMAL
    a) SEXUAL MATURITY: Delayed sexual maturity has not been reported in humans, but is seen in experimentally induced poisoning in animals. Estrus cycle changes have also been noted in animals (Gupta, 1980; Gupta, 1980b).
    b) RATS: Administration of ochratoxin A caused a delay in sexual maturation, vaginal opening, and first estrus. The cause is thought due to suppressed ovarian steroidogenesis. There was also a reduction in the weight of ovary, uterus, and pituitary gland (Gupta, 1980).
    c) RATS: Ochratoxin A administration of 5 mg/kg IP twice per week for 15 days caused estrous cycle arrest and the fall of ovarian delta5-3beta-hydroxysteroid dehydrogenase and glucose-6-phosphate dehydrogenase activity (Gupta, 1980b).

Hematologic

    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) MARROW DEPRESSION
    a) Human effects not reported. Animals experience hematopoiesis suppression, leukocytopenia, coagulopathy and depletion of lymphoid spleen elements (Chang, 1979; Peckham et al, 1971; Peckham et al, 1971; Gupta, 1979; Galtier & Alvinerie, 1976; Chang, 1981).
    b) Hematopoiesis suppression has been reported in animals.
    1) CHICKENS: Ochratoxin A (0 to 8.0 mcg/g) was given to broiler chickens from 1 day to 3 weeks old. Leukocyte count was reduced at all doses. Leukopenia was characterized by increases in concentration of heterophils and decreases in the concentration of lymphocytes (Chang, 1979).
    2) CHICKS: Suppression of bone marrow hematopoiesis was seen in chicks given ochratoxin A (Peckham et al, 1971).
    3) COCKERELS: Sublethal doses of ochratoxin A given to 1-day-old babcock B-300 cockerels produced suppression of hematopoiesis in bone marrow and depletion of lymphoid elements from spleen and bursa of fabricius (Peckham et al, 1971).
    4) MICE: Intraperitoneal injection of ochratoxin A (5 mg/kg) caused decreased hemoglobin and total red blood cells. White cell changes included increases in small lymphocytes and a fall in the count of neutrophils, basophils, and monocytes. Clotting time was increased by more than 6-fold (Gupta, 1979).
    5) TURKEYS: Ochratoxin A (0 to 8 mcg/g) was fed to turkey poults. Leukocytopenia was observed at 4 and 8 micrograms per gram (Chang, 1981).
    2) COAGULATION DISORDER
    a) RAT: Given 4 mg/kg of ochratoxin A daily by gavage over 4, 6, 8, or 10 days experienced a drop in plasma fibrinogen and a decrease in factors II, VII, and X, and in thrombocyte and megakaryocyte count. A fall in vitamin K pool causes this indirect effect similar to that of coumarin (Galtier & Alvinerie, 1976).

Immunologic

    3.19.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SUMMARY
    a) No effects reported in humans. Animal experiments demonstrated spleen and lymphatic damage (Kanisawa et al, 1977).
    2) SPLEEN DISORDER
    a) RATS: When ochratoxin A was administered to rats in either single or several doses, there was necrosis of cells in the germinal centers of the spleen and lymph nodes (Kanisawa et al, 1977).

Reproductive

    3.20.1) SUMMARY
    A) HUMAN data are lacking, mostly because human exposures to significant amounts are unusual. Exposures may occur via contaminated breads or cereals. Ochratoxin may be transferred in maternal milk to the nursing infant.
    B) ANIMAL experiments have shown ochratoxin to delay sexual maturation. It may be transferred to nursing offspring following maternal ingestion of the toxin, and is both embryotoxic and teratogenic.
    C) Ochratoxin A has been implicated in fetal death in laboratory and domestic animals, including rats, cattle, quail, mice, and hamsters.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) HUMAN data are lacking, mostly because human exposures to significant amounts are unusual. Exposures may occur via contaminated breads or cereals.
    B) ANIMAL STUDIES
    1) CONGENITAL ANOMALY
    a) Animal experiments have shown ochratoxin to be both embryotoxic and teratogenic. The mechanism of action is unknown, but theories involving enzyme activity, energy metabolism, and protein synthesis have been proposed (Creppy et al, 1980; (Warren & Hamilton, 1980).
    b) CHICKENS - Eggs injected with 0.5 to 7 micrograms per egg at 48, 72, or 96 hours into incubation developed various gross abnormalities and heart malformations. Viability was also reduced, especially with larger administered doses (Gilani et al, 1978).
    c) HAMSTERS - Pregnant hamsters were given intraperitoneal injections of 2.5 to 20 mg/kg on one of gestation days 7 to 10. Larger amounts of ochratoxin were given on the later days (Hood et al, 1976).
    1) Higher doses given on the days 7, 8, or 9 produced decreased fetal survival. Doses given on day nine also caused retarded growth.
    2) Teratogenic effects seen included short jaws, cleft lip, limb defects, hydrocephalus, tail defects, heart malformations, and ectopic gonads.
    d) MICE - Pregnant mice were given one 5 mg/kg intraperitoneal dose of ochratoxin A on one of the gestation days 7 through 12. Malformations of the skeleton, median facial clefts, open or missing eyes, limb defects, and malformed vertebrae or ribs were seen (Hayes et al, 1974).
    e) MICE - Pregnant mice were given 2 to 5 mg/kg of ochratoxin A via intraperitoneal injection or gavage on either single days or 2 to 11 consecutive days. The mothers were killed on days 15, 17, 18, or 20. The pups were killed on postpartum days 7, 21 or 35. Effects seen were similar for either IP or oral exposure (Szczech & Hood, 1981).
    1) Fetuses exposed on days 15 to 17 developed brain necrosis even though no obvious teratogenic effect was seen.
    2) Exposure at midgestation did not result in brain necrosis, but teratogenic effects were observed.
    3) Single dose exposures did not result in brain necrosis.
    4) Viability was reduced in exposed pups.
    f) MICE - Ochratoxin (2 to 4 mg/kg) and T-2 (0.5 mg/kg) were given together to mice on gestation day 8 or 10. Ochratoxin exacerbated the frequency of T-2 induced gross malformations (Hood et al, 1978).
    g) RATS - Pregnant rats given either 4 mg/kg intraperitoneally, or 5 mg/kg orally, on days 2 to 8 of gestation, produce few malformations. Only coleosomy was reported (More & Galtier, 1974).
    h) RATS - Oral administration of 0.25 to 8 mg/kg to pregnant rats on gestation days 7 to 16 resulted in skeletal malformations at doses above 0.25 mg/kg (Brown et al, 1976).
    3.20.3) EFFECTS IN PREGNANCY
    A) ANIMAL STUDIES
    1) DEATH
    a) Ochratoxin A has been implicated in fetal death in laboratory and domestic animals, including rats and cattle (Still et al, 1971), quail, mice, and hamsters.
    2) FETAL DISTRESS
    a) MICE: Pregnant mice were given one 5 mg/kg intraperitoneal dose on one of the gestation days 7 through 12. Except for the dose on day 9, all treatments resulted in fetal stunting and increased prenatal mortality (Hayes et al, 1974).
    b) QUAIL: Japanese quail given 16 ppm of ochratoxin A in their feed produced no egg hatching (Prior et al, 1978). Fertility was not affected, but there was early embryonic death (Prior et al, 1979).
    1) Fertile eggs were injected with ochratoxin A to a concentration of 50 or 100 ppb. Early embryonic death was seen (Prior et al, 1979).
    c) RATS: Pregnant rats given either 4 mg/kg intraperitoneally, or 5 mg/kg orally, on days 2 to 8, produced pups with reduced viability and lower birth weights (More & Galtier, 1974).
    d) RATS: Oral administration of 0.25 to 8 mg/kg to pregnant rats on days 7 to 16 resulted in fetal stunting, resorbed litters, and maternal deaths at doses of 4 and 8 mg/kg (Brown et al, 1976).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Several reports of the transfer of ochratoxin A in human milk have been reported (Breitholtz-Emanuelsson et al, 1993).
    2) In a longitudinally designed study, maternal blood, milk, and infant urine samples from 21 mother-child pairs were collected and analyzed for up to 6 months. Ochratoxin A (OTA) was detectable in 43 of 45 blood plasma samples (concentrations range, 72 to 639 ng/L) from lactating women. OTA was also detected in 79% of breast milk samples from the lactating women with an average level of 52 +/- 46 ng/mL. Although blood samples were not collected at the later breastfeeding stages, OTA was also detectable in 73% of milk samples from women with plasma samples that tested positive for OTA; however, milk/plasma ratios varied greatly (0.01 to 0.86) throughout the breastfeeding period and higher ratios were obtained with colostrum compared with transitory or mature milk. In addition to milk and blood samples, urine samples were collected from the exposed infants and OTA was detected in the majority of these samples (Munoz et al, 2014).
    B) ANIMAL STUDIES
    1) RATS: Administration of a single dose of ochratoxin A to lactating dams resulted in the transfer of the toxin from the milk to the nursing offspring (Breitholtz-Emanuelsson et al, 1993).
    a) Ochratoxin A was administered by gastric tube to dams on day 11 of lactation at a dose of 10, 50, or 250 mcg of ochratoxin A (in NaHCO3) per kg body weight. Concentrations of ochratoxin A in the maternal milk, and in the blood and kidneys of the pups and dams were determined at 24 and/or 72 hours after ochratoxin administration.
    b) Mean concentrations of ochratoxin A in maternal blood and milk increased in a dose-dependent fashion. Peak milk concentrations occurred at 24 hours post exposure. Concentrations of ochratoxin A in the blood of the pups peaked after 3 days of nursing, and were similar to the maternal blood concentrations measured 24 hours after exposure. The concentrations of ochratoxin in maternal milk correlated positively with the concentrations in the pup blood and kidneys.
    c) Adverse effects in the dams and offspring were not described. The ochratoxin doses used in this study were reportedly similar to doses administered in a rat carcinogenicity study conducted by the National Toxicology Program, which found increased renal tubular cell adenomas and carcinomas following daily exposure to the ochratoxin over 2 years.

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) There is inadequate human evidence, but there is some limited evidence in animals. Overall, this agent is not classifiable as to its carcinogenicity to humans.
    3.21.3) HUMAN STUDIES
    A) SUMMARY
    1) HUMANS - Inadequate evidence (IARC, 1972).
    2) ANIMALS - Limited evidence (IARC, 1972).
    3) OVERALL EVALUATION - The agent is not classifiable as to its carcinogenicity to humans (IARC, 1972).
    B) NEOPLASM
    1) Several animal studies did produce tumors:
    a) MOUSE - An oral dose of 2216 mg/kg continuously over 44 weeks in one study, and 3504 mg/kg continuously over 2 years in another, produced kidney, ureter, and bladder carcinogenic changes (RTECS, 1993).
    1) An oral dose of 1478 mg/kg continuously over 44 weeks was neoplastic in mice (RTECS, 1993).
    b) RATS - Ochratoxin A was given orally in doses of 100 or 300 micrograms/rat, for 5 days a week for 50 weeks, to groups of 5 male and 5 female rats. One tumor was seen, a hamartoma of the kidney in one of the rats on the highest dose (IARC, 1972).
    1) An oral dose of 36,050 micrograms/kg continuously for 2 years produced kidney, ureter, and bladder carcinogenic changes (RTECS, 1993).
    C) LACK OF EFFECT
    1) MICE - Each of a group of 10 male and 10 female mice received subcutaneous injections of 10 micrograms of ochratoxin A suspended in 0.1 mL of arachis oil, twice weekly for 36 weeks. After 81 weeks of study, no tumors were seen in the 7 survivors (IARC, 1972).
    2) RATS - Ten female rats received subcutaneous injections of ochratoxin A suspended in sunflower seed oil. The dose was 2.5 mg/kg injected twice weekly for 18 weeks. At week 73 and 87, 2 of 10 animals had developed fibrosarcomas; 2 of 10 controls injected with the sunflower seed oil alone also developed local fibrosarcomas by week 87 (IARC, 1972).
    3) TROUT - No tumors were seen when ochratoxin was fed to rainbow trout at concentrations of 16, 32, or 64 micrograms per kilogram of diet for 8 months (IARC, 1972).

Genotoxicity

    A) DNA damage has been noted in several animal species.
    B) Mutagenic activity was screened versus Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537. Results were negative.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes in patients with severe enteritis.
    B) Monitor renal function and liver enzymes in symptomatic patients.

Methods

    A) CHROMATOGRAPHY
    1) METHODS USED IN PLANT MATERIAL
    a) Partition and thin layer chromatography (Anon, 1965; Nesheim et al, 1973; Gimeno, 1979).
    b) High performance liquid chromatography (Josefsson, 1979; Hult et al, 1982).
    c) Reverse phase high performance liquid chromatography (Osborne, 1979) .
    d) High performance thin-layer chromatography (Lee, 1980).
    e) An enzymatic method (detection limit of 1 to 2 nanograms/gram of serum) (Hult et al, 1982).
    2) TISSUE DETERMINATION: Hult et al (1979) discussed a method for determination of ochratoxin in pig kidney using enzymic digestion, dialysis, and high performance liquid chromatography with post-column derivatization (Hult et al, 1979).
    B) OTHER
    1) SERUM SCREENING: A screening fluorescence micromethod for detection of ochratoxin A in human (or animal) sera was developed by Hult et al (1979; 1984). In the human test, 50 microliters of sera are required, and as little as 10 nanograms of ochratoxin A per mL can be detected. Positive tests should be confirmed with standard methods (Hult et al, 1979; Hult et al, 1984).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Monitor serum electrolytes in patients with severe enteritis.
    B) Monitor renal function and liver enzymes in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Decontamination methods are likely to be unnecessary or not useful. Acute ingestions of small quantities of products containing ochratoxins are unlikely to be toxic, while large amounts are not likely to be eaten.
    B) Chronic ingestion may result in toxicity, but in these cases decontamination is not helpful.
    6.5.2) PREVENTION OF ABSORPTION
    A) Decontamination methods are likely to be unnecessary or not useful. Acute ingestions of small quantities of products containing ochratoxins are unlikely to be toxic, while large amounts are not likely to be eaten.
    B) Chronic ingestion may result in toxicity, but in these cases decontamination is not helpful.
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF TOXICITY
    a) Treatment is symptomatic and supportive. Limited human data related to exposure. Treat possible enteritis, kidney damage, and liver toxicity as appropriate. Monitor fluids and electrolytes in cases of severe enteritis. Replacement should be based on individual laboratory values.
    B) MONITORING OF PATIENT
    1) Monitor serum electrolytes in patients with severe enteritis.
    2) Monitor renal function and liver enzymes in symptomatic patients.
    C) EXPERIMENTAL THERAPY
    1) PHENYLALANINE has been used in some animals tests, but has not yet been tried against toxicity in humans.
    2) ANIMALS
    a) Ochratoxin has an inhibitory effect on cultured hepatoma cells. When phenylalanine is added, there is a reversion of the inhibitory effect (Creepy, 1979).
    b) When mice were intoxicated with 0.8 mg of ochratoxin IP, it was 100% fatal. If 0.8 mg of phenylalanine was given with the ochratoxin, 97% survived. One hundred percent survived when the phenylalanine dose was increased to 1 mg (Creepy et al, 1980).

Abstracts

Case Reports

    A) ROUTE OF EXPOSURE
    1) INHALATION: One case report associates acute renal failure with inhalation of ochratoxins produced by the mold of Aspergillus ochraceus. The presence of A. ochraceus in moldy wheat to which the individual had been exposed was confirmed. Ochratoxin A was isolated from the same source. A limited animal bioassay involving the moldy wheat was also conducted, with possible adverse pulmonary, hepatic, and renal effects noted. A female farm worker developed respiratory difficulty and epigastric tension the evening after sieving moldy wheat in an enclosed granary. Her condition deteriorated, with decreased urine output and continued pulmonary complaints. She sought medical care 5 days after the initial event, and was found to have pulmonary effusion, periorbital and dependent edema. Laboratory results indicated non-oliguric acute renal failure. Additional tests confirmed the diagnosis of acute tubular necrosis, with glomerular effects ("minimal exchange" lesion). The treatment regimen included diuretics, hypouricemising agents, fluids, and a low protein/high calorie diet. Normal renal function returned after 40 days (Di Paolo et al, 1993).

Range Of Toxicity

Summary

    A) TOXICITY: Ochratoxin A is the major ochratoxin component and is the most toxic. Ochratoxin C is almost equal in toxicity while ochratoxin B is about 1/10th as toxic. Human toxicity/sensitivity is unknown. A rough estimation of toxicity based on a very sensitive species (beagles) was done. Assuming beagle sensitivity, and a safety factor of 50, an infant could eat 10 kg of a foodstuff contaminated with 20 ppb without significant adverse effects.

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) OCHRATOXIN A is the major ochratoxin component, and is the most toxic (Budavari, 1989).
    a) Human toxicity/sensitivity is unknown. A rough estimation of toxicity, based on a very sensitive species (beagles), was done (Chu et al, 1972). Assuming beagle sensitivity, and a safety factor of 50, an infant could eat 10 kg of a foodstuff contaminated with 20 ppb without significant adverse effects.
    2) OCHRATOXIN B is the less toxic dechloro derivative of ochratoxin A (Budavari, 1989).
    3) ANIMAL DATA
    a) CHICKENS: Toxicity in one-day-old chicks was closely related to the acid dissociation constant of the phenolic hydroxyl group in the dihydroisocoumarin ring (Chu et al, 1972).
    b) TROUT: Deaths were seen in rainbow trout given a dose of 66.7 mg/kg body weight IP. Pathology indicated some liver and kidney damage (Doster et al, 1974).
    4) OCHRATOXIN C is almost equal in toxicity to ochratoxin A. It is the amorphous ethyl ester of ochratoxin A (Budavari, 1989).
    a) ANIMAL DATA
    1) CHICKENS: Toxicity in one-day-old chicks was closely related to the acid dissociation constant of the phenolic hydroxyl group in the dihydroisocoumarin ring (Chu et al, 1972).
    2) TROUT: Lethal to 6-month-old rainbow trout when administered in corn oil. The IP LD50 (10 day) was 3.0 mg/kg body weight (Doster et al, 1974).
    5) TOXICITY WHEN COMBINED WITH OTHER FUNGAL TOXINS
    a) OCHRATOXIN A AND CITRININ: When both these fungal toxins are added simultaneously to hepatoma tissue cultures, RNA and protein synthesis inhibition occurs quickly, and DNA synthesis inhibition is seen shortly thereafter. The 2 toxins have an added toxicity (Creepy, 1980).
    b) OCHRATOXIN A AND RUBRATOXIN: The neonatal LD50 of ochratoxin A (3.9 mg/kg orally) was decreased 16-fold when 5 mg of rubratoxin B per kilogram was added (Hayes, 1977).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) OCHRATOXIN A
    1) LD50- (ORAL)MOUSE:
    a) 46 mg/kg (RTECS , 1993)
    2) LD50- (INTRAPERITONEAL)RAT:
    a) 12,600 mcg/kg (RTECS , 1993)
    3) LD50- (ORAL)RAT:
    a) 3.90 mg/kg; neonates (Hayes, 1977)
    b) 20 mg/kg -- chronic pulmonary edema (RTECS , 1993)
    c) 28 mg/kg (Kanisawa et al, 1977)
    B) OCHRATOXIN B

Pharmacology Toxicology

Toxicologic Mechanism

    A) Ochratoxins cause an early accumulation of glycogen in the cytoplasm of rat liver cells, which decreases rapidly (within 4 hours of an administered dose). It also causes an inhibition (site unknown) of the phosphorylase enzyme system (Chu, 1974).
    B) Toxicity of ochratoxins is related to the acid dissociation constant of the phenolic hydroxyl group (Chu, 1974).

Physicochemical

Physical Characteristics

    A) OCHRATOXIN A: Forms crystals from xylene (Budavari, 1989).
    B) OCHRATOXIN B: Forms crystals from methanol (Budavari, 1989).

Molecular Weight

    A) OCHRATOXIN A: 403.8 (Budavari, 1989)
    B) OCHRATOXIN B: 469.4 (RTECS, 1993)
    C) OCHRATOXIN C: 431.11 (HSDB , 1993)

References

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