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TRICHOTHECENE MYCOTOXINS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Trichothecenes are mycotoxins produced by a number of species of the fungal genus Fusarium. They are often found growing on various agricultural crops such as corn, wheat, and barley.
    B) Humans and animals become exposed to these agents via contaminated food, in chemotherapy, and in chemical warfare.
    C) Over 100 trichothecenes have been identified. The most frequent natural contaminants are deoxynivalenol, diacetoxyscripenol, HT-toxin, nivalenol, and T-2 toxin (Scott & Lawrence, 1989).

Specific Substances

    A) SYNONYMS FOR THE GROUP
    1) Fungal toxin T2
    2) Trichohthecene toxin
    3) 12, 13-epoxytrichothecene mycotoxins
    4) Stachybotryotoxins (a macrocyclic dilactone derivative of the trichothecene family)
    5) Nivalenol toxins
    6) DAS (diacetoxyscirpenol or 3 alpha-hydroxy- 4 beta, 15 diacetoxy, 12,13- epoxytrichothec-9-ene or anguidine)
    7) Deoxynivalenol (Also known as DON and vomitoxin)
    8) MYCOTOXINS, TRICHOTHECENE
    CONSTITUENTS OF THE GROUP
    1) 8-Acetylneosolaniol
    2) 8-n-butyrylneosolaniol
    3) 2-Deoxy-11-epi-3-alpha-hydroxysambucoin
    4) 2-Deoxy-11-epi-12-acetyl-3-alpha-hydroxysambucoin
    5) Deoxynivalenol (vomitoxin)
    6) 8-Hexanoylneosolaniol
    7) 8-Isobutyrylneosolaniol
    8) Neosolaniol
    9) Nivalenol
    10) NT-1
    11) 8-n-Pentanoylneosolaniol
    12) 8-Propionylneosolaniol
    13) Roridin
    14) T-2
    15) Veirucarin
    16) Vertisporin
    17) Verrucarol
    18) Zearlalenone

Available Forms Sources

    A) SOURCES
    1) Trichothecenes are often found growing on various agricultural crops such as corn, wheat, and barley (Bamburg & Strong, 1971; Pathre & Mirocha, 1977).
    2) Humans and animals become exposed to these agents via contaminated food, in chemotherapy, and in chemical warfare (Rosen & Rosen, 1982).
    3) In one study, Dutch cereals were investigated for the presence of various mycotoxins. 90% contained deoxynivalenol, 79% contained nivalenol, and 62% contained zearalenone. The highest concentration found was 3198 ng/g of deoxynivalenol, 1875 ng/g of nivalenol, and 677 ng/g of zearalenone (Tanaka et al, 1990).
    4) In another study, Korean cereals were investigated for the presence of various mycotoxins. In barley, the major contaminants were deoxynivalenol, nivalenol, and zearalenone, with mean levels of 170, 1011, and 287 ng/g, respectively. In corn samples, the major contaminants were deoxynivalenol and 15-acetyldeoxynivalenol, with mean levels of 310 and 297 ng/g, respectively (Kim et al, 1993).
    5) ZOOS - A study of 110 sites from 5 zoological institutions found that a significant number of fungi that were associated with sick building syndrome and poor indoor air quality could pose adverse effects on animal health and reproduction rates at these institutions. Sixteen individual sites were found to have excess levels of Penicillium chrysogenum which can colonize on cellulose (eg, straw bedding) and has been associated with sick-building syndrome (SBS). Stachybotrys chartarum, an organism associated with "black mold" was also found at two locations. The presence of these fungi may also produce adverse effects on zoo staff (Wilson & Straus, 2002).
    B) USES
    1) Although forbidden by the 1972 Biological and Toxic Weapon Convention and the 1925 Geneva Protocol there is evidence these toxins were used both in Southeast Asia and Afghanistan (Marshall, 1983).
    2) Because of their cytotoxicity, the trichothecene mycotoxins have been investigated as antineoplastic agents (Coppock et al, 1985).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Trichothecene toxins are multi-toxins affecting many systems. Acute toxicity resembles the damage done by radiation, nitrogen mustard, or mitomycin C. Primary damage is to the gastrointestinal tract, and lymphoid and hematopoietic systems. Chronic toxicity has not been reported in man.
    B) Pulmonary hemorrhage and hemosiderosis in infants and children has been associated with exposure to toxigenic fungi, including Stachybotrys atra, residing in structures with excess water damage.
    0.2.4) HEENT
    A) Visual disturbances and salivation have been reported, as have conjunctivitis, rhinitis, burning of the nasal passages, pharyngitis, and nasal bleeding.
    0.2.5) CARDIOVASCULAR
    A) Angina, tachycardia, and hypotension may occur.
    0.2.6) RESPIRATORY
    A) Shortness of breath may occur.
    B) Pulmonary hemorrhage has been reported in infants following exposure to toxigenic fungi.
    0.2.7) NEUROLOGIC
    A) Headache and vertigo may be present.
    0.2.8) GASTROINTESTINAL
    A) Anorexia, vomiting and diarrhea, which may be bloody, may occur.
    0.2.13) HEMATOLOGIC
    A) Leukopenia, sepsis, bone marrow suppression, hemosiderosis, and multiple hemorrhages have all been reported.
    0.2.14) DERMATOLOGIC
    A) Contact with skin and eyes can cause coagulation necrosis.
    0.2.19) IMMUNOLOGIC
    A) Immunosuppression as a result of granulocyte depletion has been proposed. Immunostimulation and altered IgG/IgA secretion has been demonstrated in animal or in vitro studies.
    0.2.20) REPRODUCTIVE
    A) Administration of T-2 toxin to chick embryos on day 2 of incubation resulted in rumplessness, micromelia and/or microphthalmia at some dose levels.

Laboratory Monitoring

    A) Monitor CBC, platelet count and electrolytes.
    B) Monitor chest radiograph and arterial blood gases or pulse oximetry in patients with respiratory symptoms.
    C) Gas liquid chromatography, mass spectrophotometry, thin layer chromatography, and nonspecific bioassays have been used to identify these mycotoxins.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) There are no known antidotes to trichothecene mycotoxins. Treatments are directed at supporting hemopoietic abnormalities, gastrointestinal damage, and skin damage.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) Due to gastrointestinal damage, fluid and electrolyte loss may be a significant problem. Monitor electrolyte and fluid status and replace as necessary.
    D) HEMATOPOIETIC ABNORMALITIES -
    1) Monitor for thrombocytopenia and leukopenia. Administer platelets or fresh plasma as necessary. Consider filgrastim for severe neutropenia. Antibiotics or isolation may also be necessary.
    E) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) Leukopenia may be caused by as little as 0.1 mg/kg/day for a few weeks. The exact dose necessary to cause serious human symptoms is unknown.

Clinical Effects

Summary Of Exposure

    A) Trichothecene toxins are multi-toxins affecting many systems. Acute toxicity resembles the damage done by radiation, nitrogen mustard, or mitomycin C. Primary damage is to the gastrointestinal tract, and lymphoid and hematopoietic systems. Chronic toxicity has not been reported in man.
    B) Pulmonary hemorrhage and hemosiderosis in infants and children has been associated with exposure to toxigenic fungi, including Stachybotrys atra, residing in structures with excess water damage.

Vital Signs

    3.3.3) TEMPERATURE
    A) Fever may occur (Roderick & Hasseltine, 1977).

Heent

    3.4.1) SUMMARY
    A) Visual disturbances and salivation have been reported, as have conjunctivitis, rhinitis, burning of the nasal passages, pharyngitis, and nasal bleeding.
    3.4.3) EYES
    A) VISUAL DISTURBANCES have been reported (Haig A, 1982).
    B) CONJUNCTIVITIS - Exposure to dusts containing these mycotoxins may cause conjunctivitis (Roderick & Hasseltine, 1977).
    3.4.5) NOSE
    A) RHINITIS - Exposure to dusts containing these mycotoxins may cause rhinitis, burning of the nasal passages, and nasal bleeding (Roderick & Hasseltine, 1977).
    3.4.6) THROAT
    A) HYPERSALIVATION - Increased salivation has been reported (Haig A, 1982).
    B) LARYNGITIS - Exposure to dusts containing these mycotoxins may cause pharyngitis and laryngitis (Roderick & Hasseltine, 1977). Throat irritation was reported by 61 out of 97 (63%) individuals who were believed to have trichothecene mycotoxicosis from consumption of mouldy wheat (Bhat et al, 1989).

Cardiovascular

    3.5.1) SUMMARY
    A) Angina, tachycardia, and hypotension may occur.
    3.5.2) CLINICAL EFFECTS
    A) ANGINA
    1) Angina may occur (Roderick & Hasseltine, 1977; (Haig A, 1982).
    B) TACHYARRHYTHMIA
    1) Tachycardia may occur (Roderick & Hasseltine, 1977; (Haig A, 1982).
    C) HYPOTENSIVE EPISODE
    1) Hypotension may occur (Roderick & Hasseltine, 1977; (Haig A, 1982).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOTENSION
    a) Decreased mean arterial blood pressure, cardiac index, and cerebral blood flow have been reported in swine to which T-2 toxin was administered IV (Lundeen et al, 1991). Conditions resembling septic shock, and poor perfusion of the gastrointestinal system and other organs have also been reported (reviewed in Lundeen, 1991; (Smith, 1992).
    2) HYPOVOLEMIA
    a) In one study designed to determine the cause of death in T-2 mycotoxicosis in cats, it was found that hypovolemia and polycythemia resulting from plasma leakage and internal bleeding accounts for the lethality of T-2 mycotoxicosis (Borison et al, 1991).
    3) ISCHEMIA
    a) A study on blood flow, in T-2 exposed rats, showed strong vasoconstriction in skeletal muscle, mesenteric, and renal vascular beds. The ischemia in vital organs together with a decrease in cardiac output might be the cause of rapid death in acute T-2 toxemia (Siren & Feuerstein, 1986).

Respiratory

    3.6.1) SUMMARY
    A) Shortness of breath may occur.
    B) Pulmonary hemorrhage has been reported in infants following exposure to toxigenic fungi.
    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FINDING
    1) WITH POISONING/EXPOSURE
    a) GENERAL
    1) It has been suggested that Stachybotrys chartarum (formerly referred to as S. atra) is a pathogen of both animals and human beings and the route of exposure may be due to direct contact or inhalation rather than ingestion. Studies have been conducted to determine the role of mold and the manifestation of disease. Symptoms can be benign to relatively serious and include alveolitis, bronchiectasis, and pulmonary fibrosis. Following exposure a variety of conditions have been associated with this pathogen and may include: asthma, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, emphysema, pulmonary fibrosis, and idiopathic pulmonary hemosiderosis. However, there is some controversy as to whether molds in water-damaged indoor environments are pathogenic (Hossain et al, 2004).
    B) DYSPNEA
    1) Coughing and shortness of breath may develop (Haig A, 1982).
    2) Inhalation exposure to Stachybotrys chartarum and Aspergillus versicolor, in moisture-damaged office buildings, was associated with the reported development of coughing, dyspnea, wheezing and chest tightness among employees. Moldy vinyl wall covering was found to contain the trichothecene toxin, deoxynivalenol, however it is unclear if the respiratory problems were due to this mycotoxin (Hodgson et al, 1998).
    C) PULMONARY HEMORRHAGE
    1) SUMMARY - Exposure to toxigenic fungi, including Stachybotrys atra and a Trichoderma species, has been associated with the development of pulmonary hemorrhage and hemosiderosis in infants. Contributing risk factors included a synergistic effect between exposure to the fungi and the presence of tobacco smoke, and living in water-damaged homes which may enhance fungal growth (Marwick, 1997; Etzel et al, 1998; Novotny & Dixit, 2000; Vesper et al, 2000).
    2) CASE SERIES - Severe pulmonary hemorrhage and hemosiderosis were reported in 10 infants exposed to Stachybotrys atra and other fungi in water-damaged homes, from January 1993 to December, 1994, in Cleveland, Ohio (Etzel et al, 1998). Nine of the ten infants required intubation and one infant died.
    a) RELATIVE RISK - In this aged-matched, case-control study it was determined that the matched odds ratio for a change of 10 units in the mean concentration of viable airborne S. chartarum was 9.83 (95% CI 1.08 to 3 x 10(6)), or a 10 CFU/m(3), or that an increase in the concentration of S. chartarum in the air breathed by the infant was 9.83 times more likely to be a case. The authors also suggests that other criteria (ie, consistency, coherence and specificity) supports the association between acute pulmonary hemorrhage in infants and exposure to Stachybotrys and other fungi in water-damaged environments (Etzel, 2003).
    3) CASE REPORT - A 7-year-old child presented with a chronic, non-productive cough accompanied by low-grade fever, malaise, fatigue, and decreased appetite that began 14 months earlier. A physical exam revealed late inspiratory crackles in the left lung and the patient's bronchoalveolar lavage (BAL) fluid showed the presence of hemosiderin-laden macrophages indicative of pulmonary hemorrhage. Stachybotrys atra was also isolated from the BAL fluid. Investigation of the patient's home revealed the presence of S. atra, as well as aspergillus and penicillium species that developed as a result of water damage to the structure (Elidemir et al, 1999).
    4) CASE REPORT - A 40-day-old infant developed pulmonary hemorrhage after residing for 2 weeks in a water-damaged home and subsequent acute exposure to tobacco smoke. The infant presented with tachypnea and respiratory distress that required intubation. Other symptoms included tachycardia and hemorrhage from the glottis. The chest roentgenogram showed diffuse bilateral alveolar infiltrates. Following supportive care and subsequent extubation, the child completely recovered (Novotny & Dixit, 2000).
    a) Analysis of paint chips taken from mold stains within the house revealed the presence of various fungi, including species of Penicillium and Trichoderma.
    5) LACK OF EVIDENCE - Following investigation by the CDC, it was determined that the evidence was not strong enough to prove an association between Stachybotrys atra found in water-damaged homes and the development of pulmonary hemosiderosis among infants in Cleveland Ohio from 1993 to 1996 (Anon, 2000).

Neurologic

    3.7.1) SUMMARY
    A) Headache and vertigo may be present.
    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) Headache may occur (Haig A, 1982).
    B) DIZZINESS
    1) Vertigo has been reported (Roderick & Hasseltine, 1977).
    C) ATAXIA
    1) Ataxia has been reported in exposed humans and animals (Haig A, 1982).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) Trichothecene toxin T-2 and some trichothecene metabolites administered SC or by direct application to the brain in rats resulted in convulsions, loss of appetite, decreased consumption of water, death, and brain tissue pathology including necrosis, hemorrhage, and PMN infiltration (Bergmann et al, 1988).
    2) HEART DISORDER
    a) Decreased regional blood flow following IV T-2 toxin administration has been reported in swine (Lundeen et al, 1991).

Gastrointestinal

    3.8.1) SUMMARY
    A) Anorexia, vomiting and diarrhea, which may be bloody, may occur.
    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) CASE SERIES - Ninety-seven of 165 people, who had eaten moldy rice contaminated with fusarium and T-2 toxin, experienced nausea, dizziness, vomiting, chills, abdominal distension, abdominal pain, thoracic stuffiness, and diarrhea (Wang et al, 1993). All patients recovered following symptomatic treatment.
    B) VOMITING
    1) Vomiting has been commonly reported in exposed humans and animals (Marshall, 1983; Kriegleder, 1981; Stahelin et al, 1968; Bhat et al, 1989). When DAS has been tested in human chemotherapy, it produces significant vomiting that was not relieved by the administration of various antiemetics (NRC, 1983).
    2) At low concentrations in the diet, deoxynivalenol is known to reduce food consumption (anorexia), whereas at higher doses the toxin induces vomiting (Rotter et al, 1996).
    C) DIARRHEA
    1) Diarrhea or bloody diarrhea may occur (Marshall, 1983; Bhat et al, 1989).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PANCREATIC DISORDER
    a) Pancreatic lesions of acinar and inlet cells have been reported in animal studies for DAS, T-2, and DON toxins (Coppock et al, 1985) 1985b; (Pang et al, 1986).
    2) GASTROINTESTINAL DISORDER
    a) During a study of gastrointestinal blood flow in T-2 toxin-exposed pigs, the pigs given a high-dose (2.4 mg/kg) showed only 17% normal gastric blood flow. The pigs in the low-dose (0.6 mg/kg) group showed 30% of gastric blood flow. The blood flow to the small intestine in both groups increased initially and then declined. This increase may contribute to the rapid absorption of the toxin (Beasley et al, 1987).

Genitourinary

    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEPHROPATHY TOXIC
    a) It has been demonstrated in mice that exposure to trichothecene vomitoxin induces elevated serum IgA and mesangial IgA accumulation similar to human glomerulonephritis, IgA nephropathy (Berger's disease) (Dong et al, 1991).

Hematologic

    3.13.1) SUMMARY
    A) Leukopenia, sepsis, bone marrow suppression, hemosiderosis, and multiple hemorrhages have all been reported.
    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) Hematologic abnormalities are common occurrences. Leukopenia, sepsis, bone marrow suppression, and multiple hemorrhage have been reported (Roderick & Hasseltine, 1977).
    2) The estimated dose necessary to induce leukopenia is 0.1 mg/kg/day for a few weeks. Leukopenia may last for several weeks (Haig A, 1982).
    3) Experimental studies have shown that destruction of the hemopoietic and lymphoid systems can occur in a matter of hours after hematogenous exposure (Coppock et al, 1989).
    4) Alimentary toxic aleukia, first identified in Siberia, has been associated, in humans, with the consumption of grain contaminated with T-2 toxin. The aleukia usually occurs in four stages:
    a) In the first stage, hyperemia of the mucosa may occur accompanied by weakness, fever, nausea, and vomiting. In more severe cases, acute esophagitis, gastritis, and gastroenteritis may occur. Seizures and circulatory failure may occur in rare instances.
    b) The second stage is characterized by the development of leukopenia, granulopenia, and progressive lymphocytosis. In the third stage, severe hemorrhagic diathesis, severe necrotic pharyngitis and laryngitis resulting in death, in some instances, by the total closure of the larynx. Severe bone marrow suppression may occur at this stage as well.
    c) The fourth stage is characterized by recovery, whereupon exposed individuals may be susceptible to secondary infections, and recovery may take several weeks (IARC, 1993a).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) MARROW DEPRESSION
    a) Diacetoxyscirpenol (DAS) administered IV to pigs, cattle and dogs resulted in significant bone marrow necrosis, decreased normal hematopoietic elements, and increased abnormal platelets and neutrophils. Pigs were most sensitive to the hematopoietic effects of DAS, followed by dogs and cattle (Coppock et al, 1989).
    b) Low doses of T-2 toxin SC or IP reversibly inhibit incorporation of radiolabeled iron into mouse erythrocytes and reversibly deplete granulocyte-macrophage colony-forming cells in the bone marrow of exposed mice (Faifer et al, 1992). At 48 hr post exposure, bone marrow stem cells proliferate and at 72 hr post exposure a transient, significant increase in radiolabeled iron uptake into erythrocytes occurs, effects which may be compensatory mechanisms.
    c) Both T-2 toxin and deoxynivalenol were tested on rat erythrocytes. Neither produced significant hemolysis at concentrations of 130 micrograms/mL, suggesting a threshold level for lytic activity (Rizzo et al, 1992).

Dermatologic

    3.14.1) SUMMARY
    A) Contact with skin and eyes can cause coagulation necrosis.
    3.14.2) CLINICAL EFFECTS
    A) SKIN NECROSIS
    1) Trichothecene mycotoxins are cytotoxic. They may cause skin inflammation, or necrosis.
    2) It has been suggested that Stachybotrys chartarum (formerly referred to as S. atra) is a pathogen of both animals and human beings and the route of exposure is likely by direct contact or inhalation. Primary disease appears to be due to skin contact producing dermatitis which may progress from hyperemia to crusting exudates to necrosis and finally resolution. Skin testing with volunteers has produced both local and systemic reactions (Hossain et al, 2004).

Endocrine

    3.16.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SPLEEN DISORDER
    a) Animal studies have shown histologic damage to thymus and spleen.
    2) ENDOCRINE DISORDER
    a) Testicular and adrenal cortical lesions have been reported subsequent to DAS and T-2 exposure in laboratory animals.

Immunologic

    3.19.1) SUMMARY
    A) Immunosuppression as a result of granulocyte depletion has been proposed. Immunostimulation and altered IgG/IgA secretion has been demonstrated in animal or in vitro studies.
    3.19.2) CLINICAL EFFECTS
    A) DISORDER OF IMMUNE FUNCTION
    1) Immunosuppression as a result of granulocyte depletion has been proposed (Roderick & Hasseltine, 1977). Immunostimulation and altered IgG/IgA secretion have also been demonstrated in non-human in vitro and in vivo studies (Pestka et al, 1990).
    3.19.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) IMMUNE SYSTEM DISORDER
    a) It has been demonstrated in mice that exposure to trichothecene vomitoxin induces elevated serum IgA and mesangial IgA accumulation similar to human glomerulonephritis, IgA nephropathy (Berger's disease) (Dong et al, 1991).

Reproductive

    3.20.1) SUMMARY
    A) Administration of T-2 toxin to chick embryos on day 2 of incubation resulted in rumplessness, micromelia and/or microphthalmia at some dose levels.
    3.20.2) TERATOGENICITY
    A) EMBRYOTOXICITY
    1) ANIMAL - Administration of T-2 toxin to chick embryos on day 2 of incubation resulted in rumplessness, micromelia and/or microphthalmia at some dose levels. T-2 on incubation days 3 and 4 was embryolethal (doses equal to or > 0.1 mcg) or caused rumplessness and/or microphthalmia (Vesely et al, 1992). Increased dose was not clearly associated with an increased incidence of specific defects, although the presence of normal embryos was higher as the dose of T-2 toxin decreased.

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) In one study, agricultural stock for human consumption in an area of China with a high incidence of primary hepatocellular carcinoma was found to have higher concentrations of fumonisins and deoxynivalenol than stock from an area with a low incidence of primary hepatic carcinoma (Ueno et al, 1997). Both areas had similarly high levels of aflatoxin B1.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor CBC, platelet count and electrolytes.
    B) Monitor chest radiograph and arterial blood gases or pulse oximetry in patients with respiratory symptoms.
    C) Gas liquid chromatography, mass spectrophotometry, thin layer chromatography, and nonspecific bioassays have been used to identify these mycotoxins.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Although the method developed by Rood et al (1986) makes analysis easier, it should be remembered that many of these mycotoxins are metabolized rapidly. When given to swine, there was no parent compound seen in the blood after one hour, and when given orally, there was none seen after two hours (Beasley et al, 1986). Samples taken after this may have to be analyzed for metabolites.
    B) The benefits and limitations of biological assays used to diagnose mycotoxicoses in animals have been reviewed by Panigrahi (1993). Biological assays have been replaced with qualitive and quantitative chemical methods (Snyder, 1986; Scott & Lawrence, 1989). Immunochemical methods are also available, and ELISA methods are available for assaying urine (Lee et al, 1990).
    1) Most veterinary analytical toxicology laboratories can analyze for the trichothecene mycotoxins.
    2) CYTOTOXICITY - Colorimetric MTT (tetrazolium salt) tests have been developed to compare the cytotoxicity and/or immunotoxicity of various Fusarium species which produce T-2 toxins (Visconti et al, 1991; Rotter et al, 1993).
    3) PLASMA/URINE - Rood et al (1986) have developed a method of screening plasma and urine for trichothecenes. A Clin-Elut column is used to extract the compounds. They are then hydrolyzed to their corresponding parent alcohols, and purified via a silica cartridge before derivatization for gas chromatographic analysis.
    a) When the initial urinary levels are between 50 and 1000 nanograms/milliliter, the recoveries range from 78 to 119%.
    b) In the plasma, when the initial levels are between 50 and 500 nanograms/milliliter, the recovery is between 80 to 116%. The level of detection is 25 parts per billion.
    4) FOOD - An aflatoxin specific, monoclonal antibody-based immunoaffinity chromatography assay can be used for food products (Hudson et al, 1992).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor CBC, platelet count and electrolytes.
    B) Monitor chest radiograph and arterial blood gases or pulse oximetry in patients with respiratory symptoms.
    C) Gas liquid chromatography, mass spectrophotometry, thin layer chromatography, and nonspecific bioassays have been used to identify these mycotoxins.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) All of the trichothecene mycotoxins are potent emetics and appear to act centrally and cause gastrointestinal irritation. Toxin induced vomiting can be difficult to control with antiemetics.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) ANIMAL EXPERIMENTS -
    a) Single doses of superactivated charcoal, 1 gram/kilogram, produced increased survival in rats when given up to 5 hours after a lethal dose of T-2 toxin (Galey et al, 1987). Treatment with superactivated charcoal of rats exposed to T-2 toxin also decreased the incidence and severity of organ lesions (Bratich et al, 1990).
    b) In an experiment in mice, charcoal treatment (7 grams/kilogram) orally given either immediately or 1 hour after administration of 5 milligrams/kilogram of T-2, significantly improved survival rates (Fricke & Jorge, 1990).
    c) Activated charcoal (2 grams/kilogram in 420 milliliters of water, PO) combined with other therapies (IV metoclopramide, IV dexamethasone, and PO magnesium sulfate, with or without IV sodium bicarbonate or IV normal saline) significantly increased the survival time of swine injected IV with T-2 toxin (Poppenga et al, 1987). The charcoal was administered 30 min or 4 hr after the T-2 administration.
    2) IN VITRO EXPERIMENTS -
    a) In an experiment in vitro, superactivated activated charcoal has a maximal binding capacity of 0.48 milligram toxin/milligram of charcoal and a dissociation constant of 0.078 (Fricke & Jorge, 1990).
    3) MECHANISMS -
    a) Activated charcoal may act by interfering with enterohepatic recirculation of T-2 toxin or toxic metabolites, or may bind endotoxin which may be increased in the mycotoxin-damaged intestines (Poppenga et al, 1987).
    4) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    5) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) There are no known antidotes to trichothecene mycotoxins. Treatments are directed at supporting hemopoietic abnormalities, gastrointestinal damage, and skin damage.
    B) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Due to gastrointestinal damage, fluid and electrolyte loss may be a significant problem. Monitor electrolytes and hydration, and replace as needed.
    C) MYELOSUPPRESSION
    1) THROMBOCYTOPENIA - Monitor platelets and clotting activity. Replace with platelets or fresh plasma as is necessary.
    2) NEUTROPENIA - Antibiotics or isolation may be necessary while the patient is in a compromised state. Consider use of filgrastim in selected patients with severe neutropenia. Usual dose is 5 micrograms/kilogram/day subcutaneously or intravenously.
    D) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    E) EXPERIMENTAL THERAPY
    1) Combined treatments involving metoclopramide (1 milligram/kilogram IV before and after T-2), activated charcoal (2 grams/kilogram in water PO after T-2), magnesium sulfate (0.5 grams per kilogram PO after T-2), dexamethasone sodium phosphate (6 milligram/kilogram IV before and after T-2), sodium bicarbonate (5% IV, administered according to arterial blood pH), and normal saline (0l9% IV, based on mean arterial pressure) significantly increased survival time and decreased evidence of toxicity in swine injected IV with 3 times the LD50 of T-2 (Poppenga et al, 1987).
    a) The use of all therapies combined, or all therapies combined except for the omission of normal saline or sodium bicarbonate, resulted in the maximum survival time determined (mean of 48 hrs -vs- 9 hrs in T-2 treated controls). Elimination of activated charcoal and magnesium sulfate from the treatment protocol resulted in a mean survival time of 18 hrs (Poppenga et al, 1987).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    6.7.2) TREATMENT
    A) SUPPORT
    1) In cases of inhalational exposure to trichothecene mycotoxins, treatment is SYMPTOMATIC and SUPPORTIVE.
    B) ENVIRONMENTAL INTERVENTION
    1) REMEDIATION -
    a) In 1993, the New York City Department of Health Bureau of Environmental and Occupational Disease Prevention developed guidelines regarding the remediation of Stachybotrys atra in indoor environments. Four levels of remediation have been identified and are based on the extent of visible contamination and underlying damage ((Anon, 1999)).
    1) Level 1 includes small isolated areas of 2 square feet or less (eg, ceiling tiles) and cleanup may be conducted by building maintenance staff who have had training regarding proper cleanup methods. Gloves and a half-face respirator should be worn, contaminated absorbent material should be removed in a sealed plastic bag, and surrounding areas should be cleaned with household bleach.
    2) Level 2 includes isolated areas of approximately 2 to 30 square feet (eg, individual dry wall panels) and cleanup may be conducted by trained building maintenance staff. Gloves and a half-face respirator should be worn, surrounding material should be covered with plastic sheets and taped before removal, contaminated absorbent material should be removed in a sealed plastic bag, and the surrounding areas should be cleaned with household bleach.
    3) Level 3 includes areas of more than 30 square feet (eg, > one wall board panel) and cleanup should be conducted only by personnel with hazardous materials training. Disposable protective clothing, head gear, foot coverings, gloves, and full-face HEPA respirators should be worn. Complete containment of the affected area is required (including construction of isolation barriers around the affected area using plastic sheeting sealed with duct tape, a high efficiency particulate air exhausted negative air unit, and air locks and decontamination rooms for exit from the work area), contaminated material should be removed in double-sealed plastic bags, and the work area should be HEPA vacuumed prior to removal of isolation barriers. Air monitoring should be conducted prior to removal of isolation barriers and after completion of remediation in order to assess its efficacy.
    4) Level 4 includes remediation of the HVAC systems and recommendations for remediation are the same as for Level 3, with the inclusion of: remove growth supporting material from ducts with a HEPA vacuum and disinfect contaminated material prior to removal.
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) SUPPORT
    1) Necrosis is possible. Treatment is supportive.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) Leukopenia may be caused by as little as 0.1 mg/kg/day for a few weeks. The exact dose necessary to cause serious human symptoms is unknown.

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Dose necessary to cause symptoms in humans is unknown.
    2) Leukopenia may be caused by as little as 0.1 milligram/kilogram/day for a few weeks (Roderick & Hasseltine, 1977).
    3) An official tolerance level of 1 milligram/kilogram zearalenone in grains, fats, and oils was established in the USSR in 1984. Proposed levels in other countries are 0.2 milligram/kilogram in maize in Brazil and 0.03 milligram/ kilogram in all foods in Romania (IARC, 1993).
    4) Official tolerance levels for deoxynivalenol varies by country from 0.005 milligram/kilogram to 2 milligrams/kilogram in feeds (IARC, 1993).
    5) There is great variability in the toxicity of the various tricothecene mycotoxins. Animal LD50's range from 0.5 to 10 mg/kg or more (IP in mice). The variability in toxicity is influenced by route of exposure and specific type of trichothecene mycotoxin or trichothecene mycotoxin metabolites(Bergmann et al, 1988).
    6) The cerebral toxicity of trichothecenes and trichothecene metabolites applied as a solid to rat brain have been ranked as (most toxic to least toxic): T-2 tetraol = iso-T-2 toxin > T-2-tetraol tetraacetate> T-2 toxin acetate. The LD50 of these toxins ranged from 13 mcg to 140 mcg . Subcutaneous application of the various tricothecenes resulted in lower toxicity than direct application to rat brain, with LD50s ranging from 0.75 mg/kg to 4 mg/kg(Bergmann et al, 1988)
    7) Various trichothecene mycotoxins have been tested for cytotoxicity using the cultured baby hamster kidney cells. The most toxic were the T-2 toxins (5 nanograms/mL), 4-propanoyl HT-2 (5 nanograms/mL), and 3-hydroxy T-2 toxin (5 nanograms/mL). Of the regularly seen toxins, T-2 tetraol (1 x 10(4) ng/mL), 8-beta-hydroxy trichothecene (1 x 10(4) ng/mL), sporotrichiol (2 x 10(4) nanograms/mL), 8-oxodiacetoxyscirpenol (6 x 10(4) nanograms/mL), and 8-acetyl T-2 tetraol (1 x 10(5) nanograms/mL) were least toxic. Modified trichothecenes, FS-2 and FS-3, were relatively non-toxic at levels of 1 x 10(5) nanograms/mL(Senter et al, 1991).

Pharmacology Toxicology

Toxicologic Mechanism

    A) These mycotoxins are potent inhibitors of protein and DNA synthesis in the eukaryotes (Roderick & Hasseltine, 1977). They also react (unknown site) at the cell membrane to produce a "whole cell" toxicity. They react with the SH-residue of SH-enzymes such as alcohol dehydrogenase.
    1) Trichothecene T-2 toxin also inhibits mitochondrial functions, effects cell division, effects normal cell shape and can hemolyze erythrocytes. T-2 toxin inhibits the mitochondrial electron transport system with succinic dehydrogenase as one site of action (Khachatourians, 1990).
    2) Deoxynivalenol is known to inhibit protein synthesis via binding to the ribosome (Rotter et al, 1996).
    B) Mechanisms of toxicity of various trichothecene mycotoxins and metabolites have been proposed by Bergmann et al (1988), based on toxin or metabolite structure and the results of LD50 studies in rats:
    1) The 3 alpha-hydroxyl group of T-2 toxin, HT-2 toxin and T-2 triol is believed to contribute to toxicity. Chemicals (e.g., T-2 acetate, iso-T-2 toxin, T-2 tetraol tetraacetate) which do not have a free hydroxyl at position 3 were less toxic. The presence of a free 4 beta-hydroxyl in iso-T-2 toxin and T-2 acetate also may increase toxicity, but to a lesser degree than the 3 alpha hydroxyl.
    C) Based on animal studies it has been proposed that Fusarium trichothecene mycotoxins (e.g., T-2) and certain metabolites (e.g., fusaric acid) cause hyperaminoacidemia as a result of inhibited protein synthesis, with subsequent elevations of brain tryptophan and serotonin. Loss of appetite, behavioral changes, and incoordination are attributed to these secondary neurochemical effects (Smith, 1992).
    D) DAS - This toxin is known to irreversibly block the production of protein by inhibiting polypeptide chain initiation through degradation of polyribosomes (Liao et al, 1976; Mizuno, 1975).
    E) The ED50 for protein synthesis inhibition in reticulocytes is 30 nanograms/milliliter (Ueno, 1977). Stahelin et al (1968) found that as little as 7 nanograms/milliliter would inhibit human KB cell mitotic activity. Coppock et al (1985) found that plasma concentrations of 308 to 512 nanograms/milliliter were cytotoxic to proliferative and metabolically active cells and tissues.

Animal Toxicology

Clinical Effects

    11.1.1) AVIAN/BIRD
    A) Recognized incidents of trichothecene mycotoxicoses in birds kept as household pets appear to be low. In experimental studies, successive clinical signs in pigeons, chickens, and turkeys are feed refusal, oral lesions, emesis, diarrhea, depression, drooping wings, ataxia, coma, and death. Diets containing 4 to 16 mg of T-2 toxin/kg of feed produce oral lesions in chickens, altered feathering in growing birds, and depression of the immune system (Wyatt et al, 1975; Boonchuvit et al, 1975; Williams, 1989).
    B) Hematologic manifestations are leukopenia, anemia, and coagulopathy (Doerr et al, 1981). Clinical pathological manifestations are elevated alkaline phosphatase, lactic acid dehydrogenase, and uric acid. Dietary concentrations of 8 mg of T-2 toxin/kg of feed decrease egg shell thickness, and concentrations greater than 2 mg of T-2 toxin/kg of feed decrease hatchability (Chi et al, 1977). The trichothecenes decrease weight gains of broilers, and DON increases liver lipid and triglycerides in hens (Farnworth et al, 1983).
    C) Of the domestic birds, mature chickens are more resistant to diacetoxyscirpenol (DAS), T-2 toxin, and deoxynivalenol (DON) than mature turkeys.
    11.1.2) BOVINE/CATTLE
    A) Field incidents of type A and C toxins producing mycotoxicoses have been reported in cattle. Calves are more susceptible than cows. Clinical signs for type A toxins are partial to complete feed refusal, and for type C, refusal to eat forages. Erosions and scabs can be observed on the muzzle and lips. Following ingestion, excessive salivation and kicking at the abdomen may be observed and standing posture can be similar to hardware disease. A decrease in the rate of rumen contraction, and diarrhea (often bloody) can be observed.
    B) The initial hematologic manifestation is a leucocytosis followed by a leukopenia. The leukopenia can be variable but generally consists of a lymphopenia, neutrophilia followed by a neutropenia, and a thrombocytopenia (Coppock et al, 1989). The thrombocytopenia and depletion of other clotting factors can produce a hemorrhagic syndrome (Hibbs et al, 1974). Hyperpyrexia of 2 to 3 degrees F may be observed. Diseases common in cattle can increase due to immunosuppression. Infertility and abortions can occur (Coppock et al, 1990).
    11.1.3) CANINE/DOG
    A) Although exposure appears to be rare, dogs are very susceptible to trichothecene mycotoxins (Coppock et al, 1989). Oral exposure in dogs is probably limited to type A and B toxins, and cutaneous exposure to type C toxins can occur from exposure to contaminated straw. The potent emetic action of the toxins induce ptyalism, emesis, and retching within minutes following exposure (Coppock et al, 1989).
    B) Following oral exposure, the expected clinical history is excessive panting, profuse salivation, frequent vomiting and retching, and defecation of formed stool followed by diarrhea (Coppock et al, 1989). Dogs will eat their own and other regurgitated material and relay intoxication can occur by this phenomenon.
    C) Clinical presentation is a dog with severe clinical signs of gastrointestinal irritation. The mucous membranes of the mouth and throat can be congested. Profuse ptyalism may have been observed. The animal may be retching and occasionally vomiting bile, have tenesmus, be frequently defecating a formed stool, or have diarrhea. A marked pain response can be observed when palpitating over the stomach due to severe gastric irritation caused by the toxins.
    D) Hematologic manifestations are a leukocytosis followed by a leukopenia. The leukocytosis consists of a neutrophilia with a wide variety of immature forms. Leukocytosis is followed by a leukopenia that consists of a neutropenia, and various bone marrow cells including megakaryocytes can be observed in the peripheral blood (Coppock et al, 1989). Reticulocytosis and anemia can occur from depression of the hematopoietic elements.
    E) Because of the potent immunotoxic effects of the type A toxins, chronic exposure to dietary concentrations of greater than 0.1 mg of toxin/kg of air dried feed could reduce the native resistance of dogs to infectious diseases.
    F) Following a poisoning episode, taste aversion for a particular type of food could occur.
    11.1.4) CAPRINE/GOAT
    A) Goats are susceptible to trichothecene mycotoxicosis, but clinical poisonings are not commonly reported. Generally goats are more discriminating than sheep or cattle in food selection, and probably do not continue to ingest trichothecene contaminated feedstuffs unless it is forcibly fed.
    B) Signs are marked feed refusal, head shaking while eating, ptyalism, depression, anorexia, diarrhea, decreased rumen motility, and loss of body weight. Necrotic lesions can occur in the mouth and on the lips. Infertility can occur due to decreased sperm production, and pregnant females can have spontaneous abortions (Marasas et al, 1984).
    11.1.5) EQUINE/HORSE
    A) Field incidents in Japan of intoxication with type A and B toxins have been reported in horses fed moldy bean hulls, but there are few incidents reported in North America. Unrecognized incidents of clinical poisoning of horses with macrocyclic trichothecenes (type C) may also be occurring in North America. Feed refusal and slobbering of feed are the first clinical signs. Horses appear to consume contaminated forages (type C toxins) more readily than contaminated concentrated feedstuffs.
    B) Clinical signs are erosions and scabs on the lips and erosions of the mucous membranes of the mouth and pharynx. In acute poisoning, severe colic can occur. Seizures and CNS signs can be observed and are probably due to degenerative pathologic changes in the brain. In bean hull poisoning, icterus was reported (Marasas et al, 1984).
    C) There is some evidence that both the stomach and cecum are target organs for type A and B toxins. Infertility of stallions can occur and pregnant mares may abort. Stachybotryo-toxicosis (black spotted forage disease from ingesting type C toxins) is diagnosed in horses in Hungary and may be more common than reported in Northern regions of North America (Hajtos et al, 1983).
    11.1.6) FELINE/CAT
    A) Cats are highly susceptible to poisoning by the trichothecenes. A single oral dose of 0.08 mg of T-2 toxin/kg of body weight can be fatal to cats within 3 weeks (Lutsky & Mor, 1981). The LD50 in cats is 0.5 mg (SC) of T-2 toxin/kg of body weight (Ueno, 1983).
    B) As a clinical entity, trichothecene mycotoxicoses is rare in cats. Clinical signs of intoxication are bruxism, emesis, bloody diarrhea, depression, hindlimb ataxia, conjunctivitis, anorexia, dehydration, coma, and death (Lutsky & Mor, 1981).
    C) In one study designed to determine the cause of death in T-2 mycotoxicosis in cats, it was found that hypovolemia and polycythemia resulting from plasma leakage and internal bleeding accounts for the lethality of T-2 myotoxicosis (Borison et al, 1991).
    11.1.7) ICHTHYOID/FISH
    A) Clinical reports of trichothecene mycotoxicoses in fish have not been reported. Because fish foods are good substrates for species of Fusarium, poisoning could occur. Herbivore fish (eg, grass carp) can be poisoned by feeding contaminated vegetables. The majority of intoxication incidents would be limited to type A and B toxins.
    B) In experimental studies in rainbow trout (Salmo gairdneri), clinical signs included expelling food from the mouth, anorexia, lethargic bottom-dwelling, ascites, bulging of the eyeballs due to retrograde fluid accumulation, mucoid casts attached to the anus, and retarded growth (Poston et al, 1982). Similar clinical signs would be expected in other species of fish.
    C) Clinical pathologic changes reported were depressed hemoglobin and hematocrit, and increased hepatic concentrations of vitamin A.
    D) Definitive histopathologic observations have not been reported. Observations include hemorrhagic appearance of the gastrointestinal tract, and enlargement of the gall bladder (Poston et al, 1982).
    11.1.9) OVINE/SHEEP
    A) Feed refusal is expected with type A, B, and C toxins. Stachybotryotoxicosis can occur when sheep are fed straw which was wet at the time of harvesting (Hajtos et al, 1983). Clinical signs of type A intoxication in sheep include fetid breath from necrotic lesions in the mouth, salivation, scabs on the lips, partial to complete anorexia, emesis, diarrhea (can be bloody), trichorrhexis, loss of body weight, weakness, and death.
    B) Hematologic manifestations are leukocytosis to leukopenia, granulocytopenia, lymphopenia, thrombocytopenia, and increased clotting time. Immunosuppression accompanied by an increase in infectious diseases can occur (Hajtos et al, 1983). Abortions could occur. In sheep, type C toxins have been associated with hepatosis and renal failure.
    11.1.10) PORCINE/SWINE
    A) Because of diet formulation, field incidents of trichothecene mycotoxicoses are the most common for pigs. The relative order of occurrence of trichothecenes in pig feed is DON > T-2 toxin > DAS. In Western Canada, DON is usually not observed, and DAS and T-2 toxin are of equal occurrence (Coppock et al, 1989b). Due to rain and snow delaying harvest, a large acreage of soybeans and cereal grains can be contaminated before harvest (Coppock et al, 1989b).
    B) Clinical manifestations range from feed refusal to death from intoxication. Trichothecenes are very irritating to mucous membranes and skin. Pigs will more readily eat a contaminated diet after it has been removed and subsequently provided a few days later. Anytime feed refusal or excessive feed wastage is observed, trichothecene contamination should be suspected.
    C) Typical behavior patterns are ingestion of a mouthful of contaminated grain, back up from the feeder and squeal, spit out the food, and then repeat the process; some pigs may vomit. Sows with this behavior can injure or kill piglets. Diarrhea can be observed.
    D) In lactating sows, the stress of hunger and chemical burning of the mouth can cause partial agalactia and aggression towards piglets. In feeder pigs, tail and ear biting and other forms of aggression can increase. Fatal hemorrhage can occur due to a decrease in platelets and clotting factors (Coppock et al, 1989). Infertility and abortions can occur (Glavits et al, 1983).
    E) Ingestion of feedstuffs containing greater than 1 mg of toxin/kg of feed can cause erosions of the nose, lips, and mucous membranes of the mouth and throat. DAS and T-2 toxins (type A) produce hemorrhagic necrosis of the stomach fundus (Coppock et al, 1985). Agonal vomiting can be observed. The type A toxins can produce leukocytosis followed by leukopenia and thrombocytopenia (Coppock et al, 1989). Infectious diseases can be increased because of immunosuppression.
    F) The trichothecenes can be present in essentially all of the constituents used to formulate swine diets. The most common sources are cereal grains, soybeans, and in some cases discarded supermarket produce (El-Banna et al, 1984).
    G) In laboratory tests, infusion of 0.6 mg/kg of T-2 produced blood flow reductions in the cerebrums and cerebellum. When the dose was increased to 2.4 mg/kg, reductions in blood flow to all parts of the brain were observed, as well as increased heart rate (Lundeen et al, 1991).
    H) During a study of gastrointestinal blood flow in T-2 toxin-exposed pigs, the pigs given a high-dose (2.4 mg/kg) showed only 17% normal gastric blood flow. The pigs in the low-dose (0.6 mg/kg) group showed 30% of gastric blood flow. The blood flow to the small intestine in both groups increased initially and then declined. This increase may contribute to the rapid absorption of the toxin (Beasley et al, 1987).
    I) In a study of pigs exposed to T-2 toxin via an aerosol, clinical signs of toxicity were similar to pigs exposed via an intravascular injection (Pang et al, 1988).
    J) Swine are more sensitive to deoxynivalenol than mice, poultry, and ruminants, partly because of differences in metabolism of deoxynivalenol, with males being more sensitive than females (Rotter et al, 1996).
    11.1.11) REPTILE
    A) REPTILE
    1) Feedstuffs formulated for reptiles can be a favorable substrate for growth of Fusarium spp. Trichothecene poisoning can also occur in herbivore reptiles. Fruits and some vegetables have been reported to be contaminated with trichothecenes (Harwig et al, 1979; El-Banna et al, 1984). Oral lesions and necrosis of the mouth can be observed.
    2) Clinical signs include depression, anorexia, diarrhea, and fetid odor. An increase in infectious conditions can occur and may confound signs of intoxication. Hematologic changes can include leukopenia and anemia.
    11.1.12) RODENT
    A) All rodents and lagomorphs are susceptible to trichothecene intoxication. Clinical signs are hunched posture, fetid breath, piloerection, hypothermia, ataxia, diarrhea, coma, and death (Fairhurst et al, 1987). Necrotic lesions may be observed in the mouth.
    B) Clinical pathologic features of trichothecene poisoning in rats are leukopenia, granulocytopenia, relative lymphocytosis, reticulocytosis, and a decrease in erythrocyte numbers. A diet containing 20 mg of DON/kg of feed decreased conception in Sprague-Dawley rats (Morrissey & Vesonder, 1985). The intragastric LD50 for T-2 toxin is 5.3 mg/kg for guinea pig, 7 mg/kg for rat, and 9.6 mg/kg for mouse.
    C) A study on blood flow, in T-2 exposed rats, showed strong vasoconstriction in skeletal muscle, mesenteric, and renal vascular beds. The ischemia in vital organs together with a decrease in cardiac output might be the cause of rapid death in acute T-2 toxemia (Siren & Feuerstein, 1986).
    11.1.13) OTHER
    A) OTHER
    1) ZOOLOGICAL INSTITUTIONS
    a) A study of 110 sites from 5 zoological institutions found that a significant number of fungi that were associated with sick building syndrome (SBS) and poor indoor air quality were present, which could lead to adverse effects on animal health and reproduction rates. Sixteen individual sites were found to have excess levels of Penicillium chrysogenum, which can colonize on cellulose (ie, straw bedding), and has been associated with poor indoor air quality. A Fisher exact test analysis indicated a significant nonrandom association (P less than 0.001) between high levels of P. chrysogenum and sites that had an increased incidence of poor animal health. The organism is also a significant human allergen. Stachybotrys chartarum, an organism associated with "black mold" was also found at two locations (Wilson & Straus, 2002).
    B) OTHER
    1) Exposure of herbivore zoo animals to types A, B, and C trichothecenes can occur. Clinical signs would be similar to other species.
    2) All species of laboratory, domestic and wild animals, birds, reptiles, and fish are susceptible to poisoning by trichothecene mycotoxins. The pharmacodynamics appear to be essentially the same in all species of animals and, when considering anatomical and physiological differences, clinical manifestations are analogous among species (Coppock et al, 1985) 1985b, 1989).
    3) Clinical exposure incidents occur primarily in herbivores and omnivores. Clinical poisonings in carnivores can occur because pet foodstuffs are a favorable substrate for toxigenic fungi producing type A and B toxins (Tanaka et al, 1985). The use of trichothecenes as a malicious poison should be low.
    4) All species of vertebrates are susceptible to the trichothecenes. Clinical signs would be very similar to other species.

Treatment

    11.2.1) SUMMARY
    A) GENERAL TREATMENT
    1) ACTIVATED CHARCOAL - There are no specific treatments for trichothecene intoxication (NRC, 1983). Removal of the sources of exposure is essential. In vitro studies have shown superactivated charcoal (Amoco AX-21) will bind 0.48 mg of T-2 toxin/mg charcoal (Fricke & Jorge, 1990). Activated charcoal is effective in decreasing the oral toxicity of T-2 toxin when given 1 hour following exposure (Fricke & Jorge, 1990). Superactivated charcoal is also effective in reducing the toxicity of parenterally administered T-2 toxin.
    a) Superactivated charcoal (Amoco AX-21) should be given per gavage at dose of 2 grams charcoal (dry weight)/kg body weight, and is effective following parenteral exposure.
    2) All of the trichothecenes are immunosuppressive, and prophylactic antimicrobial chemotherapy should be considered. The addition of bentonite and smectite to diets decrease the toxicity of T-2 toxin, and the mechanism of action appears to be adsorption of the toxin (Carson & Smith, 1983) Fioramonti et al, 1987).
    3) BENTONITE - The addition of bentonite clay to the diets of food-producing animals probably will reduce the biologic activity of dietary trichothecenes.
    4) SUMMARY - Remove the suspected diet and provide a diet known to be free of trichothecene mycotoxins. Type C toxins are most common in roughage and straw. Safe concentrations of trichothecene mycotoxins have not been established.
    5) There are no specific treatments for trichothecene mycotoxicoses. In dogs, attempts can be made to control vomiting and retching with morphine (1 mg IM/kg) or diazepam (2.5 to 20 mg, slow IV/kg) after the stomach is empty. Renal function should be monitored. In all species the state of hydration, electrolyte and pH balance should be closely monitored. Highly activated charcoal should be given (1 g (PO)/kg) to adsorb toxins in the gastrointestinal tract. Whole blood transfusions can be given to restore blood clotting. Antimicrobial chemotherapy should be started to protect against bacterial infections. The efficacy and safety of saline cathartics in domestic animals in the treatment of trichothecene intoxication has not been established (Poppenga et al, 1987).
    11.2.4) DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) Economically feasible methods of decontaminating feedstuffs contaminated with trichothecene mycotoxins are not available. Feeds can be blended to reduce the concentration of mycotoxins. Crop rotation can reduce infection of grain with trichothecene producing fungi (Teich & Hamilton, 1985). Kernels damaged by harvest equipment are more susceptible to infection. Insects spread fungal spores, and insects are attracted to damaged kernels (Trenholm et al, 1989). Plant disease surveys can be most helpful in predicting preharvest fungal infection of maturing crops, and the potential for subsequent mycotoxin contamination (Coppock et al, 1988) 1989b, 1989c).
    b) In vitro studies have shown superactivated charcoal (Amoco AX-21) will bind 0.48 mg of T-2 toxin/mg charcoal (Fricke & Jorge, 1990). Activated charcoal is effective in decreasing the oral toxicity of T-2 toxin when given 1 hour following exposure (Fricke & Jorge, 1990). Oral administration of superactivated charcoal also reduces parenteral toxicity of the trichothecenes.

Range Of Toxicity

    11.3.1) THERAPEUTIC DOSE
    A) GENERAL
    1) Trichothecenes are not used as therapeutic agents in veterinary medicine. Clinical studies in humans using diacetoxyscirpenol as an antineoplastic chemotherapeutic have not been successful.
    11.3.2) MINIMAL TOXIC DOSE
    A) GENERAL
    1) Because a succession of toxigenic fungi can grow in feedstuffs, a complex mixture of mycotoxins is produced and can consist of several chemical groups of mycotoxins including their precursor and degradation metabolites (Coppock et al, 1990; Kazanas et al, 1984; Foster et al, 1986). Under clinical conditions the minimum dose of a particular trichothecene mycotoxin required to produce signs of intoxication is substantially less than the dose reported in experimental studies. The relative order of decreasing toxicity is DAS, MAS > T-2 toxin > HT-2 toxin >> deoxynivalenol, nivalenol. Based on similar mechanism of toxicity and detoxification, the toxic effects of dietary exposure to multiple trichothecenes should be assumed to be additive.
    B) BIRD
    1) The LD50 of DON in day old broiler chickens is approximately 140 mg of DON/kg of body weight (Huff et al, 1981); 4 to 16 mg of T-2 toxin/kg of feed produce marked clinical signs of toxicity (Wyatt et al, 1975; Boonchuvit et al, 1975; Williams, 1989); 8 mg of T-2 toxin/kg of feed decrease egg shell thickness, and concentrations greater than 2 mg of T-2 toxin/kg of feed decrease hatchability (Chi et al, 1977).
    C) CAT
    1) A dose of 0.08 mg of T-2 toxin/kg of body weight is fatal to cats within 3 weeks, and is equivalent to a dose of 0.03 mg of DAS/kg.
    D) CATTLE
    1) Feeding 1 kg/head/day of a wheat-oat concentrate containing 1.5 mg of DON/ kg of feed did not decrease feed consumption in non-lactating dairy cows (Trenholm et al, 1985). Twenty percent mortality was observed in cows consuming 2 mg of T-2 toxin (naturally contaminated corn)/kg of body weight (Smalley, 1973).
    E) DOG
    1) A single dose of 0.5 mg of DAS (IV)/kg of body weight is fatal within 8 hours (Coppock et al, 1989). Multiple doses of 0.06 mg of DAS (IV)/kg of body weight are fatal within 4 days (Stahelin et al, 1968).
    F) FISH
    1) The no effect dose of T-2 toxin in fish is less than 1 mg of T-2 toxin/kg of diet (Poston et al, 1982). The oral LD50 of T-2 toxin in rainbow trout is approximately 6.5 mg/kg body weight (Smalley, 1973).
    G) GOAT
    1) Goats appear to have the same order of susceptibility to the trichothecene mycotoxins as other species.
    H) HORSE
    1) 2 mg of T-2 toxin(PO)/kg of body weight is a fatal dose.
    I) SWINE
    1) For swine, diets that contain greater than 600 mcg of DON and greater than 200 mcg of DAS and T-2 toxin/kg of feed may produce immunosuppression. An oral dose of 0.1 mg of deoxynivalenol/kg of body weight produces emesis (Forsith et al, 1977). Parenteral LD50 of T-2 toxin and DAS are 1.21 mg of T-2 toxin and 0.38 mg of DAS/kg of body weight (Williams, 1989). The oral LD50 of T-2 toxin in pigs is approximately 4 mg/kg of body weight (Smalley, 1973). Dietary concentrations of 0.7 mg of DON/kg of feed reduce weight gains.
    J) REPTILE
    1) Very little data are available on the dose response of reptiles to trichothecene mycotoxins.
    K) RODENT
    1) In guinea pigs, 1 mg of DAS (PO)/kg of body weight is fatal (2 deaths out of 6 animals dosed) within 24 hours (Kriegleder, 1981). By the subcutaneous and intravenous routes of exposure, the LD50 of T-2 toxin in mice is about 2.1 and 3.8 mg/kg, respectively (Mutoh et al, 1988). In a study in mice, dietary concentrations of 100 mg of DON/kg of feed results in death within a few days (Robbana-Barnat et al, 1988).
    L) SHEEP
    1) Diets containing 15.6 mg of DON (from contaminated wheat)/kg of diet fed ad libitum did not produce feed refusal, weight loss or other signs of toxicity in feeder lambs (Harvey et al, 1986). A low protein diet containing 0.3 mg of T-2 toxin/kg of diet fed ad libitum produced lymphopenia within 14 days. Similar observations were prominent in lambs dosed with 0.3 mg of T-2 toxin (PO)/kg of body weight (Friend et al, 1983).

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) GENERAL TREATMENT
    1) ACTIVATED CHARCOAL - There are no specific treatments for trichothecene intoxication (NRC, 1983). Removal of the sources of exposure is essential. In vitro studies have shown superactivated charcoal (Amoco AX-21) will bind 0.48 mg of T-2 toxin/mg charcoal (Fricke & Jorge, 1990). Activated charcoal is effective in decreasing the oral toxicity of T-2 toxin when given 1 hour following exposure (Fricke & Jorge, 1990). Superactivated charcoal is also effective in reducing the toxicity of parenterally administered T-2 toxin.
    a) Superactivated charcoal (Amoco AX-21) should be given per gavage at dose of 2 grams charcoal (dry weight)/kg body weight, and is effective following parenteral exposure.
    2) All of the trichothecenes are immunosuppressive, and prophylactic antimicrobial chemotherapy should be considered. The addition of bentonite and smectite to diets decrease the toxicity of T-2 toxin, and the mechanism of action appears to be adsorption of the toxin (Carson & Smith, 1983) Fioramonti et al, 1987).
    3) BENTONITE - The addition of bentonite clay to the diets of food-producing animals probably will reduce the biologic activity of dietary trichothecenes.
    4) SUMMARY - Remove the suspected diet and provide a diet known to be free of trichothecene mycotoxins. Type C toxins are most common in roughage and straw. Safe concentrations of trichothecene mycotoxins have not been established.
    5) There are no specific treatments for trichothecene mycotoxicoses. In dogs, attempts can be made to control vomiting and retching with morphine (1 mg IM/kg) or diazepam (2.5 to 20 mg, slow IV/kg) after the stomach is empty. Renal function should be monitored. In all species the state of hydration, electrolyte and pH balance should be closely monitored. Highly activated charcoal should be given (1 g (PO)/kg) to adsorb toxins in the gastrointestinal tract. Whole blood transfusions can be given to restore blood clotting. Antimicrobial chemotherapy should be started to protect against bacterial infections. The efficacy and safety of saline cathartics in domestic animals in the treatment of trichothecene intoxication has not been established (Poppenga et al, 1987).
    11.4.2) DECONTAMINATION
    11.4.2.2) GASTRIC DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) Economically feasible methods of decontaminating feedstuffs contaminated with trichothecene mycotoxins are not available. Feeds can be blended to reduce the concentration of mycotoxins. Crop rotation can reduce infection of grain with trichothecene producing fungi (Teich & Hamilton, 1985). Kernels damaged by harvest equipment are more susceptible to infection. Insects spread fungal spores, and insects are attracted to damaged kernels (Trenholm et al, 1989). Plant disease surveys can be most helpful in predicting preharvest fungal infection of maturing crops, and the potential for subsequent mycotoxin contamination (Coppock et al, 1988) 1989b, 1989c).
    b) In vitro studies have shown superactivated charcoal (Amoco AX-21) will bind 0.48 mg of T-2 toxin/mg charcoal (Fricke & Jorge, 1990). Activated charcoal is effective in decreasing the oral toxicity of T-2 toxin when given 1 hour following exposure (Fricke & Jorge, 1990). Oral administration of superactivated charcoal also reduces parenteral toxicity of the trichothecenes.

Kinetics

    11.5.1) ABSORPTION
    A) GENERAL
    1) All of the trichothecenes are absorbed through the skin, mucous membranes, and from the gastrointestinal tract (Kemppainen & Riley, 1984). After a single oral dose of about 1.74 mg of DON/kg of body weight, DON was detected in the blood of a cow within 10 minutes and approximately 0.6% of the dose appeared to be available (Prelusky et al, 1984).
    2) Following intragastric dosing, DON was very rapidly absorbed in swine, reaching near peak plasma levels within 15 to 30 minutes. Levels remained elevated for approximately 9 hours and began declining slowly thereafter (Prelusky et al, 1988).
    11.5.2) DISTRIBUTION
    A) GENERAL
    1) DAS, T-2 toxin, and their metabolites have a relatively large volume of distribution (Coppock et al, 1985b) 1987). However, there are few studies on the distribution of the trichothecene toxins in the physiologic compartments of the body. It appears that DAS and T-2 toxin are excreted into the gastrointestinal tract following parenteral exposure. Oral administration of superactivated charcoal appears to serve as a sink for the toxins and, by this mechanism, increases survival following parenteral exposure (Fricke & Jorge, 1990).
    2) The pharmacokinetics of DON was investigated in swine following intravenous and intragastric administration of radio-labeled toxin. The apparent volume of distribution was 1.34 L/kg, the volume of the central compartment was 0.166 L/kg, and the plasma clearance was 1.81 mL/min/kg (Prelusky et al, 1988).
    11.5.3) METABOLISM
    A) GENERAL
    1) T-2 toxin and DAS are detoxified through deacetylation by carboxyesterase and conjugation of the metabolites, and the deacetyl-products are also toxic. Monoacetoxyscirpenol (MAS), a metabolite of DAS, has essentially the same order of toxicity as DAS, HT-2 toxin has approximately one-half the toxicity of T-2 toxin, neosolaniol (a metabolite of HT-2 toxin), and scirpentriol are approximately 10 times less toxic than T-2 toxin (Bauer et al, 1985).
    2) The metabolism of DAS and T-2 toxin can be reduced by exposure to halothane and liver disease, and exposure to organophosphorus insecticides (Coppock et al, 1987; Johnsen et al, 1988). In cattle, approximately 46% of orally ingested DON can be excreted as the glucuronide conjugate (Prelusky et al, 1984). The half-life of DON in sheep after IV administration is 66.5 minutes and the half-life for formation and elimination of major metabolites is about 188 minutes. Approximately 11% of the dose is excreted as DON, and the glucuronide conjugate is the primary metabolite (Prelusky et al, 1987).
    3) Intestinal microflora can metabolize trichothecenes. In dogs, horses, and chickens, the colonic microflora metabolize DAS to the MAS form. In rats, sheep, and cattle, colonic microflora metabolize DAS to the deepoxy form (Swanson et al, 1988; Worrell et al, 1989). The deepoxy forms of the trichothecenes are essentially nontoxic.
    11.5.4) ELIMINATION
    A) GENERAL
    1) The half-life of the various trichothecenes varies with exposure to other xenobiotics and metabolic impairment due to infectious diseases (Coppock et al, 1987). The half-life of DAS ranges from 3.8 to 150.7 minutes in swine. The trichothecenes are eliminated by the renal and hepatic routes and possibly by direct excretion into the gastrointestinal tract.
    2) RESIDUES - There are concerns that residues of trichothecenes and their metabolites can enter the human food web via animal products. Doses of about 0.5 mg of T-2 toxin (PO)/kg of body weight given to a cow for 15 days resulted in 10 to 160 mcg/L of milk. A sow fed 12 mg of T-2 toxin/kg of feed excreted 76 mcg of T-2 toxin/L of milk. A cow in late lactation given a single oral dose of about 1.74 mg of DON/kg of body weight excreted approximately 0.0001% of the dose in milk. As a general rule, oral exposure concentrations of trichothecenes that would produce residues in edible porcine tissues would produce marked clinical signs of intoxication (Coppock et al, 1988). Approximately 0.13% of the dose of radiolabeled T-2 toxin given to hens was detected in eggs (Robison et al, 1978).
    3) In swine, DON was rapidly cleared essentially unchanged, and was excreted primarily in the urine, with minor elimination in bile.
    a) Although DON was eliminated rapidly and completely within 24 hours following a single intravenous or intragastric dose, the data in this study suggest that residues may undergo temporary sequestration in a tissue depot (Prelusky et al, 1988).

Pharmacology Toxicology

    A) GENERAL
    1) The trichothecene mycotoxins produce a bitter and persistent burning sensation upon contact with the tongue and mucous membrane of the mouth, and result in signs of feed refusal, head tossing, spitting out feed, and salivation. The toxins are potent emetics and the mechanism of action is excitation of the emetic center by stimulation of the area postrema and by gastrointestinal irritation. Salivation and bruxism may be signs of nausea. The toxins cause coagulation necrosis of the skin and mucosa membranes. The trichothecenes increase gastric emptying and accelerate the transit time of chyme in the intestine (Fioramonti et al, 1987), and gut permeability appears to altered; these effects produce diarrhea.
    2) The trichothecenes are potent immune suppressants and depress native responses to vaccine as well as virulent infectious particles. Increased occurrences of infectious diseases can be a manifestation of trichothecene mycotoxicoses. The trichothecenes induce leukopenia, especially a granulocytopenia, and anemia.
    3) T-2 toxin and DAS reduce conception and increase abortions, and the mechanism of action is assumed to be the cytocidal effects of the toxins on dividing cells of fetal and maternal tissues.
    4) Radiomimetic effects occur in all proliferating and metabolically active tissues, and vascular damage of the gastrointestinal tract and brain can occur (Coppock et al, 1985).
    5) All of the trichothecenes inhibit protein synthesis by inhibition of initiation and elongation, and DNA replication. None of the trichothecenes are known to react directly with DNA. The trichothecenes are not known to be carcinogenic.
    6) The trichothecenes can have a marked effect on cardiovascular function and the clinical signs mimic endotoxic shock (Coppock et al, 1985) 1985b; Pang et al, 1987). T-2 toxin induces a negative inotropic effect, and roridin-A induces a negative chronotropic effect (Bubien & Woods, 1987).

Sources

    A) GENERAL
    1) Trichothecene mycotoxins produced in feedstuffs are impure mixtures of precursor and degradation metabolites. A succession of different toxigenic fungi can also occur, and several chemical forms of mycotoxins can be produced. Thus, a complex mixture of mycotoxins can be produced in both human and animal foods (Coppock et al, 1990; Kazanas et al, 1984; Foster et al, 1986; Trenholm et al, 1989).
    2) Cereal grains unfit for human consumption are frequently diverted to animal feeds. Cereal grains can have a pink appearance from pigments produced by the toxigenic fungi. In some instances, the seeds can have a wholesome appearance and be contaminated with mycotoxins. Corn cobs and bean hulls can be highly contaminated. Milling by-products used in animal feeds have higher concentrations of toxins than whole grains (Trenholm et al, 1989; Lee et al, 1987). Feed processing will not degrade the trichothecenes.

Other

    A) OTHER
    1) GENERAL
    a) Diagnosis is based on clinical signs and finding trichothecene mycotoxins in feedstuffs and specimens. The toxins may not be uniformly distributed in the diet. The offending feedstuffs may have been eaten by the animal, wasted, or discarded by the owner. If collected during the exposure episode, liver, kidney, plasma, and feces can be assayed for the toxins and their metabolites. Samples must be preserved by freezing. The majority of veterinary toxicology laboratories can assay for trichothecenes. Limits of detection should be 0.1 mg of type A and B toxins/kg of feed.
    b) Pathologic findings include superficial lesions of the lips, nose, and oral mucosa. Hemorrhagic necrosis of the stomach and cecum occurs in swine; hemorrhagic necrosis of the cecum also occurs in cattle and possibly horses. In all species, erosions of the enteric mucosa can be observed, especially over lymphoid tissues. Hemorrhage can be observed in all parts of the body. Histologically, all rapidly dividing cells are affected. Enterocytes over lymphoid tissue and basal crypt cells are the most affected. Marked lympholysis occurs in the B-cell areas of the spleen and lymph nodes. Liver lesions are generally mild or do not occur.
    c) Hematologic findings are lymphocytopenia, large platelets, and circulating bone marrow cells including megakaryocytes and precursor cells in the erythroid series. General bone marrow depression, decreased hematocrit, decreased red and white cell numbers, microcytic hypochromic anemia, decreased serum proteins and iron, and increased serum triglycerides are evidence of intoxication (Coppock et al, 1989; Harvey et al, 1990). Activity of the coagulation and fibrinolytic systems are also decreased (Johnsen et al, 1988b).

References

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