Thiabendazole
From Wikipedia, the free encyclopedia
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Thiabendazole
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| Systematic (IUPAC) name | |
| 2-(1,3-thiazol-4-yl)-1H-benzoimidazole | |
| Identifiers | |
| CAS number | |
| ATC code | ? |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C10H7N3S |
| Mol. mass | 201.249 g/mol |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | ? |
| Half life | ? |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
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| Legal status | |
| Routes | ? |
Thiabendazole is a fungicide and parasiticide used primarily to control mold, blight, and other fungally caused diseases in fruits and vegetables. It is able to control roundworms, hookworms, and other helminth species which attack wild animals, livestock and humans.
Thiabendazole is applied to some bananas, including Chiquita brand bananas 'to ensure freshness'.
Thiabendazole is also a chelating agent, which means that it is used medicinally to bind metals in cases of metal poisoning, such as lead poisoning, mercury poisoning or antimony poisoning.
Thiabendazole is abbreviated to "TBZ". It is produced by Merck under the brand name Mintezol®.
Thiabendazole is also used as a food additive, a preservative with E number E233.
Thiabendazole is also used to treat ear infections in dogs and cats. It is sold by Merial under the brand name Tresaderm.
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[edit] Background and Toxic Effects
Thiobendazole (TBZ), more commonly referred to as thiabendazole or tiabendazole, is a general use pesticide used to control fruit and vegetable diseases such as mold, rot, blight and stain (1). TBZ was first registered as a pesticide in the U.S. in 1969 by Merck and Company, Inc (2). It is registered for use as a pre-planting dust treatment to different types of seeds and for use on mushrooms for irrigation applications (2). In addition, TBZ is registered as a spray and dip application during the waxing procedure for the different fruits and vegetables (2). TBZ hypophosphite salt uses include a ready-to-use formulation for the following non-food uses: ornamental bulbs, elm and sycamore trees (2). TBZ hypophosphite salt is also used as a preservative in paints, carpets, adhesives and textiles (2). TBZ is also a broad spectrum anthelminthic in various animal species and in humans (3). It is also shown to be effective in medicinal use as a chelating agent to bind metals (1).
TBZ is almost completely metabolized to inactive compounds and is primarily excreted by the kidney (4). Although it is considered a generally safe compound (5), the signs and symptoms attributable to TBZ toxicity were observed at the same time the highest metabolite concentrations occurred (4). Acute overexposure to this fungicide can cause dizziness, anorexia, nausea and vomiting (1). It has been shown to have low acute dermal toxicity (2) however there had been cases of severe erythema multiforme and Stevens-Johnson syndrome manifestations. Other symptoms include pruritus, skin rashes, headache, fatigue, drowsiness, drying of mucous membranes, hyperglycaemia, disturbance of vision including colour vision, leucopenia, tinnitus, enuresis, crystalluria, and bradycardia and hypotension but they occur less frequently (6). These symptoms are brief and dose-dependent (1). The thyroid and liver are the primary target organs of TBZ and has been found that it is likely to be carcinogenic at doses high enough to disturb thyroid hormone balance as seen in experiments with rats and dogs (2). At high enough doses, it caused growth suppression and decrease in bone marrow in mice (1). Other chronic effects include nephrotoxicity, as evidenced by tubular necrosis and severe kidney damage in mice and teratogenicity, causing impairment of mouse limb development and selective toxicity to embryo (7). It has also been shown to cause hepatotoxicity in humans, with several cases of intrahepatic cholestasis and micronodular cirrhosis, although its exact mechanism is still unclear (7).
[edit] Mechanism and Action of Toxicity
As a fungicide, TBZ inhibits fungal microtubular function, resulting in nondisjunction of chromosomes at cell division (8). Two types of action have been attributed to TBZ: that it inhibits transamination which is partially counteracted by exogenous pyridoxine and biotin and that it interferes with the transfer of amino acids in protein synthesis (9). However, subsequent studies resulted that TBZ’s primary mode of action against fungi is the inhibition of respiration due to a production of a lesion in the mitochondria (9). NADH and succinic oxidase as well as the respective cytochrome c reductases were inhibited by low concentrations of TBZ, but cytochrome c oxidase was unaffected, indicating that the block precedes it (9). The resulting decreases in other metabolic functions such as protein synthesis are just secondary to the impairment of mitochondrial function and unavailability of energy generation (9).
As an anthelminthic, its action might involve inhibition of the fumarate reductase system of worms, thereby interfering with their source of energy (10). Fumarate is one of the components of the citric acid cycle, which is a common pathway in organisms, and this possible mode of action of TBZ may be relevant in assessing the risks of humans after acute exposure (11). TBZ may also suppress the assembly of microtubules in worms, thus inhibiting secretion of parasite acetylcholinesterase leading to the termination of the worm (12). The basic pattern of drug metabolism involves several liver drug oxidizing and conjugating enzymes. The predominant metabolite formed from CYP1A2-catalyzed (7) TBZ metabolism is 5-hydroxythiabendazole (5-OHTBZ) which was formed by aromatic ring hydroxylation (3). 5-OHTBZ is further converted to a glucuronide or a sulfate conjugate and is eliminated in the urine and bile (7) (Appendix 1). Oral administration of TBZ to sheep, cattle and goats, and humans and dogs resulted in a rapid absorption from the gastrointestinal tract and excretion in urine and feces (3). Other metabolites include 4-hydroxylthiabendazole, 2-acetylbenzimidazole, N-methylthiabendazole acid, and benzimidazole (7). Current research indicates that TBZ-induced nephrotoxicity is a result of P450 dependent oxidative cleavage of the thiazole moiety in TBZ to a proximate toxicant, thioformamide (5). Epoxidation of the C=C double bond of the thiazole rings of TBZ occurs, and after its subsequent hydrolysis, the resulting epoxide would then decompose to form thioformamide and benzimidazol-2-ylglyoxal (13). However, it was also reported that TBZ irreversibly binds to tissue proteins through a CYP1A2-mediated mechanism (7), suggesting the existence of an electrophilic reactive intermediate although its clinical structure has not been identified (3). CYP1A2 was the only isoform in both liver and lung tissues, TBZ’s main sites of biotransformation, to increase protein bound residues levels (13). This reactive intermediate can be trapped by GSH, confirming that it had undergone oxidation to an electrophilic species (7). TBZ has been shown to increase the depletion of renal and hepatic GSH in vivo (14) and its depletion leads to more incidence of toxicity (15). The formation of this intermediate is attributed via bioactivation of 5-OHTBZ. Structural similarities between the 5-hydroxybenzimidazole portion of TBZ and p-amino-substituted phenolic compounds such as acetaminophen suggests that 5-OHTBZ can undergo metabolic activation to quinine imine-like species via oxidation by enzymes systems such as P450 or peroxidases (7) (Appendix 1). The early and extensive 5-hydroxylation of TBZ could compete with the usual metabolic pathways leading to the formation of the protein bound residues (3). Significant correlation was found between the rates of 5-hydroxylation and the formation of these residues (3).
[edit] Environmental Occurrences, Typical Levels and Routes of Exposure
TBZ (2-(4-thiazolyl) benzimidazole) is a synthetic compound available as 500 mg chewable tablets and as a 500 mg/5 mL oral suspension (16). It is also available as a wettable powder, emulsifiable concentrate, flowable concentrate, granules and water-dispersible granules (1). Usage data from 1987-1997 indicates an average domestic use of approximately 41,000 lbs. active ingredient (a.i.) per year for pre-harvest usage and approximately 109,000 lbs. a.i. per year for post-harvest usage (2). TBZ and its metabolites, 5-OHTBZ and thioformamide, contribute to the toxicities observed in livestock and humans (Appendix 1).
Multiple use of TBZ may cause entry of its residues into the human food chain, either through direct exposure or through exposure to agricultural products and to food-producing animals (13). Birds and mammals can be exposed with the use of TBZ as foliar sprays or granulars by a variety of routes, including ingestion, dermal contact, and inhalation (2). Exposure to wildlife is not relevant until the TBZ-treated seeds are planted back to the fields, and therefore are of minimal danger to birds and mammals (2). Peak concentrations in plasma occurred 4 to 7 hours after dosage, with the concentration decreasing rapidly afterwards (17). Radioactive labeling quantified 85% of the compound eliminated in the urine (65%) and feces (20%) after three days (17). No residual TBZ or its metabolites were detectable in tissue after administration however small quantities of the drug appeared in the milk of lactating animals (17). The presence of an electrophilic reactive intermediate binding to tissue proteins, however, can increase health risk for consumers (13). When 1000 mg (approximately 14 mg/kg) thiabendazole was administered orally, plasma concentrations peaked at 13 to 18 parts per million (ppm) within an hour (18). Within 4 hours, 40% of the dose was excreted, and within 24 hours, 80% was excreted, mostly in the urine as metabolites of the compound (18). Metabolites are distributed throughout most body tissues in sheep, but detectable in only a few tissues at low levels (less than 0.2 ppm) at 16 days and at very low levels (0.06 ppm or less) after 30 days (19).
Endpoints for acute and chronic exposure and reference doses for dietary exposures were determined (2). Reference dose is 0.1 mg/kg/day (1) with children ages 1-6 having the highest exposure (20). The amounts of TBZ through food exposure were found to be 0.056 mg/kg/day, 0.053 mg/kg/day, and 0.76 mg/kg/day for U.S. population, females ages 13-50 and children ages 1-6, respectively (2). No observed adverse effect level (NOAEL) is observed to be 10 mg/kg/day while the lowest observed adverse effect level (LOAEL) is 30 mg/kg/day in both acute and chronic exposure (2). Established tolerances, based on current use data, are adequate for TBZ residues in different plants such as bananas, carrots, citrus fruits, mushrooms and potatoes (2). Reassessment of tolerance in animal products and some plants such as banana pulps and sweet potato are currently being evaluated (2).
Levels found in the environment are not of major concern. The peak concentration found in surface water is 2.4 parts per billion (ppb) while less than 0.01 ppb were found in groundwater (2). Allowable exposure to water were set as 0.043 mg/kg/day, 0.047 mg/kg/day and 0.23 mg/kg/day for U.S. population, females ages 13-50 and children ages 1-6, respectively (2). TBZ is of minimal threat to drinking water and is not a concern (2). There have been no recorded circumstances where the level of TBZ has been unusually high in the environment (2). The only non-occupational risk exposure expected to occur may include short-term application of TBZ-treated paints by adults and exposure to TBZ-treated carpets by children and infants (2).
However, it was found that TBZ is highly toxic to freshwater estuarine fish and other invertebrates (2). The lowest LD50 is >0.1ppm but <1ppm and it is categorized as highly toxic to freshwater fish (2). Nonetheless, the risk of leaching and exposure is very low because of its high affinity to soil and its rapid photolysis in water. The acute or chronic level of concern from maximum seed treatment of wheat and other crops did not exceed the toxic dose for freshwater fish and invertebrates (2). There is minimal potential risk to terrestrial animals or aquatic animals resulting from the use of this fungicide to control diseases as a seed treatment and as a post-harvest treatment (2). LD50 in birds and other mammals such as rats exceed 2000 mg/kg/day and of no concern because it is practically nontoxic as compared to the levels present in the environment (2).
[edit] Environmental Fate
It has been shown that TBZ is quite persistent in the environment. TBZ is stable to photolysis in soil and to hydrolysis (2), with a calculated half-life of 933 days (21). Average recoveries of 14C-labelled TBZ molecules in irradiated and unirradiated soil were about 98% and 104%, respectively (21). Trace levels of TBZ can be detected as high as 0.033ppm (detection limit of 0.01ppm) (2). It showed strong binding to soil due to its high soil/water partitioning coefficients (2), limiting the amount available for leaching into ground water and for runoff into surface water (2). The adsorption of TBZ to soil was studied in different kinds of soil and it showed KOC values ranging from 1104 and 22467, indicating its very strong affinity to soil (21). Desorption of TBZ was also low, with KOC values from about 1336 to 18325 (21). Leaching studies indicated that majority of TBZ remained at the surface of the soil (21).
Under aerobic and anaerobic conditions, it does not metabolize significantly (2). Its fate in microbially active sandy loam soil was studied under aerobic conditions and it was degraded with an aerobic half-life of about 733 days (21). Low levels of benzimidazole and 5-OHTBZ were found as degradation products, measured around <2.5% and <0.5%, respectively (21). There is an increase in the activity of unextractable 14C-labelled TBZ molecules during the study from 1.25% to 20.2% after three months, alongside the increase of volatile material consisting of mainly CO2 (21). These results were consistent to the observation that TBZ is fairly stable in soil but eventually mineralized under aerobic conditions to CO2 (21). Very little degradation was observed at anaerobic conditions with bendimidazole as a degradation product (2).
TBZ, however, undergoes rapid photolysis in water when exposed to artificial sunlight, with a half-life of approximate 29 hours (21). Thiabendazole, in aqueous pH 5 buffer solution exposed to xenon lamp for 96 hours at 25ºC, undergoes rapid photolytic degradation, with a half life of approximately 29 hours (2). Photodegradation involves primarily the structural alteration of the thiazole ring (2). Benzimidazole-2-carboxamine, benzimidazole, and benzimidazole-2-carboxylic acid were identified as degradation products of photolysis (2).
There is no data of TBZ’s inhalation toxicity (22) and degradation in air. TBZ is non-volatile at room temperature; therefore, there is no potential for acute and intermediate-term duration exposure (2) (22) (20).
Because of TBZ’s persistence, its residues are taken up by crops and fruits. There is a predominant axoplasmic movement of TBZ which results in measurable levels of TBZ residues in shoot tissues such as leaves and straw, and relatively less in storage tissues such as grains and roots (21). Further experiments concluded that TBZ does not penetrate into the fleshy tissues and does not undergo metabolic transformation since benzimidazole is not detected (21).
[edit] Conclusion and Future Research Needs
TBZ was, and still is, extensively studied since its introduction in 1969 by Merck and Company, 1969 (2). Levels in the environment are of minimal concern and TBZ is considered generally safe and nontoxic to humans, as shown by its LD50 values in mammals and its measured exposure risks. Bioaccumulation risk is low because of its rapid absorption and subsequent excretion. However, aside from its thiazole moiety’s well-documented nephrotoxicity, the exact mechanism and structure of its electrophilic reactive intermediate toxicity is still unclear. The in vivo relevance of 5-OHTBZ activation by peroxidases and P450 enzymes and the observed consequent GSH depletion have not been established fully (7). They were just presented as possible mechanisms of toxicity. Further studies are still needed to fully determine the extent of its toxicity. Because of the almost negligible levels of TBZ in the environment, current exposure guidelines are reasonable and appropriate. TBZ continues to be used as post-harvest treatment of different crops and fruits. Although it is generally nontoxic, TBZ is still persistent and it would useful if faster ways of degradation can be established. Except for inhalation toxicity, its environmental risks are accounted for and they present detailed prevention procedures. The effects and levels of this pesticide can be anticipated and controlled.
Nevertheless, with the changing agricultural practices today and the introduction of new breed of crops, it will be necessary to study if it will change the activity of TBZ in these conditions. Interactions with other pesticides or other compounds will need to be reassessed in accordance to the introduction of new compounds. New drugs are also being introduced. Since it is also used as an anthelminthic, it is also important to determine its drug interactions with these drugs to eliminate possible adverse effects. The available information describing the adverse effects of TBZ is inadequate and most of their mechanisms are still unclear.
[edit] References
1.Extoxnet; thiabendazole; Oregon State University, http://extoxnet.orst.edu/ pips/thiabend.htm. [Accessed October 28, 2006].
2.United States Environmental Protection Agency. Reregistration Eligibility Decision (RED) Thiabendazole. Prevention, Pesticides and Toxic Substances, 2002.
3.Coulet M, Eeckhoutte C, Larrieu G, Sutra JF, Hoogenboom L, Huveneers-Oorsprong M, Kuiper H, Castell J, Alvinerie M, and Galtier P. Comparative metabolism of thiabendazole in cultured hepatocytes from rats, rabbits, calves, pigs, and sheep, including the formation of protein-bound residues. J Agric Food Chem 1998; 46: 742-748.
4.Bauer L, Raisys V, Watts M, and Ballinger J. The pharmacokinetics of thiabendazole and its metabolites in an anephric patient undergoing hemodialysis and hemoperfusion. J Clin Pharmacol 1982; 22: 276-280.
5.Mizutani T, Yoshida K, and Kawazoe S. Formation of toxic metabolites from thiabendazole and other thiazoles in mice. Identification of thioamides as ring cleavage products. Chem Res Toxicol 1994;22:750–755.
6.MICROMEDEX® Healthcare Series; Tiabendazole; Martindale – The Complete Drug Reference, site. [Accessed October 28, 2006].
7.Dalvie D, Smith E, Deese A, and Bowlin S. In vitro metabolic activation of thiabendazole via 5-hydroxythiabendazole: identification of a glutathione conjugate of 5-hydroxythiabendazole. Drug Metabolism and Disposition 2006;34(4):709-717.
8.Watanabe-Akanuma M, Ohta Toshihiro, and Sasaki Y. A novel genotoxic aspect of thiabendazole as a photomutagen in bacteria and cultured human cells. Toxicology Letters 2005;158:213-219.
9.Allen P and Gootlied B. Mechanism of action of the fungicide thiabendazole, 2-(4’-thiazolyl)benzimidazole. Applied Microbiology 1970;20(6):919-926.
10.Parfitt, K. Martindale. The Complete Drug Reference, 32nd Ed. London: Pharmaceutical Press, 1999.
11.IPCS Inchem; Toxicological evaluation of certain veterinary drug residues in food; WHO Food Additives Series, http://www.inchem.org/documents/jecfa/ jecmono/v49je03.htm#2.1
12.Gilman AG, Goodman LS, Rall JW, et al. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 7th. Macmillan Publishing Co, New York, NY, 1985.
13.Coulet M, Eeckhoute C, Larrieu G, Sutra JF, Alvinerie M, Macé K, Pfeifer A, Zucco F, Stammati AL, De Angelis I, Vignoli AL, and Galtier P. Evidence for cytochrome P4501A2-mediated protein covalent binding of thiabendazole and for its passive intestinal transport: use of human and rabbit derived cells. Chemico-Biological Interactions 2000;127:109-124.
14.Mizutani T, Ito K, Nomura H, and Nakanishi K. Nephrotoxicity of thiabendazole in mice depleted of glutathione by treatment with DL-buthionine sulphoximine. Food Chem Toxicol 1990;28:169–177.
15.Mizutani T, Yoshida K, and Kawazoe S. Possible role of thioformamide as a proximate toxicant in the nephrotoxicity of thiabendazole and related thiazoles in glutathione-depleted mice: structure-toxicity and metabolic studies. Chem Res Toxicol 1993;6:174-179.
16.Product Information: Mintezol®, thiabendazole. Merck & Co, Inc, West Point, PA, 1998.
17.Tocco D, Egerton J, Bowers W, Christensen V, and Rosenblum C. Absorption, metabolism, and elimination of thiabendazole in farm animals and a method for its estimation in biological materials. The Journal of Pharmacology and Experimental Therapeutics 1965;149(2):263-271.
18.Edwards IR, Ferry DG and Temple WA. Fungicides & related compounds, In Handbook of Pesticide Toxicology. Hayes, W. J. and Laws, E. R., Eds. Academic Press, New York, NY, 1991.
19.U.S. National Library of Medicine. Hazardous Substances Databank. Bethesda, MD, 1995.
20.Directorate E - Public, animal and plant health: Unit E1 Legislation relating to crop products and animal nutrition. Review report for the active substance thiabendazole. European Commission – Directorate-General Health & Consumer Protection, 2001.
21.Pesticide Residues in Food – 1997 Evaluations. FAO Plant Production and Protection Paper 145. Food & Agricultural Organization. Rome, 1998.
22.Gaunt, Patricia. Thiabendazole – Report of the Hazard Identification Assessment Review Committee. Health Effects Division, 1999.
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| Antibiotics | Griseofulvin, Hitachimycin, Natamycin, Nystatin |
| Topical Azoles | Clotrimazole, Econazole, Fluconazole, Ketoconazole, Miconazole, Oxiconazole, Sertaconazole, Sulconazole, Tioconazole |
| Other topicals | Ciclopirox, Ethylparaben, Flucytosine, Salicylic acid, Selenium sulfide, Terbinafine, Tolnaftate |
| For systemic use | Amphotericin B, Anidulafungin, Caspofungin, Griseofulvin, Itraconazole, Terbinafine, Voriconazole |
| Other | Posaconazole, Thiabendazole, Tea tree oil |
