Toxicology of Thiram (Tetramethylthiuram Disulfide): A Review

R R Oalvi PhO, A3T

Oepartment of Physiology and Pharmaeology, Se 001 of Veterinary Medicine,Tuskegee Un ivers i ty, skegee, AL 36088

(Reeeived May 31,1988; Aeee ted June 7,1988)

Thiram, tetramethylthiuram disulfide, isextensively used as an agricultural fungi-cide for both foliage application and seedtreatment. It is also used as a nut, iruitand mushroom disinfectant as well as arepellent for rodents and certain largeanimaIs that cause damage to field crops(1,2). The fungicide is an ingredient oicertain medicated soaps, and suntan andantiseptic sprays. In addition, it is usedas a rubber accelerator in tire industryand an antioxidant in plastic industry. Itmay also be used in the blending of lubri-cating oils. This chemical can be foundin the environment as a degradation productof the two widely used fungicides, ferbamand ziram (3).

Thiram is a white crystalline solid com-pound, insoluble in water but soluble inmany organic solvents such as chloroform.It is stable under normal storage conditions;however, there can be a loss of its activityon prolonged exposure to air, heat andmoisture. It is decomposed by acids.Thiram can enter the body through inhalationof dust, spray or misto Other routes in-clude ingestion, and skin and eye contact.Workers from rubber and lubricating oilindustries are at a greater risk of exposure.The exposure leveI of thiram in the air atworkplace should not exceed 5 mg/cubic meterduring any 8-hr workshift for 40-hr workweek. No-adverse effect leveI of thiram inwater has been reported to be 0.035 mg/l.According to a published report, the highestno-effect leveI for the rat is 48 ppm inthe diet fed to the animaIs during a three-generation study (4). On the other hand,a recent study has shown that the no-effectleveI for the rat is 38 ppm (5), Residuetolerances for thiram when used as fungi-cide have been set at levels up to 7 mg/kgfor variety of fruits and vegetables. TheWHO recommended acceptable daily intake(AOI) is 5 ~g/kg oi body weight (6).

TOXICITYExcessive exposure to thiram may produce

irritation oi mucous membranes, conjunctivi-tis, rhinitis, sneezing and coughing inthe exposed subject. Skin irritation witherythema and urticaria may also occur.Allergic contact derrr.atitishas been report~ed in workers who had worn rubber glovescontaining thiram. A similar type oi con-tact dermatitis has been seen in rabbitsfollowing intracutaneous administration of0.1 ml of 0.5% thiram (7). On the otherhand, a sing1e app1ication oi thiram to480

the skin oi rats and rabbits in ~ce :~~=of an oily solution in doses oI O -2_::mg/kg and 500-1000 mg/kg, respect~-e:~did not produce either skin irriLa~~~~ C~

general toxicity. Similarly, re_ea~eê a~-plication of the compound to the sk~= ~-rabbits in a dose of 50 mg/kg d:' _duce any skin maniiestations (8).

The acute oral toxicity (LD50) o: ~=~~a=for mammals ranges frem 230 to 2,8 ° =5 ~5(Table 1). AnimaIs killed by sing:e ~a:doses of thiram showed hyperemia, = ca:ulceration oi the gastro-intesLi a: ~ra~-,focal necrosis oi liver and rena~ -'b~:esand patchy demye1ination in Lhe cere~e::~and medulla (9). Symptoms ai ac ~e ~L~ra=poisoning in humans include nausea, ,a=~~~=g,diarrhea, headache, lethargy, d~zz~=ess,ataxia, coniusion, drowsiness, f acc~~paralysis and death. li deaLh ôoes co-occur, recavery tends to be co~p:eLe w~~~~=1 or 2 w~eks.Chronic exposure oi rats to 100, 300 a=à

500 ppm dietary thiram resul-eà in reô'cegrawth rate, nervous dysiuncLians, cyrai'hyperplasia, calcification af braic aoincreased mortality rate (11). AnaL erchronic taxicity study in rats sbawed Lha~300 ppm thiram in the diet caused rise icwhite blood cells, and SGPT and SC~ ind:-cating liver damage (12). In his st dy,the author also observed falI in gammaglabulin leveI in the serum ai thirarn-expasedrats. Other studies have shown growth re-duction as the dietary leveI exceeds 100ppm (13). In a study conducted by Russianworkers, chronic oral administration ofthiram retarded the growth oi rats, decreasedb100d hemaglobin levels, inhibited bloodcatalase and peraxidase, and caused destruc-tive-dystrophic changes in the spleen,liver, and ather organs (14).

Productian af abnarmal eggs in large henpopulation has been attributed to ieedingof maize treated with thiram (10). Chicks

Table 1. Oral toxLcl~y of thlram 1n d1ff~rent 90ecle9 (2,10)

Species Oral Toxlcltv (mq/kq)

RatMiceRabbitHamstersCatSheeoPiasMallard ducksPheasants

620-640. toSO2050-2500. L0503S0. LOSO2S0. toxic dose230. lethal dose225, lethal dose

1000. lethal dose)2800. tOSO485-932. tOSO

Vet Hum Toxicol 30 (5) October 1988

fed 40 ppm of dietary thiram caused legweakness while goslings lost weight andshowed leg deformities at a leveI of 150ppm. Lower egg production, weight lossof the ovary and oviduct and decrease inserum calcium leveI have been reported inbobwhite quail following 10ng-term exposureto thiram (15). Similarly, chronic exposureof sheep to low leveI of thiram has beenreported to cause abortions in pregnantanimaIs. Prolonged ~:cupational exposureto thiram has been found to increase theincidence of hypertension, myocardiodystrophy,diseases of the hepatobiliary system, thyroiddiseases, and gastrointestinal diseases (16).Other effects of prolonged cccupationalexposure to thiram include lachrymation,photophobia, conjunctivitis, reduced visionacuity and corneal sensitivjty, and increasedpressure in the retinal artery (17).

Thiram has been found to be teratogenicin hamster (18) and mice (8). It causesmutagenic effects in mice characterizedby chromosomal aberrations in bone marrowcells (19).

METABOLISM

Published reports suggest that the meta-bolism of thiram probably plays an importantrole in its toxicity. For example, Nitscheet aI (20) reported that the fungicidesferbam, ziram and thiram are not stableunder certain environmental conditionsand can be degraded to toxic products suchas carbon disu1fide, hydrogen su1fide anddimethylamine. These researchers were ableto determine dimethylamine, a possiblecarcinogen, as a degradation product ofthiram under in vitro acidic conditions. Onthe other hand, carbon disulfide, anothermetabolite of thiram, was detected by Mer-levede and Peters (21) in the expired airfollowing oral administration of thiram tomano A recent report by Dalvi and Deoras(22) suggests an involvement of livermicrosomal enzymes in the formation ofcarbon disulfide which was detected in theexpired air of rats administered thiramintraperitoneally. Similarly, Hodgson etaI (23) administered ferbam, a fungicidethat degrades to thiram, orally to ratsand found carbon disulfide as a metabolitein the expired air while other metabolitesdimethylamine and dirn8thyldithiocarbamatewere identified in the urine.It has been reported that tetraalkyl-

thiuram disulfides such as disulfiram reactwith thiol compounds (eg reduced glutathione)present in reticulocytes~and perhaps other .cells to yield dialkyldithiocarbamates asmetabolites (24,25) which subsequently arebiotransformed to carbon disulfide by liverenzymes (26,27). An identical liver metabo-lism of thiram to dimethyldithiocarbamateand carbon disulfide has been postulated(22). Disulfiram, an ethyl analogue ofthiram which is several times less toxicthan thiram, has been shown to cause liverdamage probably through its metabolism tocarbon disulfide, a highly liver toxic com-pound (26,28). There is an evidence to

s'ggesL that thiram is also toxic to li 'eras oanifested by inhibition of hepaL~C ~~cro-so aI enzymes and elevation of the aCL~viL'o: some serum enzymes usually used as 'markers of liver damage (22, 29-31).

MECH~NISM OF ACTION/INTERACTIO'S

Se 'eral mechanisms for the toxic e:iec~sof thiram can be proposed. They are ~os-:vrelated to its metabolism and inhibi-io~ .of certain enzymes produced bv thir~ orits me1:aboli t es, Carbon d í suLf í de , a .e::ab-olite of thiram, is a well known neuro-toxicant and some of the central ervo'ssystem toxicity of thiram may be a Lrib ~edto this metabolite. Similarly, this e~ab-olite may account for part of the heoa-o-toxic effects seen in thiram intoxicâtior..Another metabolite of thiram, d~me 'y ci~'io-carbamate, can be responsible for cho:~~-esterase inhibition and consequently :orneurological disorders caused by 1:hira=.(32,33). Chelation of certain important e_e-ments by dimethyldithiocarbamate, wh~c~ areessentia1 as cofactors for many enz-~e_,may also result in decreased enzy es ac::~'i-ty in the nervous system leading 1:0 ce~r -toxic effects.Disulfiram (ANTABUSE) has been reoor-e' LO

be a potent inhibitor of dopamine 3:h.drox: -ase (34). Since disulfiram and ir~ arestructural anologues and produce s~~i:artoxic effects, inhibition of dopami~e ~-hydroxy1ase by thiram leading 1:0ce~1:ra:nervous system manifestations is possib_e.Certain key sulfhydryl enzymes such as hexo-kinase and amino acid oxidases are alsoinhibited by disulfiram and thirarn, b sproviding another biochemical basis :or -_eirtoxicity (9).

The basis for disulfiram as ao alcoholaversion drug is that it inhibits alde' ydedehydrogenase and produces discomfor~ iaalcoholic patients taking the drug andalcohol together. This is though1: to bedue to accumulation of ace~aldehyde. 10-tolerance to alcohol has been observed inworkers exposed to thiram, manifested byflushing of face, palpitation, rapid pulse,dizziness and hypotension (35). Thesetoxic effects can also be attributed tothe inhibition of aldehyde dehydrogenaseby thiram and subsequent accumulation ofacetaldehyde. Another ioteraction ofthiram involves its chemical reaction withnitrite at acid pH in stomachs of guineapigs in vivo which gives rise to N-nitro-sodimethylamine, a potent carcinogen (11).

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