M e t y in the chemical loborotory
edited by MALCOLM M. RENFREW University of idaha MOSCOW.Idaho 83843
Is Thioacetamide a Serious Health Hazard in Inorganic Chemistry Laboratories? Hannu Elo University of Helsinki. Vuorikatu 20. SF-00100 Helsinki 10. Finland
A couple of decades ago, thioacetamide was introduced into elementary chemistry laboratories to replace hydrogen sulfide gas as an analvtical reaeent in aualitative inorganic anaiysis. hi was dbne largely hecause hydrogen sulfide was known to constitute a health hazard-and to have an awful
Teachers of chemistry have been concerned about the use of thioacetamide in , :--:--. . & .. .. :
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nogenic properties ot this reagent were recognized. Hence, we welcome this welldocumented contribution to our safety column, but we wish to change the emphasis somewhat. Our consultant on toxicology, Blaine McKusick, difters from theauthor in rating the degree of hazard: thioacetamide should be classified as a moderate carcinogen accord ng la present standards of the Amer can conierence of Governmonta industr'la"nyglenrsrs. ' ' .. Qtutious handling, as recommended in the ,ACS Safety in Academic Chemistry 7 ~ . " ~ ; o c,"*h -A "- 4, 7 ""A "9, ,, :,, Labc...., minimize hazards: that is, persons who prepare the dilute ~olutionstor Student laboratories must exercise full precautions (work in a good hood and wear protective gloves). StudenlIS using the solotions must avoid skin conta13 and wash up when leaving the laborat01 ry.
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Leftover reagent is conveniently destroyed by heating it at 45-50' for an hour with 5 molar equivalents (25% excess) ot sodium hypochlorite In the form of commercial laundry bleach. which is usually 5.25% (0.75 N) in sodium hypochlorite. The reaction mixture can be flushed down thedrain with a large excess of water (National ReSearch Council. Prodent Practices for Disposal of Chemicals fmm Laborate ries: National Academy Press, Washington. DC, 1983. p 68).
The hypochiarlte converts thmacetamide toacetamide, whlcn thaanicie callsa carcinogen, but which is close to the borderline that separates carcinogens fmm nancarcinogens. Certainly it is less danger-
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smell. Thioacetamide does not share the last-mentioned unpleasant property, so it is easy and convenient to handle. But even such a comoound mav in fact have deleterio u r e t f e c t s m human health l l n f o r t u n n t r l ~ . th~risthemat-nliow i t h ihiuacctamide. And w e n mure unimunatc in that it*dangarous properties seemingly are not well known by many of those people who are using it. Obviously, the compound is principally used by students who are at the very beginning of their chemistry studies. Because even their instructors often seem to be unaware of its hn~nrdourpoirntial, I w r h tl, present hcrca collecr~onol'dataun its torrceffects.'l'hr lirt is hv nu rncans nmplele hut shwld in any case given an impression of the dangerous potential of this commonly used compound. In the author's opinion, the most dangerous property of thioaeetamide is its carcinogenicity. In animals there is no doubt that this compound is a hepatocarcinogen and also has other deleterious effects on the liver. Thus, when Gupta administered to 150 albino Wistar rats 0.032% thioaeetamide in the diet and killed the animals a t various intervals, he found localized areas of cholangiofihrasis after 11 weeks. Of 36 animals killed between nine and 23 weeks. 22 had chdangmfihrusis, Id had bile duct tumors and fiw ~howcdc y ~ t i cdilataums o f hilr ducts. Nosuch changes were obrerved in 50 controls ( I ) . In a later paper, he reported that metastases of liver tumors were observed in the ovaries of most female rats similarly treated with thioacetamide for 47 weeks or longer ( 2 ) . Fitzhugh and Nelson, who reported a study on the effects of the compound on albino rats, also found it to be tumorigenic in the rat liver and, in addition, to be a patent producer of nodular cirrhosis (3).Several other investigators have also reported that thioacetamide is tumorigenic in rats (see refs 4 4 ) . The formation of cirrhosis has also been firmly documented by many groups (2, 7 , 8 ) . Also in mice, thioacetamide is a hepatocarcinogen. Thus, Gothoskar et al. reported a study in which Swiss-strain mice, 2 months old, were put on a diet containing 0.03% thioaeetamide. Control and treated mice were killed at the ages of 6,9,13, and 17 months and were studied. In the 17-monthold group, 12 out of 13 treated mice had developed hepatomas. Although metastatic lesions were not seen, these tumors were diagnosed as carcinomas and were transplantable. In the mice killed s t earlier times, gen-
eralized hypertrophy of hepatic cells, hyperplasia of biliary cells, and cirrhosis were observed. In controls, no liver tumors were seen (9). In addition to its carcinogenic potential, thioacetamide also has hepatotoxic properties. Thus, in a dietary concentration of 0.03290,it was reported to induce cytological changes rapidly in the parenchymal cells of rat liver, the most striking effects being the doubling of nuclear volume, increased nucleolar and cell volumes, and altered basophilia of the cytoplasm. The changes were well developed within a few days of treatment. They were, however, a t least partially reversible on withdrawal of thioacetamide from the diet. At the same time with the cytological changes caused by thioacetamide, there was a considerable increase in the weight of the liver ( 8 ) .Essentially similar results have been reported also when thioacetamide was given subcutaneously to rats. In addition to liver damage, some cytological changes were also detected in the kidneys (10). The acute toxicity of fairly large doses of thioacetamide has also been studied (7.11): it is moderately toxic by the oralrbute: Thus, Ambrose et al. reported that rats invariably died within a few days after an oral dose of 200 mg ar more per kg body weight ( 7 ) . With another strain of rats, however, essentially different results were obtained with the same dose. The toxicity was much lower, and no early deaths were encountered. This dose of thioacetamide, however, consistently produced widespread necrosis of the liver after 24 hours when administered by various routes. The first change, apparent after 6 hours, was theloss of glyeogen and cytoplasmic hasophilic bodies (11). I t has even been stated that "the ease of production and the constancy of hepatic damage in acute thioaeetamide toxicity makes this substance a useful agent in the study af the biochemical changes underlying this type of liver damage" ( I 2 ) ,and it has been used in many studies. Various biochemical changes also have been reported to occur in the liver after thioacetamide administration ( 5 , 1 2 ) .When mice were put on a diet containing 0.03% thioacetamide. their liver elvcoeen content and the activities of glueoneogenic enzymes were significantly decreased after two
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months. Later, other biochemical changes were also ohsewed (5). Large doses of thioacetamide also have been shown to impair mitochondrial function rapidly (12). In addition, thioacetamide induces liver ornithine decarboxylase, this property being made use of in biochemical studies on ornithine deearhoxylase inhibitors (13). Thioaeetamide is also known to he mutagenie. Mutagenicity tests on Drosphila melanocaster showed a sienificant increase in sex-linked rercrriue lethals alter treatment with thiuacrtamidc, both after mjertionand after feeding of males (141. The compound has also been found to have mutagenic and recombinogenic activity in microbial systems (15-18). Like some other carcinogens, thioacetamide also produces hormone imbalance in immature chicks bv increasine serum progesterone concentratrons, and. , induces obwuu~lyas a result of t h ~ also ovalhumin synthesis (19). Thioacetamide is possibly metabolized in viva to acetamide, which is less careinogenic. For a short review of the metabolism and pharmacokinetics of thioacetamide, the reader is referred to ref. 6. Taken together, the results reviewed above indicate that thioacetamide is a powerful carcinogen and also has other serious adverse effects. Although the data presented pertain mainly to oral administration, there is so far no reason to believe that other routes of challenge (such as inhalation and skin contact) would be less dangerous. Therefore, care should be exercised when handling the compound. In the author's opinion, all skin contact should he rigorously avoided, and all experiments where dusts or vapors of the compound may be formed should be performed in a goad hood. I t is especially important to inform students about the carcinogenic potential of the compound and to make sure that they obey the necessary precautions. Possibly the use of the compound should he restricted to a minimum. ~
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Literature Cned I. Gupta, D.N. Nature (London) 1955,175,257, 2. Guota. D. N. J. Poth. Boct 196C 72.116. ~, -. 3. Fi~ku~h,O.G;Nelaon,A.A.Science 1948,108,626. 4. Svobada,D.: Hierinaon. J. CancwRaa. 1968.28.1103. . . 5. Bbide. S. V. ~ r . Cancer 2
[email protected],504. 6. IARC Monographs on the Euoluotion of C ~ r c i n o e ~ n i c ~
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u.s.A., 49SheridaoAvenue. Albany, NY 12210.) 7. Amhrose,A. M.: DeEds. F.: Rather L. J. J . I d . Hvg. Tolical. 1949,31.158.
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8. Rather. L. 3. Bull. Johns Hophim Hosp. l951.88,36. 9. Gothas!ax, S. V.: Talw&ar, G.V.: Bhide. S. V. Br. J. Comer 1910,24,498. 10. Kleinfeld,R. G. ConcrrRes. 1957,17,954. 11. Gupta.D.N. J.Poth.Bocl. 1956,56,183. 12. Gallagher,C.H.:Gupta.DN.;Juddh,J.D.;RPPs,K,R. J Pofh. Bod. 1956,72,193. 13. Soanouaky,G.:Lu!wo, J . ; G w e b , E.:Zuretta,M.F.J. Mod. Chem. IJIIE. I R I S L O 14. Megnusson.3.; Ramel. C. MutotionRoa. 1978,58,259. 15. Ichinotaubo. D.; Mower, H. F.: Setliff J.; Mandel, M . MvtalionRos. 1977,46,53. 16. Simm0n.V.F. J . N a f l . ConcerInst. lW9,62.901. 17. Simmon, V. F.; Rasenlusnz,H. S.; Z i r , E.: Poirier. L. A. JNaLI. Conearlnst. 1979,62,911. 18. Poirier, L. A,; de Serres, F. J . Notl. Gamer Inst. 1979. m 0,~
Journal of Chemical Education
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