XI. I'll AiaiACOLOGY 469 



(aiuH)Us and oral administration were t'oiind lo he 1:(>: 10. 'I'lieso data on 

 lethal dos(>s in mice and rabbits \k\\v been conrnnicd.- In monkeys, intra- 

 venons administration of 200 mji. per kilogram tailed to elicit any symp- 

 toms,' and only (iOO m^. pci- kilo^iam caused the first toxic symptoms.- 

 It is interesting to note that dojj;s and i)articularly monkeys are less sensi- 

 tive than rodents. Lethal doses of thiamine mononitrate as determined in 

 mice antl rabbits were not significantly different from those of thiamine 

 hydrochloride.^ 



On intra\enous injection of 50 mg. per kilogram tlaily for a period of 4 

 weeks, rabbits failed to show loss in weiglit, or other toxic manifestation. 

 No pathologic tissue changes were found on autopsj'.- Rats have been 

 maintained for three generations on a daily intake of 0.08 to 1.0 mg. of 

 thiamine, i.e., doses up to one hundred-fold of the daily requirement for 

 the vitamin, without any untoward effects.^" Other observations that daily 

 subcutaneous injections of 0.1 mg. of thiamine, though not affecting growth, 

 caused impairment of lactation and cannibalism and decreased fertility in 

 the second generations^ can hardly be taken as evidence of thiamine toxicity, 

 since these experiments were inadequately controlled, and the same mani- 

 festations were obtained in rats without thiamine injections on adding 

 manganese chloride to that particular diet.^- In the light of subsequent 

 discovery of other nutritional factors essential for the rat, these effects were 

 more likely due to inadequacy of the diet than to the injections of thiamine. 

 Prolonged daily administration of 1 mg. of thiamine to weanling rats main- 

 tained on a diet deficient in another B vitamin (riboflavin, pyridoxine, or 

 pantothenic acid) failed to cause significant effects on the weight of these 

 animals or on the manifestations of their deficiencj^ state.^^ 



The data on acute toxicity and the absence of evidence of cumulative 

 to.xicity give evidence for the very large therapeutic margin of thiamine. 

 The ratio between the daily requirement for thiamine and its lethal dose 

 has been variously estimated at from 600 to 70,000 (depending on species 

 and route of administration). 



Xo toxic efTects of thiamine administered by mouth have been reported 

 in man. Parenterally, doses of 100 to 500 mg., in single and repeated injec- 

 tions, have been given to patients.^'*"" Toxic or other effects have not been 



'" R. R. Williams and T. D. Spies, Vitamin Bi (Thiamine) and Its Use in Medicine, 



p. 286. The Macmillan Co., New York, 1938. 

 " D. Perla, Proc. Soc. Exptl. Biol. Med. 37, 169 (1937). 

 '= D. Perla and M. Sandberg, Proc. Soc. Exptl. Biol. .Med. 41, 522 (1939). 

 " K. Unna and J. D. Clark, Am. J. .Med. Sci. 204, 364 (1942). 

 " C. D. Aring and T. D. Spies, J. Neurol. Psychiat. 2, 335 (1939). 

 " E. L. Stern, Am. J. Surg. 39, 495 (1938). 

 '«N. Jolliffe, /. Am. Med. Assoc. 117, 1496 (1941). 

 " .\. Ruskin and G. M. Decherd, Jr., Am. J. .Med. Sci. 213, 337 (1047). 



