THE RELATIVE TOXICITY OF GERMANIUM AND ARSENIC FOR THE ALBINO RAT

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1 THE RELATIVE TOXICITY OF GERMANIUM AND ARSENIC FOR THE ALBINO RAT F. S. HAMMETT, J. H. MULLER AND J. E. NOWREY. JR., From The Wislar Institute of Anatomy and Biology, and the John Harrison Chemical Laboratory of the University of Pennsylvania, Philadelphia Received for publication September, The element germanium has a certain historical interest in the development of the science of chemistry in that it is one of the three substances the properties of which were foretold by Mendelejeff () by the aid of the periodic law. Its name is derived from the fact that it wa.s discovered by Winkler () in Germany in the silver ore at Freiberg. The chemical reactions and compounds of germanium somewhat resemble tin and the other members of the tin group, arsenic and antimony On account of this similarity and because germanium lies next to arsenic in the periodic system it seemed worth while to determine whether the element exhibits a similar toxicity towards the living organism as does arsenic, or whether it is relatively nontoxic as is tin. In the experiments which are here reported there was used a 0. per cent solution of germanium dioxide in Ringer s solution. The oxide was a sample of the chemically pure compound prepared and used by Muller () in his determination of the atomic weight of the element. For the testing of the toxicity of the arsenic there was prepared a 0. per cent solution of arsenic trioxide in Ringer s solution. Both of these stock solutions were sterilized before administration. The animals used in the study were mature, over 00 days old, non-pregnant female albino rats. As Hunt () has reported that the resistance of the animal organism to poison varies with the diet, it should be noted that the diet for the animals used here was uniform throughout. TH} JOUR. OC Vu RM. AND EXPER. THERAP., voi.. XIX, NO.

2 HAMMETT, MULLER AND NOWREY An attempt was made to administer the oxides by mixing them with the food; but it was soon found that quantitative dosage by this method was not attainable. Consequently the compounds were given by subcutaneous injections. Each animal was weighed immediately before the injection of the solution of the oxide, which was accomplished while the rat was under light ether anesthesia. The dosage in each case was graduated according to the weight of the animal and the amount that it was desired to administer per kilo of body weight. Three of animals were used for the determination of the toxicity of arsenic trioxide. The first, a preliminary, covered a wide range of dosage in order to determine approximately the lower limits for the fatal dose. The second and third were within narrower limits. In the study of the effect of germanium but two of rats were used because it was found that the germanium oxides is quite non-toxic even in relatively enormous doses. The results are given in the accompanying tables. It is seen that germanium differs markedly from arsenic with respect to its toxicity for the albino rat in that amounts of the former up to 0 mgm. per kilo of body weight produce neither death nor apparent evidences of harmful effect. Hence in so far as toxicity for the organism is concerned germanium resembles tin more than it does arsenic. This is physiological evidence that germanium is more closely allied to the tin group than to the arsenic group with regard to ts position in the periodic system. The results of the injections of arsenic trioxide show (table ) that by and large mgm. per kilo of body weight can be considered as the lethal dose for the average adult female albino rat. All of the rats which were injected with arsenic and which did not die, later developed areas of necrosis at the site of the injection. No necrosis followed the injection of the germanium dioxide. Comparing these results with arsenic with the reports of other investigators on studies of arsenic toxicity on lower animals we have been unable to find any references to work done on

3 GERMANIUM AND ARSENIC TOXICITY TABLE The results of the subcutaneous injections of arsenic tn oxide solution RAT-O NUMBER BODY WEIGHT AsuO INJECTED REMARE preliminary gm mg. mg Second Third

4 0 HAMMETT, MULLER AND NOWREY the albino rat. For the rabbit, guinea-pig, dog, cat and mouse, Willberg () reports the maximum tolerated dose of potassium arsenite to be to mgm., mgm., mgm., to mgm., and. to. mgm. respectively per kilo of body weight. Brouar- TABLE The results of the subcutaneous injections of germanium dioxide solutions RAT-P NUMBER BODY WEIGHT GeO INJECTED REMARKS First gm. mg. mg Second del () observed that a dose of mgm. per kilo of arsenious acid is fatal for the rabbit, while a dose of mgm. per kilo when injected subcutaneously is fatal to the guinea-pig. Towles () working with mice reports the minimal lethal dose of potas-

5 GERMANIUM AND ARSENIC TOXICITY sium arsenite as from to mgm., per kilo body weight when injected subcutaneously. When we come to compare our results with those scattered throughout the literature with respect to the fatal dose for man we are confronted with the lack of experimental data. Nevertheless Joachimoglu () has given the fatal dose for man as lying between 0. and 0. grams. This is equivalent to. to. mgm. per kilo body weight of a 0-kilo man. In the basis of these values the rat is from two to four times as resistant to arsenic as is man. This difference in resistance to fatal poisoning by arsenic of the two species is probably due to differences in the rates of the processes concerned in protein metabolism. For calculations made from the values published by Folin and Morris () for the protein metabolism of the albino rat as expressed by the urinary nitrogen excretion show that the nitrogenous excretion of the normal rat is from two to four times that of the average man, using the values published by Folin () in as the basis of the nitrogenous metabolism of the latter. This is further supported by the observations of Ringer and Murrell () which demonstrate that arsenic is a protoplasmic poison and destruc-. tive of nitrogenous tissue, and the fact that the nitrogenous metabolism of the rat is in many essentials entirely comparable with that of man with respect to the partition of the urinary nitrogen (). SUMMARY AND CONCLUSIONS A comparison of the relative toxicity of germanium dioxide and arsenic trioxide for the albino rat shows that the former can be administered subcutaneously in doses up to 0 mgm. per kilo of body weight of the experimental animal with no apparent harmful effects. The latter usually produces a fatal result when similarly given to mature, non-pregnant female animals in the ratio of mgm. per kilo of body weight. Moreover the injection of arsenic trioxide solutions is followed by marked necrosis and sloughing at the point of injection, which phenomena are not sequelae of the injection of germanium dioxide solutions.

6 HAMMETT, MULLER AND NOWREY It is therefore evident that germanium does not possess the toxicity for the living organism such as is exhibited by arsenic. It would appear from these results that the albino rat is more resistant to poisoning by arsenic than is man. Correlated data indicate that this difference is due to the difference in the degree of the protein metabolism of the two species. REFERENCES () MENDELEJEFF, D.: In Remsen s Inorganic Chemistry. th ed, 0, New York. Henry Holt and Company. () WINKLER, C.: J. Prakt. Chem., xxxiv,. () MULLER, J. H.: Jour. Am. Chem. Soc.,, xliii,. () Hur, R.: Hyg. Lab. Bull., U. S. Pub. Health Ser.,,. () WILLBERG, M.: Biochem. Z.,, li,. () BROUARDEL, G.: These de Paris,, cit. by Willberg. () TOWLES, C.: Jour. Pharm. and Exper. Therap.,, viii,. () JOACHIMOGLU, G.: Pharm. Post.,, xlix,. () FOLIN, 0., AND MORRIS, J. L.: Jour. Biol. Chem.,, xiv, 0. () F0LIN, 0.: Am. Jour. Physiol., 0, xiii,. () RINGER, S., AND MURRELL, W.: Jour. Physio., -,,.