The Toxicity of Caffein: An experimental study on different species of animals

Chapter III: Part 3

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February 14: 3.45 p. m., 17 cc 2 per cent caffein solution injected into the lumbar muscles of the right side; 4 p. m., reflexes increased; 4.15 p. m., jumped off the table and had wild convulsions, became very restless, walked about the laboratory; 4.25 p. m., had convulsions occasionally; 4.30 p. m., extremities extended and quite rigid; 4.35 p. m., convulsions and death.

_Rabbit 582. Gray male. Weight, 1,870 grams._

February 14: 4.15 p. m., 18 cc 2 per cent caffein solution injected into the lumbar muscles of right side; 5 p. m., reflexes increased; walked about in the room, then rested; 5.15 p. m., had short spasm when handled.

February 23: Alive; good condition.

The data presented in these experiments show that the toxicity of caffein when injected into the muscles of the lumbar regions is the same as when injected into the gluteal muscles. The rabbits of series A received approximately 0.2 gram caffein per kilo and two died as a result of this treatment. The other two survived but symptoms of caffein intoxication were observed.

In series B smaller doses proved fatal, from which it would appear that caffein is more toxic when injected into the lumbar muscles. Further observations, however, failed to corroborate the results obtained in this series. Thus, in series C, 130 to 150 mg of caffein per kilo injected into the lumbar muscles produced mild symptoms only. Experiments with larger doses showed that 0.180 gram caffein per kilo may cause death. It will be noticed, on the other hand, that rabbit No. 455 survived a dose of 0.2 gram per kilo. New experiments were therefore carried out in which the same amounts of caffein in proportion to the weight of the animals were injected into the lumbar muscles as into the gluteal muscles. As shown in the experiments of series D, one rabbit (No. 581) died shortly after caffein was injected into the lumbar muscles; two recovered. Two of the three which received injections into the gluteal muscles were found dead the next day; one recovered. Post-mortem examination failed to indicate the presence of any abnormalities. The rate of absorption of caffein from the gluteal and from the lumbar muscles seems to be, therefore, the same, or not to differ very much. The observations of Auer and Meltzer(7) are of interest in this connection. According to their investigations adrenalin is more rapidly absorbed from the lumbar than from the gluteal muscles. This is in all probability due to the greater delicacy of the test they employed (since they judged the rate of absorption by the effect of adrenalin on blood pressure) as well as to the much greater activity of the substance.

TABLE 4.--_Intramuscular injections._

SERIES A.

SERIES B.

----+--------+-------+----------+-----------+----------+-------------
307| 1,175 | 0.136 | 5 hours |6 hours, | Lumbar |Gray female.
| | | | 20 minutes| |
306| 1,860 | .134 | 3 hours |4 hours | do. | Do.
181| 1,230 | .130 | 4 hours |5 hours | do. |Gray.
----+--------+-------+----------+-----------+----------+-------------

SERIES C.

----+--------+-------+----------+-----------+----------+-------------
425| 1,520 | 0.131 | 1 hour |Survived | Lumbar |Gray.
426| 1,405 | .142 |30 minutes| do. | do. |Gray female.
427| 1,830 | .153 |50 minutes| do. | do. | Do.
453| 1,160 | .200 |30 minutes|Less than | do. |Gray male.
| | | | 20 hours | |
455| 1,185 | .200 | do. |Survived | do. |Gray female.
428| 1,650 | .180 | |Less than | do. |Gray male.
| | | | 20 hours | |
429| 1,340 | .200 | | do. | do. | Do.
----+--------+-------+----------+-----------+----------+-------------

SERIES D.
----+--------+-------+----------+-----------+----------+-------------
577| 1,380 | 0.200 |10 minutes|Less than | Gluteal |Gray male.
| | | | 18 hours | |
578| 1,670 | .210 | do. | do. | do. | Do.
579| 1,490 | .200 |15 minutes|Survived | do. |White and
| | | | | | gray male.
580| 1,510 | .200 | | do. | Lumbar |Gray male.
581| 1,680 | .200 |15 minutes|50 minutes | do. | Do.
582| 1,870 | .192 |45 minutes|Survived | do. | Do.
----+--------+-------+----------+-----------+----------+-------------

Examination of Table 4 shows that 14 rabbits received from 180 to 210 mg caffein per kilo. The appearance of symptoms in these rabbits varied considerably. In some increased reflexes could be noticed in 10 to 15 minutes after the injection of caffein; in others it was delayed 2 or 3 hours. It might be added that the onset of symptoms occurred in many cases very soon after the administration of the drug--on an average about 10 to 30 minutes after the drug was injected. After smaller doses were administered by injection into the lumbar muscles the appearance of symptoms was delayed several hours in some cases. The duration of life in these 14 rabbits varied considerably. Eight of them died within 1 to 20 hours; six survived. About 0.2 gram caffein per kilo may be regarded as the minimum fatal dose, while the minimum toxic dose is somewhere between 130 and 150 mg per kilo.

INTRAVENOUS INJECTION.

These experiments were carried out on well-fed, full-grown gray rabbits. The diet for several days preceding the experiments consisted of oats or carrots, which were given ad libitum. The injections were made into the ear veins from a burette or by means of a syringe, the temperature of the caffein solution being about 40° C. Attention was also directed to the effect of the rate of injection and of the concentration on the toxicity. The minimum toxic as well as lethal doses were determined as shown in the following experiments.

SERIES A.

In these experiments the rate of injection was about 1 cc of 2 per cent caffein solution per minute.

_Rabbit 194. White, female. Weight, 1,310 grams._

October 19: Injected 7.5 cc 2 per cent solution caffein (115 mg per kilo) into the ear vein. Rabbit showed stiffness; paralysis of extremities appeared soon after.[C] Rabbit survived.

[C] Time of injection inadvertently omitted, but was probably not
slower than in the other cases of this series.

_Rabbit 556. Gray, female. Weight, 1,635 grams._

January 31: 2 p. m., 11 cc 2 per cent caffein (134 mg per kilo) injected into ear vein, in about 11 minutes; 2.10 p. m., convulsions, rabbit remained lying on its side; during the rest of the hour it had convulsions occasionally; 3.20 p. m., convulsions and died. Rabbit did not urinate after the injection of caffein.

_Rabbit 557. Gray, female. Weight, 1,580 grams._

January 31: 2.30 to 2.37 p. m., 7 cc 2 per cent caffein injected from the burette at the rate of 1 cc per minute; 2.37 p. m., flow of liquid ceased, veins were engorged and bled freely, injection was continued by means of a syringe; 2 cc 2 per cent caffein injected in two minutes; injections discontinued as convulsions appeared; 2.50 p. m., rabbit raised itself but fell over; 3.10 p. m., rabbit assumed normal attitude, walked about the floor without manifesting any signs of the effects of caffein; 4.30 p. m., walked about, gait normal, condition seemed to be good.

February 1: 2 p. m., condition good, appetite good, total amount of caffein injected, 9 cc 2 per cent solution, or 114 mg per kilo.

_Rabbit 558. Gray, female. Weight, 1,590 grams._

January 31: 3 p. m., given 8 cc 2 per cent caffein in eight minutes; 3.10 p. m., violent convulsions; 3.20 p. m., rabbit was stretched out on his abdomen, extremities extended, urinated; 4.30 p. m., looked normal; was able to walk about.

February 1: 2 p. m., condition good, appetite good.

_Rabbit 292. Belgian hare, male. Weight, 1,770 grams._

February 18: 4.26 to 4.39 p. m., 12.5 cc warm caffein solution (0.141 gram per kilo) injected into ear vein, convulsion followed when this quantity was injected, tonic rigidity of limbs followed soon after; 4.52 p. m., condition unchanged, rabbit on floor, limbs stretched out, and lying on abdomen.

_Rabbit 294. Belgian hare, female. Weight, 1,350 grams. Carrot diet for about 10 days before the experiment._

February 19: 12.20 p. m., 5 cc 2 per cent caffein (74 mg per kilo) injected into ear vein in five minutes, edema of the ear, other ear used, 3.5 cc injected in 10 minutes, repeated convulsions; 1.25 p. m., rabbit still alive, frequent attacks of convulsions; 2.30 p. m., found dead. Total amount injected in 15 minutes, 8.5 cc, or 0.126 gram per kilo.

It will be observed in the preceding experiments that symptoms of severe intoxication were present in all of the six rabbits, but only two of these (Nos. 294 and 556) died from the effects of caffein. Of those which survived, three received doses of 100 to 114 mg caffein per kilo, and another (No. 292) received 141 mg of caffein per kilo. The death of rabbits Nos. 294 and 556 may be regarded therefore as a case of exceptionally low resistance to caffein.

SERIES B.

Doses of 160 to 200 mg caffein per kilo were employed in these experiments. The rate of injection was 1 cc per minute, with the exception of Experiment 254, in which 10.8 cc 2 per cent caffein were introduced in 17 minutes and 25 seconds.

_Rabbit 562. Gray female. Weight, 1,650 grams. Diet, oats._

February 1: Injection began at 3 p. m., injected 10 cc in 12 minutes; 3.01 p. m. to 3.09 p. m., 3 cc injected, convulsions; 3.09 p. m. to 3.14 p. m., 3 cc injected, followed by violent convulsions, marked opisthotonos; 4.30 p. m., rabbit died; total quantity injected, 16 cc.

_Rabbit 561. Gray female. Weight, 1,450 grams. Diet, oats._

February 1: Injection began at 11.40 a. m.; 11.48, rabbit struggled, 7 cc 2 per cent caffein injected; 11.50, convulsions, 10 cc 2 per cent caffein total amount injected; 11.55 a. m., injections stopped; injections resumed 11.58, violent convulsions, injections discontinued, total quantity received, 14.5 cc 2 per cent caffein solution; 1.30 p. m., found dead, did not urinate, 25 cc urine found in the bladder.

_Rabbit 560. Gray male. Weight, 1,620 grams. Diet, oats._

February 1: Injection began 11 a. m.; 11.10 a. m., 7 cc 2 per cent caffein injected, rabbit struggled; 1 cc was injected during the next three minutes, rabbit struggled but there were no convulsions, injection stopped; resumed at 11.15 a. m. and continued 10 minutes, 8 cc 2 per cent caffein introduced during this time; total amount caffein injected, 16 cc; reflexes markedly increased; 12 noon, tetanic convulsions off and on until 2 p. m., then remained stretched out on abdomen, extremities extended.

February 2: 9 a. m., found dead.

_Rabbit 559. Gray female. Weight, 1,875 grams. Diet, oats._

January 31: 4 p. m., convulsions after injection of 9 cc 2 per cent caffein in 14 minutes; 4.08 p. m., convulsions after injection of 7 cc caffein in 8 minutes; 4.10 to 4.12 p. m., injected 2 cc more, rabbit lying stretched out on abdomen, extremities extended; total amount of caffein injected, 18 cc (190 mg per kilo).

February 1: 2 p. m., condition good, walked about, appetite good, passed 155 cc dark, reddish-brown urine since 5.30 p. m. previous day.

_Rabbit 279. Gray and white female. Weight, 1,320 grams._

February 24: 10.09 a. m., 6 cc 2 per cent caffein passed rapidly into jugular vein; 10.15 a. m., involuntary twitching of muscles of legs, but no other symptoms; 10.23 to 10.26, 3 cc of 2 per cent caffein injected; 10.27 to 10.28, 2 cc 2 per cent caffein injected, convulsions; 10.29, convulsions stopped; 10.32, convulsions; 11 a. m., rabbit lying on its side, anterior extremities paralyzed, posterior extremities contracted, no clonic convulsions, breathed deeper and more slowly than normal; 11.10 a. m., rabbit died, had no convulsions immediately before death; amount of caffein injected, 11 cc 2 per cent solution, or 0.166 gram per kilo.

_Rabbit 254. Belgian hare, female. Weight, 1,285 grams. Diet, oats._

November 12: 1.30-1/3 to 1.47¾ p. m., received 10.8 cc 2 per cent caffein from burette into ear vein, after injection of 6.2 cc dyspnoea, 6.7 cc struggling, convulsions; at 1.50½ p. m., released from holder, paralysis especially marked in the anterior extremities; 1.50 p. m., recovered, survived; total amount injected, 10.8 cc 2 per cent caffein in 17 minutes and 25 seconds, or 0.16 gram caffein per kilo.

_Rabbit 255. Belgian hare, male. Weight, 1,105 grams. Diet, oats._

November 12: 2.31¾ to 2.35¼ p. m., received 3.7 cc; from 2.37-1/6 to 2.46-1/6 p. m., 5 cc injected; after injection of 6.1 cc convulsions followed by dyspnoea, then continuous struggling; when 8.3 cc were injected rabbit had another convulsion; 2.47 p. m., tonic contraction of anterior extremities; amount injected, 8.7 cc (158 mg per kilo) in 15 minutes and 35 seconds.

_Rabbit 567. Gray female. Diet, oats._

February 6: Injection began at 4.11 p. m.; 4.18, convulsions after injection of 5 cc 2 per cent caffein; 4.21, convulsion after total injection of 8 cc; 4.24 p. m., injection resumed and 2 cc more introduced; 4.28 p. m., convulsions, injected 2 cc more; total caffein injected, 12 cc, or 162 mg per kilo; 4.40 p. m., rabbit paralyzed in posterior extremities; 5 p. m., found dead.

In the eight experiments comprising series B rabbits Nos. 567, 254, 279, and 255, which may be designated as Group II, received doses of 162, 160, 166, and 158 mg, respectively. Nos. 562, 561, 560, and 559, which may be designated as Group I, received about 200 mg caffein per kilo. In Group II, which received the smaller doses, one (No. 254) survived. This may be regarded as exceptional, since, as was shown in the experiments of the preceding series, even smaller doses may be fatal. About 160 mg per kilo is, therefore, the smallest surely fatal dose. This might be regarded as a contradiction of the results obtained for rabbit No. 559, but it will be noticed that in this case diuresis was very marked. The results of experiments Nos. 294 and 255 are of interest in this connection, since they indicate that a moderate difference in the rate of injection is without any effect on the toxicity of caffein. The greater resistance to caffein of rabbit No. 559 is in all probability due, therefore, to increased diuresis.

SERIES C.

In these experiments the minimum toxic dose was determined. The conditions were the same as in the experiments of the other series.

_Rabbit 293. Belgian hare, female. Weight, 1,610 grams. Diet, oats._

February 18: 3.40 to 3.43 p. m., 4 cc 2 per cent warm caffein solution injected into ear vein, convulsions when 3 cc were injected, repeated attacks; 4 p. m., raised itself on legs, but fell over immediately and lay stretched on abdomen.

February 19: 9 a. m., rabbit looked normal, apparently recovered.

_Rabbit 227. White male. Weight, 2,320 grams._

October 26: 3.29¼ to 3.37½ p. m., injected into ear from burette 6.7 cc 2 per cent caffein, no symptoms; experiment discontinued; survived.

_Rabbit 563. Gray female. Weight, 1,650 grams. Diet, oats._

February 6: Injection began at 1.02 p. m., injected 3.5 cc 2 per cent caffein (42 mg per kilo) in four minutes, 0.6 cc more within the next two and one-half minutes, total amount injected 4.1 cc; 1.10 p. m., hypersensitive, some disturbance of muscular coordination; restlessness; 1.35. p. m., reflexes decreased, urinated and walked about, gait normal. Under observation for several days; no symptoms noted.

_Rabbit 564. Gray female. Weight, 1,515 grams._

February 6: Injection began at 1.26 p. m., 3.5 cc 2 per cent caffein (46 mg per kilo) injected at the rate of 1 cc per minute; 1.30 p. m., reflexes increased; 1.34 p. m., marked paresis of the extremities, rabbit stretched out on abdomen, legs abducted and partly extended, able to hop about but gait disturbed, no untoward symptoms noticed, under observation for several days after experiment.

_Rabbit 565. Gray female. Weight, 1,545 grams. Diet, oats._

February 6: Started to inject at 3.40 p. m., received 2.5 cc 2 per cent caffein intravenously in two minutes or 32 mg per kilo, under observation all afternoon, no symptoms.

_Rabbit 566. Gray female. Weight, 1,900 grams. Diet oats._

February 6: Injection began at 3.05 p. m., received 3 cc 2 per cent caffein intravenously in three minutes or 31 mg per kilo, no symptoms observed.

These experiments show that a dose of about 50 mg per kilo when injected intravenously produces mild symptoms, such as increased reflexes. In the four experiments with this amount of caffein these effects were observed in each case. In the experiments in which smaller quantities, 30 mg per kilo, were given intravenously there was no manifestation of symptoms. A dose not over 50 mg per kilo may, therefore, be regarded as the minimum toxic dose when injected intravenously under the conditions stated.

SERIES D.

A 0.5 per cent caffein solution was used in these experiments in order to test the effect of concentration on its toxicity; the rate of injection was 1 cc per minute.

_Rabbit 569. Gray male. Weight, 1,475 grams. Diet, oats._

February 6: 11.50 a. m. to 12.01 p. m., injected 10 cc 0.5 per cent caffein; 12.03 to 12.12 p. m., injected 10 cc of 0.5 per cent caffein; 12.13 to 12.26 p. m., injected 10 cc of 0.5 per cent caffein, total amount injected, 30 cc; 12.20, passed 35 cc of urine; 12.30, increased reflexes, but no convulsions; 4 p. m., reflexes increased.

February 11: Alive, condition good.

_Rabbit 574. Gray female. Weight, 1,555 grams. Diet, oats._

February 8: 10.25 to 10.33 a. m., injected 4 cc of 0.5 per cent caffein in salt solution, injection discontinued for five minutes; 10.38 to 11.10, injected 30 cc, total amount of caffein solution received, 34 cc; 11.55 a. m., very sensitive; reflexes markedly increased.

February 9: Alive, condition good.

_Rabbit 571. Gray female. Weight, 1,530 grams. Diet, oats._

February 7: Injection 3.18 to 3.50 p. m., received 30 cc in 32 minutes, not hypersensitive; 3.55, restlessness and weakness of extremities; 4.10 p. m., control of anterior extremities impaired, distinctly paretic but tried to walk about, died the same afternoon.

_Rabbit 568. Gray male. Weight, 1,605 grams. Diet, oats._

February 7: Injection 10.53 to 11.01 a. m., injected 10 cc 0.5 per cent caffein; 11.03, injection resumed after two minutes interval; 11.14, received 10 cc 0.5 per cent caffein intravenously in 11 minutes; 11.16, injection resumed; 11.35, received 12 cc 0.5 per cent caffein, total amount of caffein solution received, 32 cc; 12.30 p. m., urinated 14 cc of bloody urine; 12.55 p. m., convulsions and death a few minutes later. Autopsy showed congestion of viscera, but no other lesions.

_Rabbit 570. Gray female. Weight, 1,225 grams. Diet, oats._

February 7: 2.06 to 2.35 p. m., injected 24.5 cc 0.5 per cent caffein, reflexes increased but no convulsions, paresis especially marked in the anterior extremities; 3 p. m., passed urine which was normal in appearance, reflexes not increased but rabbit was weak.

February 9: Found dead. _Autopsy_: Liver, spleen, and kidneys congested; large intestines hemorrhagic; omentum congested and showed the presence of small caseous nodules; liver showed adhesion to diaphragm; viscera presented the appearance of intraabdominal infection.

Of the five rabbits of this series three died as a result of the administration of caffein. The other two which survived showed mild symptoms only, such as increased reflexes, but no evidence of severe poisoning such as was observed after the injection of the same doses of caffein in series A when a 2 per cent solution of caffein was injected. Convulsions were noticed in one case only (No. 568); paresis in two cases (Nos. 570 and 571). The nervous symptoms even in this group, therefore, were much milder than in series A. The percentage of death, however, was greater than in series A, in which the concentration of caffein was four times as great. It is quite probable that the strain on the heart due to the sudden increase in volume of the blood and its dilution might be an important factor in increasing the toxicity of caffein. It is conceivable that doses just sufficiently large to depress the normal heart may cause paralysis of an already overstrained organ.

SERIES E.

In the two experiments of this series the rate of injection as a possible factor influencing the toxicity of caffein was tested. A 2 per cent caffein solution was injected at the rate of 1 cc in two and one-half to three minutes.

_Rabbit 572. Gray male. Weight, 1,770 grams. Diet, oats._

February 8: Injection began at 3 p. m., discontinued at 3.37 p. m., and resumed at 3.38 p. m.; rabbit was restless; injection finished at 3.52 p. m. Total quantity received, 17.4 cc 2 per cent caffein intravenously in 52 minutes; struggled intermittently during the injection; anterior legs paralyzed.

February 9: Found dead.

_Rabbit 573. Gray male. Weight, 1,810 grams. Diet, oats._

February 8: Started to inject at 1.35 and discontinued at 2.27 p. m.; received 18 cc 2 per cent caffein intravenously in 52 minutes; reflexes markedly increased soon after; 2.45, passed bloody urine; 4.30 p. m. reflexes increased; no other symptoms.

February 9: 9 a. m., found dead.

It will be observed that some retardation of the onset of symptoms was caused by slower injection, but the final result was the same as when the injections were made more rapidly. It is quite probable, therefore, that a much slower rate of injection may lessen considerably the toxicity of caffein.

From the results of the experiments by intravenous injection summarized in the table, it appears that the minimum toxic dose for rabbits of a 2 per cent caffein solution, injected at the rate of 1 cc per minute, is about 50 mg per kilo. Twice the dose induces severe symptoms and may be fatal; 160 mg per kilo are surely fatal. If the rate of injection is diminished, the toxicity of caffein is lessened, but this effect is not marked unless the injections are very slow. Dilution of the caffein solution suppresses to some extent the nervous symptoms, but the toxicity, on the contrary, seems to be increased.

TABLE 5.--_Intravenous injections._

SERIES A.

----+--------+-------+-----------+-----------+-------+---------------
| |Caffein| | Duration | |
No.|Weight. | per | Symptoms. | of life. | Diet. | Remarks.
| | kilo.| | | |
----+--------+-------+-----------+-----------+-------+---------------
|_Grams._| _Mg._ | | | |
194| 1,310 | 114 |Present |Survived |Oats |White female.
556| 1,635 | 134 |10 minutes |20 minutes | do. |Gray female.
557| 1,580 | 114 |Present |Survived | do. | Do.
558| 1,590 | 100 | do. | do. | do. | Do.
292| 1,770 | 141 | do. | do. | do. | Do.
194| 1,350 | 126 | do. |10 minutes |Carrots| Do.
----+--------+-------+-----------+-----------+-------+---------------

SERIES B, GROUP I.

----+--------+-------+-----------+-----------+-------+---------------
562| 1,650 | 200 | |1½ hours |Oats |Gray female.
561| 1,450 | 200 | | do. | do. | Do.
560| 1,620 | 200 |Present |Less than | do. | Do.
| | | | 24 hours | |
559| 1,875 | 190 | do. |Survived | do. | Do.
----+--------+-------+-----------+-----------+-------+---------------

SERIES B, GROUP II.

----+--------+-------+-----------+-----------+-------+---------------
279| 1,320 | 166 | |1 hour | |Gray and white
| | | | | | female.
254| 1,285 | 160 | |Survived |Oats |Gray female.
567| | 162 | |About 45 | | Do.
| | | | minutes | |
255| | 158 | |Died | |
----+--------+-------+-----------+-----------+-------+---------------

SERIES C.

----+--------+-------+-----------+-----------+-------+---------------
293| 1,610 | 500 |Present |Survived |Oats |Gray female.
227| 2,320 | 570 |None | do. | |White male.
563| 1,650 | 500 |Present | do. | do. |Gray female.
564| 1,515 | 460 | do. | do. | | Do.
565| 1,545 | 320 |None | do. | do. | Do.
566| 1,900 | 310 | do. | do. | do. | Do.
----+--------+-------+-----------+-----------+-------+---------------

SERIES D.

----+--------+-------+-----------+-----------+-------+---------------
569| 1,475 | 100 |Present |Survived |Oats |Gray male.
574| 1,555 | 112 | do. | do. | do. | Gray female.
571| 1,530 | 100 | do. |About | do. | Do.
| | | | 2 hours | |
568| 1,605 | 100 | |20 minutes | do. |Gray male.
570| 1,225 | 100 | |Less than | do. | Do.
| | | | 20 hours | |
----+--------+-------+-----------+-----------+-------+---------------

SERIES E.

----+--------+-------+-----------+-----------+-------+---------------
572| 1,770 | 200 |Present |About |Oats |
| | | | 24 hours | |
573| 1,810 | 200 | | do. | do. |
----+--------+-------+-----------+-----------+-------+---------------

SUMMARY.

The results of the experiments on rabbits show considerable variation in the toxicity of the single dose. Individuals differed so widely in their resistance to this drug that the same experiments had to be repeated many times with each method of administration before satisfactory conclusions could be drawn. This is strikingly illustrated in the experiments by intravenous injection in which a dose of nearly 0.2 gram per kilo was not fatal. Similar instances of exceptional resistance or of sensitiveness to caffein were observed when it was given in other ways. A comparison of the toxicity of caffein administered by different methods in this investigation shows well-marked differences in its activity, although they are not quite so striking as similar experiments with other alkaloids reported by several observers. The toxicity of caffein in these experiments on the rabbit indicates that it is greatest when given by vein and least when given by mouth. The ratio of the minimum toxic doses by these two methods of introduction of caffein was about 7.1; the relation of the minimum fatal dose was about 3.1. The toxicity when given subcutaneously is about 15 to 20 per cent greater than when given by mouth. The difference between the intramuscular and subcutaneous injection is even more marked. The toxicity of caffein when injected into the muscles is about midway between that administered by the subcutaneous and intraperitoneal routes, and is about half that injected intravenously. Meltzer and Auer,(58) who experimented with a number of drugs found that the intramuscular method of administration is as effective as the intravenous, fluorescin forming the only exception according to their observations. In the experiments of Sollman and Brown(81) with ergot, the effect was quite different from those obtained by Meltzer and Auer(58) with the drugs they used. It is quite possible that the result obtained with ergot is merely illustrative of a difference in the behavior of various substances in this regard. This appears probable on account of the difference in the rate of absorption for various substances. Thus, according to Achard, Gaillard, and Ribot (Compt. rend. Soc. biol., 1907, _62_: 90), absorption from the peritoneal cavity varies with the concentration of the solution and the size of the molecule. The smaller the molecule and the greater the concentration the more rapid the absorption. That the rate of absorption from the intramuscular tissues is unequal and varies for different substances appears from the experiments of Meltzer and Auer.(58) The difference was very striking between intramuscular and subcutaneous administration of curara or adrenalin; the results were somewhat different with morphin and with fluorescin. As shown in their protocols, the onset of the symptoms after the intramuscular injection of morphin was sooner than after subcutaneous injection, but in time the difference diminishes and disappears altogether. The absorption of fluorescin is much faster when the intramuscular path is used than when given subcutaneously, but the writers state that the rate falls far behind that of the intravenous administration. The difference in toxicity we observed between feeding by mouth and subcutaneous injection, although distinct, was not very great. It was much less than Maurel(55) obtained with the hydrobromid of caffein in the rabbit. Whether this difference between his results and ours is due to the use of the pure alkaloid in our experiments and the hydrobromid employed by Maurel can not be stated at present with any degree of accuracy. It is hoped that the work in progress in the laboratory will throw some light on the subject in the near future. But Maurel's(56) experiments show that various substances behave differently in this regard. Thus the toxicity of strychnin, he states, is three times as great when given subcutaneously as when given by mouth and six times that of the minimum fatal dose by vein. It may be remarked, however, that examination of his data shows that his doses are much too large for the rabbit. In experiments with other drugs little or no difference between the two modes of administration was noticed. Thus, digitalin was but slightly more active when given subcutaneously than by mouth, while the toxicity of emetin hydrochlorid was just the same, whichever one of these methods of introducing the substance was used. Differences in the toxicity of substances have also been observed between subcutaneous and intravenous modes of administration, but here, too, the differences for various substances were unequal.

EXPERIMENTS ON GUINEA PIGS.

The toxicity of caffein was studied in a large number of individuals. The experiments were conducted on full-grown animals and were carried out at different seasons of the year in a variety of ways. Special attention was given to diet as a possible factor influencing resistance to caffein, and the effect of different modes of administration on toxicity. Some animals were therefore fed oats, some carrots, others received both hay and oats. Caffein was introduced subcutaneously, intraperitoneally, and by mouth.

SUBCUTANEOUS INJECTION.

SERIES A.

Preliminary experiments carried out on three guinea pigs, which received 360, 300, and 290 mg of caffein per kilo subcutaneously have shown that such doses were rapidly fatal. Two of the animals were seized with convulsions half an hour after the introduction of caffein and died during the attack. The other had tetanus two minutes after the injection of caffein. Repeated attacks followed, which terminated in the death of the animal two and a half hours later. The fatal and toxic doses must therefore be considerably under 0.3 gram of caffein per kilo when introduced by this path and smaller doses were therefore injected. The results are shown in the experiments of the next series.

SERIES B.

Experiments with 2 decigrams per kilo constituted this series.

_Guinea pig 20. Female. Weight, 497 grams. Diet, oats._

April 2: 5 cc 2 per cent caffein injected subcutaneously at 11.30 a. m.; 1.50 p. m., spasm of short duration. Died at 3 p. m., three and one-half hours after injection.

_Guinea pig 38. Brown male. Weight, 570 grams. Diet, carrots and oats week previous to injection._

February 11: 3.50 p. m., 6 cc 2 per cent caffein injected subcutaneously in back (210 mg per kilo); 4.15, reflexes increased, had convulsion of short duration when disturbed; 4.45 p. m., on handling, repeated convulsion and paralysis; 5 p. m., guinea pig lying on his side, respiration difficult and labored.

February 11: 5.05 p. m., guinea pig found dead, 2 hours and 15 minutes after injection.

_Guinea pig 37. Male. Weight, 820 grams. Diet, carrots and oats during week preceding the injection of caffein._

February 11: 3.35 p. m., 8.5 cc 2 per cent caffein injected subcutaneously in the back; 5 p. m., pig very sensitive, anterior extremities paralyzed when handled, frequent spasms of posterior extremities, no symptoms noticed before 5 p. m., although watched all the time; 5.05 p. m., guinea pig on his legs and looked normal. No attack on handling.

February 12: 9 a. m., found dead; died within 18 hours.

_Guinea pig 13. Female. Weight, 618 grams. Diet, oats._

March 29: 2.45, 6 cc 2 per cent caffein injected subcutaneously (0.194 grams per kilo).

March 30: Died at 4 p. m., 25 hours after injection.

_Guinea pig 36. Male. Weight, 850 grams. Fed oats and carrots for one week previous to injection._

February 11: 3.30 p. m., 8.5 cc 2 per cent caffein injected subcutaneously into back; 5 p. m., somewhat more sensitive than normal, no other symptoms, no effect on handling; 5.05 p. m., no symptoms.

February 12: 9 a. m., found dead, about 18 hours after injection.

The results of these experiments, as observed in five guinea pigs, indicate that two decigrams of caffein per kilo of animal produce symptoms within a half to about two and a quarter hours after injection. Death followed in two guinea pigs 70 minutes to 1 hour after the first manifestations of symptoms. Two others died during the night, while one lived 25 hours after the injection of caffein. Even 2 decigrams caffein per kilo weight might therefore be fatal to the guinea pig. Experiments carried out later have shown, however, that the resistance to caffein is appreciably greater in some guinea pigs. This is indicated by the following experiments, in which doses of 0.2 to 0.24 gram caffein per kilo were administered by the same path.

SERIES C.

_Guinea pig 66. Yellow and dark brown male. Weight, 510 grams. Diet, oats._

October 4: 5 cc 2 per cent caffein (0.2 gram per kilo) injected subcutaneously in the back at 3 p. m.; 5 p. m., no symptoms.

October 5: 9 a. m., alive; condition good.

October 9: Found dead. _Autopsy_: Congestion of liver, kidney, and small intestine.

_Guinea pig 65. White and black male. Weight, 510 grams. Diet, oats._

October 4: 5 cc 2 per cent caffein (0.2 gram per kilo) injected subcutaneously in the back at 3 p. m.; 5 p. m., no symptoms.

October 5: 9 a. m., condition good.

_Guinea pig 60. White and gray female. Weight, 320 grams. Diet, oats._

October 3: 2.25 p. m., 3.5 cc 2 per cent caffein (0.219 gram per kilo) injected subcutaneously in the back; 3.40 p. m., convulsion with recovery; 3.50 p. m., frequent spasms with paralysis, especially of anterior extremities; 5.30 p. m., tetanus when removed from cage and put on floor.

October 4: 8.50 a. m., found dead. _Autopsy_: Congestion of small intestines, lungs, liver.

_Guinea pig 57. White and gray female. Weight, 350 grams. Diet, oats._

October 3: 2.15 p. m., 3.5 cc 2 per cent caffein injected subcutaneously in the back (0.2 gram per kilo); 3.40 p. m., convulsions with recovery; 5.30 p. m., no marked symptoms.

October 4: 8.50 a. m., alive, active.

October 6: Found dead at 9 a. m. _Autopsy_: Congestion of lungs and liver; kidneys petechiated; severe gastro-enteritis.

_Guinea pig 68. Yellow male. Weight, 785 grams. Diet, oats._

October 6: 11.35 a. m., 7.8 cc 2 per cent caffein (0.2 gram per kilo) injected subcutaneously; 12 noon, reflexes increased markedly; 4.20 p. m., reflexes the same as at 12 noon.

October 7: 9 a. m., dead. _Autopsy_: Lungs congested; liver congested and fatty; spleen congested, kidney showed hemorrhagic spots; gastric mucosa necrotic; small portion of small intestine inflamed.

_Guinea pig 69. White male. Weight, 585 grams. Diet, oats._

October 6: 11.40 a. m., 5.8 cc 2 per cent caffein injected subcutaneously; 12 noon, reflexes increased, but not as much as in No. 68; 4.20 p. m., guinea pig hypersensitive, reflexes increased more than at 12 noon.

October 7: 9 a. m., alive.

October 15: 9 a. m., found dead.

_Guinea pig 61. Brown and black female. Weight, 330 grams. Diet, oats._

October 3: 4 p. m., 4 cc 2 per cent caffein (240 mg per kilo) injected subcutaneously; 5.30 p. m., reflexes increased; runs, but drags posterior extremities.

October 4: 8.50 a. m., found dead.

_Guinea pig 62. White, yellow, and black female. Weight, 335 grams. Diet, oats._

October 3: 4.05 p. m., 4 cc 2 per cent caffein (238 mg per kilo) injected subcutaneously in the back; 5 p. m., convulsions; 5.20 p. m., convulsions, alternating with paralysis of anterior and posterior extremities.

October 4: 8.50 a. m., found dead.

_Guinea pig 70. White and brown male. Weight, 545 grams. Diet, oats._

October 7: 3 p. m., 6.5 cc 2 per cent caffein (238 mg per kilo) aqueous solution injected subcutaneously; 3.50 p. m., reflexes increased.

October 9: 9 a. m., found dead.

_Guinea pig 71. Brown and white male. Weight, 540 grams. Diet, oats._

October 7: 3 p. m., 6.5 cc 2 per cent caffein solution (0.24 gram per kilo) injected subcutaneously; 3.45 p. m., reflexes increased, tetanus.

October 9: 9 a. m., found dead.

_Guinea pig 72. Brown and white male. Weight, 560 grams. Diet, oats._

October 7: 3 p. m., 6.5 cc 2 per cent caffein (0.232 gram per kilo) aqueous solution administered by subcutaneous injection; 3.35 p. m., reflexes increased.

October 10: found dead. _Autopsy_: Nos. 70, 71, 72 showed congestion of organs.

The reaction to caffein in the experiments of this series (C) showed considerable variation. The appearance of symptoms, as well as the final outcome of the experiments, differed markedly in a number of cases, notwithstanding the fact that the conditions were the same; thus the administration of 0.2 gram per kilo to guinea pigs, all of which received the same diet, induced no symptoms in two of the animals (Nos. 66 and 65), while marked symptoms were observed in the other four; in two of these the symptoms appeared in one hour and a quarter after injection, and in two others (Nos. 68 and 69), mild symptoms only appeared in 20 or 25 minutes. The last two were under observation for 4 hours longer, but there was no visible change in their condition. The duration of life in all of these guinea pigs, as indicated in the table, likewise varied. Two (Nos. 60 and 68) died during the night after they received caffein, one survived (No. 65), and three others (Nos. 57, 66, and 69) lived 2½, 5, and 9 days, respectively. Experiments with larger doses likewise showed differences in the behavior of these animals toward caffein, but they were not quite so marked. As shown in the table, symptoms appeared in from 35 minutes to 1.5 hours after injection. The duration of life was less than 1 day in two pigs, about twice as long in two others, and in one case between 2 and 3 days.

A comparison made with results obtained in the preceding series shows a striking difference in the resistance to caffein. As 2 decigrams per kilo proved more rapidly fatal to the guinea pig than the larger doses employed in the later experiments, this difference in the resistance to caffein may be due to several factors. As pointed out in the experiments on rabbits, age might be an important factor influencing the toxicity of caffein. Unfortunately, no accurate data were available on the age of the guinea pigs, but they were all apparently full grown, although they differed in weight considerably. The difference in their ages was in all probability not very great. Moreover, it will be observed that the resistance in series B and C differed in animals of approximately the same weight. This is evident on comparing experiments Nos. 20, 38, and 13 of series B with Nos. 65, 66, and 69 of the next series. Again, further inspection and analysis of these tables show no difference in the toxicity, although there may be considerable difference in the weight, from which it may be concluded that the animals were of about the same age or that this plays no part in the resistance to caffein in the guinea pig.

Diet is another factor which should be taken into consideration in this connection. The recent work of Hunt(39) indicates that this may influence the resistance of animals to some poisons. Our experiments, however, fail to show any difference in the toxicity of the caffein in guinea pigs, whether fed oats, carrots, or both, for different results were obtained on the same diet, and there seemed to be little or no difference in the toxicity of caffein when the diet was different. Other explanations suggest themselves to account for the results obtained. Seasonal changes have been assigned by a number of investigators as a cause of variation in the resistance to drugs. According to Focke,(24) frogs are more susceptible to digitalis in the spring than in the summer, while Moschkowitsch(61) and Edmunds(21) reported the very opposite results. Schmiedeberg's(80) observations on strophantin in frogs were in harmony with those of Edmunds(21) and Moschkowitsch.(61) Similar results were reported with guinea pigs. Harrington's(34) experiments indicate that stimulation of the vagus is less effective from October to January than from February to April, when they are also much more susceptible to operative procedure. Hunt found that the resistance of guinea pigs to aceto nitril is about twice as great in the summer months as it is in January and February.

Race might also be thought of as an important factor in this connection. Since the guinea pigs used at different seasons of the year were of several varieties, there is no reason to suppose, however, that the varieties experimented upon in the summer were more resistant than those used in the winter and spring. It is highly probable, therefore, that the greater resistance to caffein of the guinea pigs of series C than those of series B was due to seasonal variation.

Doses of 0.20 to 0.24 gram caffein per kilo weight, therefore, may be regarded as the minimum fatal dose for the guinea pig, depending upon the season. Since 0.2 gram per kilo proved to be rapidly fatal in series B, this quantity was perhaps not the minimum fatal dose for the guinea pig at the season during which the experiments were made. Additional tests with smaller doses were therefore carried out during February and March. The results are shown in series D.

SERIES D.

_Guinea pig 49. Male. Weight, 510 grams. Diet, oats for 1 month previous to experiment._

March 17: 3 p. m., 4 cc 2 per cent caffein (0.16 gram per kilo) were injected subcutaneously; 4.40 p. m., reflexes increased; 5.40 p. m., no symptoms.

March 18: 9 a. m., found dead, died in less than 18 hours. _Autopsy_: Hemorrhage into abdominal cavity; liver and spleen unduly congested; intestines injected; hemorrhagic area at point of injection.

_Guinea pig 40. Male. Weight, 630 grams. Diet, oats and carrots one week previous to injection._

February 12: 11 a. m., 5 cc 2 per cent caffein (0.158 gram per kilo) injected subcutaneously into back.

February 13: 1 p. m., still alive.

February 14: 9 a. m., found dead.

_Guinea pig 45. Female. Weight, 435 grams. Diet, oats for about one month previous to injection._

March 17: 3 p. m., 3.5 cc of 2 per cent caffein injected subcutaneously in the back (0.160 gram per kilo); 4.35 p. m., no symptoms; 5.40 p. m., no symptoms.

_Guinea pig 39. Male. Weight, 820 grams. Diet, oats and carrots._

February 12: 11 a. m., 6 cc (0.15 gram per kilo) 2 per cent caffein injected subcutaneously in back.

February 14: 9 a. m., alive; seemed to be in good condition; found dead at 1 p. m.

_Guinea pig 41. Weight, 660 grams. Diet, oats and carrots one week previous to injection._

February 12: 11 a. m., 5 cc (0.15 gram per kilo) 2 per cent caffein injected subcutaneously.

February 14: 2 p. m., pig alive; apparently normal.

February 18: Guinea pig still alive and apparently in good condition.

_Guinea pig 46. Female. Weight, 470 grams. Diet, oats about one month previous to experiment._

March 17: 3.15 p. m., 4 cc (0.170 gram per kilo) 2 per cent caffein injected into back subcutaneously; 4.35 p. m., reflexes increased, tremors on handling marked; 5.40 p. m., no change, symptoms about as before.

March 18: 2.30 p. m., no symptoms.

The experiments of this series (D) likewise showed a considerable difference in the resistance of the individual guinea pigs. Nos. 41, 45, and 46 survived; the rest of the pigs died within 18 hours to 2 days after the administration of caffein. Since an autopsy was held on one only, it is impossible to assign a cause for the variation in the toxicity of caffein in these guinea gigs, as the diet and the other conditions under which the experiments were conducted were the same. It was found in the experiments on cats and rabbits that the presence of morbid processes tends to increase the toxicity of caffein. The observations of Ophüls(66) are of interest in this connection. He found spontaneous lesions of the kidney and liver in a large proportion of guinea pigs examined. The greater susceptibility to caffein of guinea pigs Nos. 39, 40, 49, is probably due therefore to some pathological change which increased its toxicity. About 0.2 to 0.24 gram per kilo may therefore be regarded as the minimum lethal dose for the normal guinea pig when caffein is introduced subcutaneously, the minimum toxic dose being about 150-160 mg per kilo.

Experiments were also conducted to determine the largest dose which does not produce any visible effects. In a number of tests with from 100 to 120 mg caffein per kilo (series E, see Table 6, p. 51) no manifestation of nervous or muscular disturbance nor any departure from the normal in respiratory activity was observed. Such quantities may be regarded as the largest doses which are surely safe for these animals. It is quite possible, therefore, that the greater variation in the toxicity of caffein observed in these experiments is due to morbid conditions. Moreover, there is some evidence that caffein increases the toxicity of certain poisons, as shown by Hale(33) for acetanilid. Is it not possible that caffein may similarly be affected by poisons circulating within the body? Indeed the recent work of Loeb(23) makes this supposition highly probable. This investigator found that caffein and adrenalin injected together produce myocarditis in the rabbit. It is conceivable that the combined action of caffein and some preexisting poison may cause changes which terminate in the death of the animal. The delayed death of guinea pigs after the administration of caffein observed in this and other series may probably be accounted for in this way.

Experiment 57 lends some support to this view. The condition of the kidneys and the presence of a severe gastro-enteritis are sufficient to account for the death of this case. Again the frequent association of gastro-enteritis and congestion of the organs in caffein intoxication found in different animals makes it highly probable that these lesions were caused by caffein.

INJECTION INTO THE PERITONEAL CAVITY.

The experiments were carried out with different doses. All the guinea pigs in this series were kept on a uniform diet, consisting of oats. Most of them were of average size and there were no wide variations in their weights. The experiments of series A with the smallest doses were conducted in March and April; all the other experiments it will be noticed were made in October.

SERIES A.

_Guinea pig 41. Weight, 700 grams. Diet, oats._

April 1: 3.30 p. m., 4.5 cc 2 per cent caffein (130 mg per kilo) injected into peritoneal cavity. 5.35 p. m., symptoms present but no tetanus.

April 2: Found dead about 2 p. m., duration of life about 22 hours. _Autopsy_: Subcutaneous hemorrhage at the point of inoculation; serious exudate on visceral and parietal peritoneum with marked inflammation of peritoneum; portions of intestines showed slight enteritis.

_Guinea pig 49. Male. Weight, 370 grams. Diet, oats._

April 1: 3.15 p. m., 2.5 cc 2 per cent caffein (135 mg per kilo) injected into the peritoneal cavity; 5.30 p. m., symptoms present; reflexes increased, but no tetanus. Guinea pig survived.

_Guinea pig 47. Female. Weight, 550 grams. Diet, oats since about February 4._

March 17: 3.30 p. m., 3.5 cc 2 per cent caffein (127 mg per kilo) injected into peritoneal cavity; 4.35 p. m., increased irritability present, but not marked; 5.40 p. m., symptoms about the same as before.

March 18: 2.30 p. m., condition good; no symptoms. Survived.

_Guinea pig 50. Female. Weight, 290 grams. Diet, oats._

April 1: 3.30 p. m., 2 cc 2 per cent caffein (138 mg per kilo) injected into peritoneal cavity; 5.35 p. m., symptoms present; reflexes much increased, but no tetanus. Survived.

SERIES B.

_Guinea pig 51. Yellow female. Weight, 415 grams._

October 1: 9.50 a. m., 3 cc (144 mg per kilo) 2 per cent caffein injected into peritoneal cavity; 4.30 p. m., no symptoms, although under observation all day.

October 3: 2 p. m., alive.

_Guinea pig 52. White male. Weight, 450 grams._

October 1: 9.45 a. m., 3.5 cc, 2 per cent caffein (155 mg per kilo), injected into peritoneal cavity; 4.30 p. m., no symptoms developed since injection.

October 3: 2 p. m., alive.

_Guinea pig 58. Brown and white male. Weight, 490 grams._

October 1: 9.45 a. m., 4 cc, 2 per cent caffein (163 mg per kilo), injected into peritoneal cavity; 4.30 p. m., no symptoms developed since injection.

October 3: 2 p. m., alive.

October 8: Found dead. _Autopsy_: Congestion of lungs, spleen, liver, kidneys, and small intestines.

SERIES C.

_Guinea pig 59. Gray and white. Weight, 375 grams. Diet, oats._

October 3: 2 p. m., 3.75 cc (0.2 gram per kilo) injected into peritoneal cavity; 2.15 p. m., reflexes increased but not markedly; 4 p. m., reflexes still more increased; no other symptoms; 5.30 p. m., no symptoms.

October 4: 8.50 a. m., guinea pig alive and active.

_Guinea pig 58. Brown and white. Weight, 380 grams. Diet, oats._

October 3: 2 p. m., 3.8 cc caffein (0.2 gram per kilo), 2 per cent solution, injected into peritoneal cavity; 2.10 p. m., hind legs extended, then tetanus; attack lasted a few seconds, after which pig raised himself on his legs, but reflexes remained much exaggerated; 4 p. m. to 5.30 p. m., no symptoms of caffein intoxication.

October 4: 8.50 a. m., guinea pig alive and active.

_Guinea pig 56. Gray and white male. Weight, 440 grams. Diet, oats._

October 1: 11.30 a. m., received 4.6 cc of 2 per cent caffein solution (0.2 gram per kilo) into abdominal cavity; 11.45 a. m., stiffness and rigidity of posterior extremities, reflexes increased; 12.30 p. m., hind legs paralyzed, reflexes increased; 4.35 p. m., no symptoms, guinea pig in good condition.

October 3: Still alive in good condition.

October 14: Died. _Autopsy_: Anterior lobe of right lung hepatized. Small portion of small intestine edematous. Other organs normal.

_Guinea pig 55. White and yellow male. Weight, 690 grams. Diet, oats._

October 1: 11.30 a. m., received 6.5 cc of 2 per cent solution caffein (188 mg per kilo) into peritoneal cavity; 11.40 a. m., stiffness in all extremities, reflexes markedly increased; 12.30 p. m., reflexes increased, anterior and posterior extremities paralyzed; 3 p. m., found dead.

SERIES D.

_Guinea pig 67. Gray and yellow male. Weight, 330 grams. Diet, oats._

October 5: 11.25 a. m., 4 cc of 2 per cent caffein injected into peritoneal cavity (240 mg per kilo); 11.30 a. m., tetanus--survived, convulsions off and on. Death at 2.55 p. m. _Autopsy_: Severe gastroenteritis; kidney petechiated; congestion of lungs and liver.

_Guinea pig 63. Gray and white male. Weight, 340 grams. Diet, oats._

October 5: 11.20 a. m., 4 cc of 2 per cent caffein (235 mg per kilo) injected into peritoneal cavity.

October 14: Alive and in good condition.

_Guinea pig 64. Brown and black female. Weight, 305 grams._

October 5: 11.35 a. m., 3.8 cc 2 per cent solution caffein (250 mg per kilo) injected into peritoneal cavity; 11.40 a. m., tetanus--survived, convulsions off and on, died at 4.15 p. m. _Autopsy_: Findings exactly the same as in No. 67.

Examination of the results of the experiments by intraperitoneal injections showed that 0.2 gram caffein per kilo was toxic in two guinea pigs (Nos. 59 and 58). Severe symptoms were observed within 15 minutes in No. 56 and within one hour in No. 55 after the administration of approximately the same dose of caffein. One of these died within three and one-half hours; the other, No. 56, made a good recovery from the acute effects. This amount of caffein may be regarded, therefore, as the minimum toxic dose for the guinea pig when injected into the peritoneal cavity. This is corroborated by the experiments of series B in which smaller doses failed to show any muscular, nervous, or respiratory symptoms, nor were there any after effects noticed, as all of them survived and were kept under observation for some time. The guinea pigs of series A, however, seem to contradict these results. It will be remarked that appreciably smaller doses induced symptoms in all of them, and one case terminated fatally. The seasonal variation, as already pointed out, is in all probability likewise responsible for the difference in the resistance between the guinea pigs of series A and B. Tests were made also to determine the minimum fatal dose. For this purpose the experiments of series D were performed. The resistance of No. 63 in this series is quite striking. We are unable to explain such a discrepancy in the results obtained under practically uniform conditions. The minimum fatal dose of caffein, when injected into the peritoneal cavity, is therefore about 240 to 250 milligrams per kilo. These amounts, it will be observed, were rapidly fatal, in striking contrast to the results obtained when such doses were injected subcutaneously. This is probably due to a better absorption from the peritoneal cavity than from the subcutaneous tissues.

ADMINISTRATION BY MOUTH.

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The Toxicity of Caffein: An experimental study on different species of animalsChapter III: Part 3

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