The Toxicity of Caffein: an Experimental Study on Different Species of Animals

Part 1

Issued April 4, 1912.

U.S. DEPARTMENT OF AGRICULTURE,

BUREAU OF CHEMISTRY--BULLETIN No. 148.

H. W. WILEY, CHIEF OF BUREAU.

THE TOXICITY OF CAFFEIN:

AN EXPERIMENTAL STUDY ON DIFFERENT SPECIES OF ANIMALS.

WILLIAM SALANT, Chief Pharmacological Laboratory, Division of Drugs,

AND

J. B. RIEGER, Assistant Chemist.

WASHINGTON: GOVERNMENT PRINTING OFFICE. 1912.

LETTER OF TRANSMITTAL.

U. S. DEPARTMENT OF AGRICULTURE,

BUREAU OF CHEMISTRY,

Washington, D. C., November 14, 1911.

Sir: I have the honor to submit for your approval a manuscript on the toxicity of caffein, which is the first of a series of reports to be made by Dr. Salant on the pharmacology of this drug; the conclusions here reported are, therefore, in some particulars to be regarded as tentative. The data obtained are primarily of use in the execution of the food and drugs act, but are capable of much broader application.

Acknowledgment is made of the assistance rendered by Dr. John R. Mohler, Chief of the Pathological Division, Bureau of Animal Industry, and his assistants, in performing the autopsies recorded in this report. I recommend the publication of the manuscript as Bulletin No. 148 of the Bureau of Chemistry.

Respectfully,

H. W. WILEY, Chief.

Hon. JAMES WILSON,

Secretary of Agriculture.

This publication may be procured from the Superintendent of Documents, Government Printing Office Washington, D. C., at 15 cents per copy

CONTENTS.

Page. Introduction 5

Historical review of the literature on the toxicity of caffein 9

Acute caffein intoxication 18

Experiments on rabbits 18 Subcutaneous injection 18 Administration by mouth 26 Injection into the peritoneal cavity 28 Intramuscular injection 33 Intravenous injection 37 Summary 42

Experiments on guinea pigs 43 Subcutaneous injection 43 Injection into the peritoneal cavity 47 Administration by mouth 49 Summary 52

Experiments on cats 53 Subcutaneous injection 53 Injection into the peritoneal cavity 56 Administration by mouth 57 Summary 59

Part 2

Experiments on dogs 60 Administration by mouth 60 Subcutaneous injection 60 Experiments on puppies 61 Summary 62

Chronic caffein intoxication 63 Experiments on rabbits 63 Experiments on dogs 75

Discussion of results 91

General summary and conclusions 95

Bibliography 97

THE TOXICITY OF CAFFEIN.

INTRODUCTION.

Comparative physiology has established the fundamental fact that some properties are common to all forms of living matter. But the same method of inquiry has also led to the recognition of marked differences in the physiological processes of various species of animals. Among the most important investigations which contributed to the knowledge of such variation of function are the studies in comparative metabolism. It is now recognized that metabolism is in some respects quite different in herbivora and in carnivora. Some forms of oxidation are much greater in the rabbit than in cats and dogs. Nuclein metabolism presents important differences in the rabbit and in man, while the mode of neutralizing acid in the body may be cited as another variation in the metabolism of these forms. Perhaps the most striking examples of differences in the metabolism of different organisms is furnished by the results of studies on the fate of certain poisons introduced into the body.

The classical experiments of Bunge and Schmiedeberg(15) on the synthesis of hippuric acid are of interest in this regard. It will be recalled that in the dog the synthesis takes place in the kidney; the rabbit is able to form hippuric acid in the liver as well as in the kidney, while frogs can synthesize hippuric acid even when both of these organs have been removed or excluded from the circulation. Observations on the fate of some of the alcohols of the fatty acid series have likewise shown that these substances may be combined with glycuronic acid in some animals but not in others. According to Thierfelder and Von Mering,(84) tertiary alcohols are combined in this manner in the rabbit but not in the dog. According to Neubauer,(64) the primary and secondary alcohols are so combined in the dog as well as in the rabbit, but to a greater degree in the latter.

The small figures refer to the bibliography at the end of this bulletin.

Pohl(73) found that amyl alcohol is largely eliminated by the lungs in the cat and in the dog. The protocols of his experiments show that 65 per cent of the alcohol given these animals was thus recovered, while he recovered only 22 per cent of this substance in the expired air of the rabbit. Examination of the urine showed the presence of glycuronic acid. Hofmeister's(37) work with tellurium in the dog is of interest in this connection. He made the important discovery that some animals possess the power of methylation as well as of demethylation. Abderhalden and Brahm's(1) experiments with pyridin show that the same is true of young dogs when on a meat diet. His experiments on rabbits with this substance were negative.

The metabolism of caffein and theobromin furnish another illustration of differences in the physiological mechanism of animals. Although the substances found in the urine of man, dog, and rabbit after the administration of caffein and theobromin were the same, the quantities varied considerably. According to Krüger and Schmidt,(47) over 14 per cent of the theobromin introduced into the rabbit is eliminated as 7-methyl xanthin in the urine. The dog eliminates only about 0.67 per cent. On the other hand, the amount of tri-methyl xanthin eliminated was only 3 per cent in the dog and not quite 1 per cent in the rabbit.

It appears, therefore, from studies in comparative metabolism, whether endogenous or exogenous, that well-marked physiologic and chemical differences exist in various species of animals. That pharmacological action may likewise vary in different species of animals is shown by the following investigations. According to Guinard,(31) who made an exhaustive study of morphin, the reaction to this alkaloid varies in different forms of life, both qualitatively and quantitatively. He established its narcotic effect in the dog, rabbit, guinea pig, white mice, and rats, while for the cat, horse, ox, sheep, hog, and goat it is, on the contrary, a stimulant. Moreover, there is no evidence of cerebral effect. The stimulating effect of morphin on the nervous system in some animals was also observed by Noe(65) in experiments with this substance on the hedgehog.

Guinard(29), (30) has also shown that morphin has no narcotic effect in the marmot, although this animal is very sensitive to the drug. Two milligrams per kilo were found to be a surely fatal dose for this animal. His experiments on the comparative toxicity of morphin(30), (31) show a considerable range of variation in different species. Thus the fatal dose for the dog was found to be 0.65 per kilo, while 7 mg per kilo is the fatal dose for the horse. About twice the amount is fatal for the ox and 0.2 mg per kilo kills the pig. Experiments with other drugs has shown that a considerable range of variation in resistance exists in animals of different species.

Noe's(65) studies on the comparative toxicity of chloral brought out the interesting fact that the rabbit is more resistant to it than the hedgehog and the latter more resistant than the guinea pig. Perhaps the most striking example of a difference in reaction of the same substance in widely different species is that furnished by apocodein, quinin, and yohimbin. According to Gunn(32) these substances have been found to cause vasodilation in warm-blooded animals, but they constrict the blood vessels of the frog.

Experiments with apomorphin likewise show that the reaction to this substance varies in different species of animals. The resistance of the cat to this drug is, according to Guinard(31), ten times greater than that of the dog, and the latter is more sensitive than the rabbit to the crystalline form of apomorphin when given intravenously. According to Kobert(45) amygdalin is without effect on dogs, but it is poisonous to rabbits. Lapicque(49) found that the toxicity of curara varies in different species of frogs, the dose required to produce paralysis in Rana esculenta being three times greater than in Bufo vulgaris. Weir Mitchell(59) pointed out long ago that turtles stand enormous doses of curara. Schmiedeberg's experiments with caffein on Rana temporaria and Rana esculenta (and more recently those of Jacobi and Golowinski(42) with caffein, theobromin, and theophyllin) are also of interest in this connection. These experimenters observed well-marked differences of reaction to methyl-xanthins in these closely allied forms.

Experiments with quinin have shown that the action of this substance differs in some animals. It causes a fall of temperature immediately after its administration in the guinea pig, but frequently produces, at first, a rise of temperature, followed by an unimportant fall, in rabbits, dogs, and man.

The numerous investigations which have been carried out on the effect of atoxyl within recent years have contributed much to the comparative pharmacology of this substance. Although the symptoms and organic changes produced by this substance in a variety of animals present no great differences, the resistance of some has been found to vary; according to Köster(46) it is more toxic for dogs than for rabbits. A number of other substances have been found by various experimenters to vary in toxicity for different species of animals. Cantharadin, phenol, atropin, and strychnin may be mentioned as illustrations.

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