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 Schmiedeberg¹⁵[A] 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.

Pohl⁷³ 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's³⁷ 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's¹ 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 Noe⁶⁵ 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's⁶⁵ 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 Gunn³² 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 Guinard³¹, 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 Kobert⁴⁵ amygdalin is without effect on dogs, but it is poisonous to rabbits. Lapicque⁴⁹ 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 Mitchell⁵⁹ 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 Golowinski⁴² 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 KÖster⁴⁶ 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.

Pharmacological studies on lower forms of life have also revealed marked variations in the effect of some poisons. Observations made by Danilewski¹⁸ with hydrochinone indicate that solutions of 1 to 100 or 200 are toxic to Celentrates, causing paralysis in these organisms. Echinoderms are killed within one or two hours in 1 to 1,000 or 2,000 solution, while in Vermes even weaker solutions cause tetanus and finally paralysis. The experiments of Drzewina¹⁹ with potassium cyanid are also interesting in this connection. Teleosts placed in 100 cc of sea water containing twentieth-normal potassium cyanid showed signs of asphyxia and died in 10 to 20 minutes. Actinia placed in a solution of sea water containing five times as much potassium cyanid were active on the thirteenth day of the experiment. Similar results were obtained with other marine organisms.

From these data it is evident that the toxicity of a substance may vary considerably in different forms of life. It has been shown also by some investigations cited by Salant⁷⁸ that the action of drugs may be modified by different conditions in the environment as well as in the subject of the experiment. The recognition of the importance of these factors in determining pharmacological action has contributed much to the elucidation of the mechanism by which drugs and other substances produce physiological effects in the body. Moreover, such knowledge has often enhanced the therapeutic value of pharmaco-dynamic agents and has frequently served to avert effects of an undesirable character in man and domestic animals. The results obtained in one species of animals under a particular condition do not admit, therefore, of universal application. Furthermore, the nature of the action of a drug can only be partly learned from the manifestation of its acute effects. Equally important, therefore, especially in studies on toxicity, are the changes produced in chronic intoxication.

That the acute effects of a substance can hardly be considered a correct estimate of its toxicity is shown by the evidence obtained in experiments on tolerance and cumulative action of drugs; for the toxicity of a substance may diminish when the substance is given steadily for a long time if the body acquires tolerance for it. Arsenic, morphin, and cannabis indica may be cited as illustrations of drugs, the toxicity of which decreases with repeated doses, while digitalis and lead show a tendency to increased toxicity when similarly administered. Moreover the acute and chronic effects are sometimes qualitatively different. According to Igersheimer⁴¹ the symptoms in acute atoxyl intoxication are nausea, vomiting, and diarrhea. These symptoms are absent in chronic intoxication, in which trophic disturbances of the skin and inflammation of the mucous membranes were the effects produced. That the acute action of atoxyl differs from the chronic effects was likewise shown by experiments on animals. The studies of von Anrep⁵ on chronic atropin intoxication are of interest in this connection, as he found that after 10 to 15 injections of atropin there is no manifestation of symptoms such as is observed in acute intoxication, while the effects on the circulation are also less marked, the acceleration of the pulse being less than after the same dose in a normal subject not accustomed to its use. When the administration of atropin is continued for a longer time its usual effects on the pulse disappear altogether; there is, on the contrary a decreased frequency of the pulse. If atropin has been administered for from two to three weeks, respiration is likewise affected.