8 THE TOXICITY OF CAFFEIN. 



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 Sal ant 78 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 import- 

 ance of these factors in determining pharmacological action has con- 

 tributed much to the elucidation of the mechanism by which drugs 

 and other substances produce physiological effects in the body. More- 

 over, 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 manifes- 

 tation 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 Igersheimer 41 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 ani- 

 mals. The studies of von Anrep 5 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. 



