Equally interesting is the observation of the writer, that in the guinea pig the difference in the toxicity between the subcutaneous and intraperitoneal injections is very slight, while in the cat the toxicity of caffein is the same whether given by mouth or injected into the subcutaneous tissues, and is markedly less when injected into the peritoneal cavity. The experiments on dogs show considerable variation of effective dose when given by mouth, but the interesting observation was made that the toxic dose by mouth may be smaller in some cases than the average dose by subcutaneous injection. If the resistance to caffein by subcutaneous injection of the different species of animals experimented upon in the present research be compared, it will be noticed that the gray rabbit or Belgian hare, which is more resistant than the other varieties employed, stands more caffein in proportion to the weight of the body than the other animals. Although the minimum fatal dose was found to be somewhat larger for the guinea pig than for the gray rabbit when caffein was injected intraperitoneally, it was on the contrary smaller by other paths of introduction, and approximated quite closely the minimum fatal dose for rabbits of the other varieties. Cats as well as dogs were found to be distinctly less resistant to caffein than the herbivora. There are a number of factors far more important than zoological differences which influence the toxicity of caffein. Some of these are age, season, and pathologic conditions. As these factors have already been dwelt upon in their appropriate places, further discussion might seem unnecessary, but owing to their importance in determining the action of a drug, emphasis is desirable. Especially is this the case with pathological conditions in relation to toxicity. While no positive proof of diminished resistance to caffein in pathological conditions was obtained by subjecting the suggestion to experimental test, it was observed in these experiments on rabbits that death occurred in some individuals after small doses which are usually not even toxic. The findings at autopsy indicate the presence of pathological conditions. The same was observed in some experiments on cats and dogs. It is extremely probable, therefore, that disease modifies the reaction of the organism to caffein as well as to other drugs.(78)