Alexander Lipschiitz ^oi 



free hormone (Lipschiitz, Bellolio, Chaume and Vargas"); nevertheless, its 

 rate of absorption is not less and is probably greater than that of the free 

 hormone (Lipschiitz and Vargas;"" Emmens*'). It remains true, however, in 

 accordance with our conception of the importance attributable to the continu- 

 ous maintenance of a tumorigenic threshold-level of foUiculinemia, that 

 the timing conditions are fundamental for tumorigenesis elicited by estrogens. 

 If a continuous flow of estrogen is established in the body from a sub- 

 cutaneously or intraperitoneally implanted tablet of free estrogen, fibromato- 

 genesis is produced in the course of several weeks, the c[uantities absorbed 

 being several times smaller than those which are necessary when three injec- 

 tions are given per week for a period of several months (Lipschiitz and Vargas;'* 

 Chaume and Vargas*^). This is true also for other estrogens, such as free 

 estriol (Szabo"'), and especially estrone (Thibaut''). Tumorigenesis can be 

 elicited with a total of 300 to 400 jxg. of estrone absorbed in the coiuse of three 

 months from a subcutaneously implanted pellet (pi. 2, fig. 7). On the other 

 hand, thirty-eight injections of 300 ^ug. of estrone given in oily solution in the 

 course of three months, or a total of 1 1,400 /^g., thirty times that absorbed from 

 a pellet, are not sufficient to produce abdominal fibroids (Lipschiitz, Rodriguez 

 and Vargas;** Rodriguez*"). On the other hand treatment with a highly tumori- 

 genic ester such as estradiol benzoate fails to elicit fibroids if each injection- 

 week is followed by two wrecks free from injections; similar treatment may be 

 prolonged for a whole year without appearance of fibroids (Lipschiitz, Rod- 

 riguez and Vargas^) (pi. 2, fig. 8). 



Carcinogenic hydrocarbons have been studied only sporadically as yet with 

 reference to the necessity of continuous administration. The few data available 

 rather favor the assumption that here also continuity of the tumorigenic 

 stimulus is important. When studying the timing conditions for the carcino- 

 genic action of benzpyrene in mice. Peacock and Beck"^^ found that epitheli- 

 omas appeared when painting with a solution of 0.3 per cent was repeated 

 twice weekly for a period of two to three months. If the painting during the 

 three-month period is, however, intermittent, no applications being made dur- 

 ing alternate months, then the incidence of tumors diminishes. It will prob- 

 ably be possible to demonstrate the importance of continuity of application 

 of the carcinogenic hydrocarbons in a more striking manner when more suit- 

 able concentrations and intervals are devised. Further proof of the importance 

 of the timing factor in tumorigenesis elicited by hydrocarbons will be men- 

 tioned in the next paragraph. 



3. Reversibility a7id Irreversibility of the Tumoral Reactiori. As already men- 

 tioned, atypical proliferation in the lUerine mucosa induced by estrogens 

 rarely persists after the withdrawal of estrogens. The situation is the same in 

 the case of connective tissue tumors induced by estrogens. This reversibility 

 of the condition is in general considered as fundamentally different from 

 what would have been expected if the proliferation were a real tumor. The 

 epithelioma induced by painting with carcinogenic hydrocarbons may on the 



