50 I. BERENBLUM AND N. TRAININ 



itself, is miicli weakened by the evidence presented here. Any indirect action 

 of urethane — i.e. by depressing the bone-marrow activity, seems to have been 

 excluded. On the other hand, no evidence of a specific, direct action of urethane 

 on the thymus has so far been reported, though quite a marked depression of 

 the thymus by urethane has recently been observed in our laboratory, by 

 L. Fiore-Donati and A. M. Kaye (unpublished). But whether this plays a role 

 in promoting action is doubtful. Further experunents are in progress to 

 answer this question; and in the meantime, any conclusions on the subject 

 would be premature. 



The possibility that the virus is already present in normal C57BL mice, 

 but in insufficient amounts, and that radiation causes its concentration to 

 reach an effective level for leukaemia to express itself, woidd leave out of 

 account the role of promoting action, unless one were to assume that the 

 action of urethane and that of radiation are identical — which has been 

 excluded. 



That mice of a low-leukaemia strain might possess a precursor- virus, and 

 that radiation causes its conversion into a complete virus — a possibility 

 previously considered on hypothetical grounds by Kaplan (1961), not only 

 lacks any supporting evidence, but also leaves out of account the role of a 

 promoting phase in leukaemogenesis, so effectively performed by urethane. 



The same criticism may be levelled against the possibility that radiation 

 casuses the formation of a complete leukaemia virus de novo. There is, in 

 addition, the fact that the virus, obtained from tissues of a low-leukaemia 

 strain following multiple radiations, is only demonstrable when injected into 

 newborn mice, whereas the transmissible factor, in the present experiments 

 involving single radiations, becomes effective for leukaemia-induction when 

 injected into adult mice to which urethane is subsequently given. 



On the balance, it would seem that the evidence so far available supports 

 the possibility that initiating action (e.g. by a single dose of radiation) leads 

 to the formation of a precursor- virus de novo, and that promoting action (e.g. 

 by urethane) causes it to be converted into an active virus. 



If this proved to be true, it would have far-reaching implications, not only 

 in relation to the mode of action of ionizing radiation, but also in relation to 

 carcinogenesis in general. 



In conclusion, we should like to refer briefly to two of the most intriguing 

 problems in radiation leukaemogenesis: (i) the fact that divided small doses 

 of radiation are more effective than a single large dose for leukaemia induction, 

 and (ii) the question of whether there is a threshold dose for radiation 

 leukaemogenesis . 



When all the data from our own experiments, involving single doses of 

 radiation, at different dose levels, with and without urethane treatment, 

 respectively, are recorded on a graph, plotting leukaemia incidence against 



