CHROMOSOME ABERRATIONS IN LIVER CELLS 257 



cells constitute a very small fraction of the total number of cells of the body, and this is 

 probably wliy we see no life-shortening from nitrogen mustard. For mice susceptible to 

 leukaemia mduction, nitrogen mustard might be expected to cause some shortening of 

 the life-span, and Dr. Upton has observed this. The real point of the nitrogen mustard 

 experiments reported here is that they removed the objection to the somatic mutation 

 theory of ageing created by the demonstration that nitrogen mustard does not cause hfe- 

 shortening in this strain. 



UPTON: I was very much fascinated by the nice demonstration in the animal that the 

 neutron is a more effective chromosome breaker. This differentiation between the 

 mduction of pomt mutations as opposed to gross chromosomal derangements lead us to 

 try the triethylene melamine and from our work it would seem in fact that this agent, for 

 the same degree of lethaUty in mice judged on a 30-day survival, did exert a far greater 

 Ufe-shortening effect and this tempts me to correlate it with the findings which you have 

 presented. We think it might be instructive to compare wider varieties of chemical 

 mutagens or alkylating agents, to see whether or not there was a general correlation 

 between chromosome-breaking effectiveness and life-shortening effectiveness. 

 CURTIS: I quite agree with you. We must know more about the basic mechanism of action 

 of the chemical mutagens before we can make meaningful comparisons. 

 ALEXANDER: I think I can make a suggestion as to why you found that HN2 — the oldest 

 nitrogen mustard — did not shorten life-span, while we found another mustard, and 

 myleran, effective. The reason we chose not to work with HN2 was that, although this 

 is a radiomimetic compound one cannot, in fact, kUl animals with acute single doses by a 

 radiomimetic pathway because it also acts centrally. Therefore from such radiomimetic 

 behaviour it isn't at all possible to give a comparable dose of HN2 because if one works at 

 well below the lethal dose then it's radiomimetic but when one comes up to somewhere 

 near the true lethal dose one can't acliieve true bone-marrow killing because it kiUs 

 centrally first. I would like to hazard a guess that the reason why HN2 doesn't show this 

 effect is that at the true radiomimetic activity level you in fact use only a smaU fraction of 

 the dose which the rest of us using other compounds were able to give. 

 CURTIS: You are probably correct, but I should pomt out that our mice were given almost 

 lethal doses of mustard three times a week for more than half their total Ufe-span and if 

 there had been any appreciable cliromosomal effect on Uver cells it should have been 

 evident. 



MULLER: I wanted to make a point following Dr. Curtis's mention of the two-hit curve for 

 cliromosome aberrations. Tliis, of course, is true at higher dose-rates because many 

 cliromosome aberrations that lead to losses of clu-omosomes and chromosome bridges are 

 caused by the union of pieces derived from two different breaks. That's the predominant 

 method at relatively high dose-rates but it's theoretically to be expected that when you 

 go down to exceedmgly low dose -rates such as you get with ordinary clironic treatment 

 that you hardly ever have two breaks near enough in both space and time ever to get the 

 broken ends cormected with one another. Then the predominant cliromosome loss which 

 comes from single breaks of the kind that I was discussing (and for simphcity' ssake I left 

 the other ones out of my discussion so as to concentrate on the simpler case) would mean 

 that when you use very massive doses — acute doses — that you had considerably more 

 shortening of Ufe for the given total dose than from the same dose used chronically. Tliis 

 would also mean that this same evidence showed that what you were dealing with was 

 not point-mutation — mutations in genes — because they're not affected by dose-rate. 

 MOLE: Can I ask one embarrassmg question of Dr. Curtis? As far as Ufe-shortening is 

 concerned, isn't there only one way to interpret your experiments, and that is that 

 mitotic abnormahty in the regenerating liver has nothing to do with it! 



