Interview with William Russell and Bob Cumming

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Oak Rioge Kational Lab. Y TW N NARD : Since our time is limited,it might be best to start with one question thatI ' v e always found difficult to answer. tic effects of internal emitters never received any overt attention,to That i s why the genespeak of,atleast in this country until so late in the game. RUSE LL : Well, when we started our work,there was no adequate infor - mation on gene mutation and induction by any form o f ionizing radiation mitted gene mutations o r small deficiencies or chromosomal abberations i n There was work on some elaborations but nothing on trans - that category. So we started with the easiest thing t o do, easiest thing t o measure i n terms of dose and so on, which was external radiation. Maybe we half expected t o resolve the big uncertainties in a short time. But we rapidly found that the predictions made from Drosophila on which the permissible levels were based at that time were different in the mouse. We rapidly found that the mouse was giving,in the first case, much higher mutation rates than Drosophila. simply a matter o f measuring DNA damage i n any organism and extrapolating. Our first estimate was that the mouse was about 15 times as sensitive as So one couldn ' t simply argue that it was Drosophila, but then we also found a few years later that some of the main principles supposedly worked out i n Drosophila were not holding i n the mouse. Well, after we bad established that the mouse was alot more sensitive than Drosophila, we then started exploring such things as the shape of the dose-response curve. We immediately found departures from the linear relationship seen with Drosophila a t the higher dose level, and that led us into using low dose rate. Drosouhila-based principle was that, as you well know, it didn ' t matter The firmly established

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what the dose rate was or what the doses were. Then we rated the ciose independent of dose r a t e . Well, we very rapidly found the radiological effects of dose rate in the spermatogonial stage of the mouse. I t took several years of research t o follow u p the different dose rates at which mutations occurred. So one of the basic principles had been worked out. What people thought for Drosophila turned out notto be true for the mouse. So we were led into many different paths. If all of that turned out like Drosophila, we probably would have been on to internal emitters much sooner. But we had so much todo on the external radiation side that the internal emitters got pushed aside. instrumentation used in measuring dose andso on, but the extra complexities. Also I think it was perhaps a general feeling that atleast for many of them(internal emitters) concentration in particular tissues and so on, Perhaps,partly not only because of the that genetic effect might be less important than the somatic effects. was not usually an organ of deposition. Well, I presume another principle reason was that the gonad . RUSSELL: Yes, that I think was the core.... CUMMING: The early populations I think were when transformation or transmission was relatively unimportant, not important atall. the transformation o r transmission was investigated i n more detail. I guess i t was still thought notto be much of a problem. Not a scientific problem? Were we overly protective using the CUMMING : We wanted the set-up isolated to minimize the amount of

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about putting our other mice and other important experiments going on without being sure that we didn ' t raise our background. we setup an isolation type of procedure ....We could recover most ofthe total amount inhaled over several weeks by atrap coming out into ice. We setup for a couple of weeks. We were a liTtle bit paranoid, 1 guess you might say, By taking samples after the single injection, we could calculate the amount of radioactivity. CUMM ING : I t depends on the cell stage. What kind of changes were you looking for ? CUMMING : Some of those were witha higher initial injected dose. I t was a fairly substantial dose. We found out that the tritium beta isa mutagenic agent. We got a pretty good number of changes. [Discussion went tothe RBE for tritium. Too faint for transcription. They favored slightly over one, N.S.] [This must be about the idea of an RBE of 1.7 o r 2.0 for certain levels STANNARD: A factor of 2.0,as far as radiation protection i s concerned, i s almost within experimental error anyway. important t o know scientifically. On the basis of dose estimate, i t would be probably on the borderline 2 s I would favor 2.0 rather than 1.0 since it is not significantly This allows for some uncertainty inthe dose estimate. significant.But you realize there is some uncertainly inthe dosimetry.

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Some people take the point of view, "Well, why don ' t we say i t ' s 1.0." My point of view is that the only genetic study that has been done with the estimate of 2.0 seems t o be a better thing to go for. RUSSELL: 'We realized that our estimates for plutonium were not based on any data. Then two o r three things came up. One was there was evi - How did you happen t o get into the plutonium business: dence from the tritium study that the concentrating factors were ? . And the dose estimate there was around 2.5.It may have been higher than plutonium. And also the possibility of a high RBE. So all these factors together indicated perhaps the theoretical estimates of the risk that had been made might be considerable underestimates. u p work i n several laboratories, England, Argonne with Grahn, etal. Then of course with the possibility of dose rate effects with These considerations started RUSSELL: Grahn. And soall of us began to think maybe we should include specific work on plutonium: So that ' s actually how we got into it. Again, we argued that the risk estimates were based on no data so far as transmitted gene mutation was concerned. by that time rather than AEC. times, probably did. Argonne people forgetting plutonium i n the right form, in the monomeric I guess that must have been ERDA . .Considerations may have started in the AEC They decided that they would support specific locus So that ' s how we got involved. We cooperated very closely with the Did they bring it down ?

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RUSSELL : Li ndenbaum did i t . CUMMING : Yes, Lindenbaum came down and worked in our facility here t o produce the final solution that was injected. vein injection. Made it into a citrate, monomeric citrate form, andit was injected into the tail vein. Brian has some evidence that the endpoints that he looked at didn ' t increase with time as they ought to with the plutonium sitting there in the animal. His data are not, as I understand it,still pure enough t o say that,but there are various possible ways, as I ' m sure you can guess, as t o why the effect might not go up. The particles might concentrate; there might be some unknown elimination; Then I think in terms of the long-term exposure of They did the final getting it in monomeric form over here. We g o t the plutonium here. Then ... They helped with the tail We're thinking of doing another one on this. Largely because spermatogonial cells,the long-term exposure might kill the ones that are close t o the particles,so you might have a biological effect. might be either a physical or a biological reason for it not increasing with time as i t ought to. The total number of mutations we have i n the specific locus test is, I ' v e forgotten now, but anyway i f you divide i t up even into two time periods or three or four time periods, there aren ' t enough mutations i n each group to be where there i s any change, any departure from the linear increase that you'd expect. We really need another experiment. But the risk based on just the total rate over the total time period i s a b o u t the same as acute x-rays judged by the dose work They're checking on the doses, got a similar result. Since you wouldn't

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expect with alpha particles any dose-rate effect, so since i t ' s acting like low LET radiation essentially,it means a n RBE of one. STANNARD: Yes. That was indicated in that very nice report that your task group for NCR P got together. still in progress when the last report was written. because I h a d t o keep my book and the NCRP in separate compartments. biological complications there. out of water for a fairly long period, and some o f them died as a result STANNARD: That's too bad. tion rate than i n the other experiments. want t o repeat it. As I recall, there were some experiments You were going t o look How did those data come out ? Ididn ' t bring along the NCRP stuff We're sort of sitting on those data because there ' s some There was an accident where the mice were In that experiment, the survivors were giving a higher mutaThat ' s another reason why we I t ' s possible that we could match perhaps some of the conditions that were occurrjng in that accidental drop off i n water. guess the food was a l s o , b u t the water is the one we were primarily interested the absence o f water rather than the dose way or other. systematically with internal emitters,that we've had some experience with,at the role of metabolism in affecting the dose. mental modifications of metabolism a s something that we've worked with quite a bit for chemical mutagens. they would have less effect. Again, those data are not significantly different from the earlier They also had a very long cell period which was probably due t o or maybe the dose acting i n some You had some ideas on exploring that. Yes. In other words, what we would like to do is t o look One would think that,for internal emitters, You can have very profound effects of chemical

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mutagens changing the external condition slightly. One would think that he,wouldn’t produce as much f o r internal emitters, but apparently he can. Water metabolism f o r tritium water apparently can have very large effects on the full dose. This is an area ve would like to knov more abouc. RUSSELL : Bow would you fee labour that,Newell ? They had a limited water supply, and I guess itran out finally. Some o f them died off in this experirnenz. biological ef fecrs ? STARNARD : I guess the ching thar comes t a mind vith out giving it much.thought is specific activity.If the tritium was staying around and the rota1water con rent vas decreased, the specific It was an accident in the supply of Can you think of any reasons why that might up the activity of the body water woul6 have increased. t o do another round about the szne size KO increase che numbers over the ones we reported already t o see where there might be any arr p zy I think we probably will get np?rova1 dep z rr ure froc the expected linear increase vi rh tine, had aboitt the sane rare, th cn there vast his third one vllere the also KO check mutation rate went up by about a factor of2. With small samples, asI say, i t is not significantly different,

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but: ue'rt: worried abour it because of the chcnge in the physical RUSSELL : That ' s in tritium. STANNARD: Oh, I ' m sorry. I was thinking about a repeat Of the plutonium experiment - chat it would be really astounding if i t : were repeared and the RBE cime out fo be tenor twenty. It still sews as Lhaugh the c vi den ce is all pointing to a lower RBE for the alpha emitters for genetic effects than for somatic effects. CUMM I NG : Yes. The dosimetry seems to indicate that plutonium becomes lodged and effectively stays there for the life of the animal. They should accumulate dose throughout their life. The question then is whether that means an increasing mutation frequency for animals that have been exposed for longer Sort of ir rita zing to have s one ching fhar's scg geste d and no: be able to prove ic bine vz:; Oi tlie other. STi.:JNAIU): Well, with the amount o f work it is for you toget one data point,I ar, wtlre you have to have infinite patience. biological effect.Idon ' t know the direct R BE on the target cell.

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this sort other than the real UE differ en co. SO if ueget more data in the early periods, which is sort of suggested that Grahn has, that the true R5E might be higher than one,bur the operational RBE so far as transmitted generic e ffe ccs might g3 d o ~ 3t o one. It's that sort of scientific question chat I think L'C'd like tu knov. probably pretty safe. the effect will be an RBE of one. @nl' tobe in the liter at urz and I ' m not sty posed tL be covering the very re ce2cwork,I ' m SO darn interested in it that I'm tempted t o razz to atleast refer to itin one way or another. In terns of huzard,Z think ve ' r e Ge're saying that over the long operation are point mutations, is a kind of a single hit mechanism and therefore you ' d expect a 10.: =E? right in the middle of an alpha track that YOU wipe out the cell. SOit nigh: be zn ionization occurring on the They have this wasted energy. Now any so-called hot spots that would have occurred

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in testis would only increase the cose and make the effectiveness per unit of dose stiil loser? STA\WARC : So the mOSt conservative dose calc ul arion woulc b e assunling average dose in uniform d is tribE tion. 1s Khat r.ttat you CLR.P!ING : Yes. There are tcn ways of looking at the dose. One is just taking a Kissue and counting the radioactivity per unit Of weighs r-hich averages everything. And then the other thing is t o do auto radio graphics ta dies where you look et the d is tri buri on cf rhe dosi: wii h in thi. tissue. Tn<n you bring chose L …