Interview with Charles Sanders

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Ih TER VIEW WITH CHARLES SANDERS - SYNOPSIS 1. m o r response vs. distribution of dose in lung Total number of tumors about the same but different kinds and Only possible difference with Pu-238 oxide particles Differences become minimal at low doses (1.5 rads) - get tumors at 4.5 rads Remember the material is moving in the lung Every experiment gives 1-2 tumors at less than 18 rads Pu is in sharp particles - cerium is diffuse 2. Single vs. divided doses 4. Hamsters - transplantation to cheek pouch Differences between labs Species differences in incidence and vigor of tumors Intratracheal vs. inhalation - a factor also 5. Predicts dog and rat experiments will show essentially the

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DISCUSSION WITH CHUCK SANDERS June7,1979 bat tell e Pacific Northwest Laboratory SANDERS : ...a lso done work with inhaled cerium oxide(high fired haled americium oxide.We ' re interested in how that type of ex - po sure influences the tumor response. Of course, you get the added burden of liver and bone tumors and other tumors added on to the soluble.It turns out that on a nano curie deposited base,the total tumor burden is no different between an animal given in hala - tion of a soluble vs.insoluble transuranic,assuming everything else is equal. What happens is that you get about the same number of a de no - carcinomas with an insoluble as you do with soluble,but you get very few,ifany,sarcoma type of tumors(spindle cell cu late type of inhaled transuranic insoluble particulates of Pu - 239 oxides,whereas americium and curium and the soluble 238 inthe experiments we did produced very few tumors.The.reason being that the pathogen es is for the s quam o us cell,bronchi o geni c, ' i f you will,which we don ' t see hardly any of. The s quam o us cell tun or requires a scarring effect.For an extensive scarring effect, we uses quam o us cell met apl asia.Well,you get that with a parti - cu late material wb,ich is concentrating in the bronchus.The soluble transuranic s will cause,if you get a high enough dose, diffuse radiation of an area,whereas the particulate forms will cause a very spotty but very severe radiation effects. The

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result is that if you want to kill an animal with radiation p neum on it is, it only takes a couple of thousand rad s with curium,but it takes 10,Oi)O rad s with plutonium,soit ' s quite a difference there. the tumor responses with the plutonium oxides are quite different, You get about twice the number of tumors talking about higher doses now,lower doses you don ' t ' get these lesions)but a this her doses you get enough concentration --o fdose to cause these type of tumors.There was quite a difference there in in the tumor response with respect todos ime try in the lung. Anyway, if you look at the total tumor burden,both in the lung and in liver and bone,there is really very little difference because what the curium loses in the s quam o us cell,it gains in sarcomas (os teo geni c sarcomas) and a few liver tumors and probably some other ones,so that the total tumor risk is really quite comparable between the two. Now if you look at the doses vs.lung tumor response, and you do a hazard analysis like we've done using probability models or other models,Idon ' t really understand, good things that the statistic i zns do, and you analyze the data, and you compare the. the question, "What is the predicted or estimated lung tumor incidence at1.5rads " to the lung - or whatever the maximum perm is - sib le is right now.There is really no difference in the answer. There i s some difference in the type of model you choose, but if you. use the same model and you com2are soluble vs.insoluble,there is really no difference. 238 oxide particles.We were getting much hotter particles in the The only possible difference is with plutonium

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lung than with239. They are roughly the same particle size,in which case the238 is much less effective compared tothe230, but if you go back down tothe moderate t o low doses,there is really ,la differ en ' ce in the end point of 1.5rad s as to how many tumors YOU are going toget - that ' sthe reas'on you are doing the ex peri - ment, whereas at the higher doses,there are some differences. SANDERS: I t ' shard to get a really - confident handle on the dosime try at those real low doses.We have the.deposition values ; we are talking about groups now.If you give animals a couple of nana curies and you k i ' l l 'em and look at them several hundred days,. there is so little activity there that the dos ime try is2problem,but besed on averages, yeah, w e ' re getting tumors at4rads,5rads. Every experiment we've done has given us one o r two tumors a t doses less than10rad s in the lung.If you were to do a stat is - tical analysis of those low eos es, you would say it is significant, I f you do a statistical analysis just at the very low doses,it ' s So,it ' sthe way you analyse the data that significant it is. But it I5 an observation that is observed in every experiment, End the ip ter preta tion indicates that dose distribution doesn ' t really.play dete rmi ne show big factor in lung cancer.However,if you look at the auto radio - srams of the 0xiC.e plutonium, yo= get really nice,sharp particles, and the curium is very diffuse. I t ' s got to be a huge difference.But if you consider all the nocion that ' s so ing on in the lung with those particles with breathing and. motion of the particle and motion of cells 2nd mction

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fraction ing those exposures over monthly intervals for five or r ix months with respect to the lung,Idon ' t really thin h there will be any change inthe tumor response compared with sins le exp ~ sure.But with respect to the bone,I think there is going to be a tremendous increase because the bone turnover rate is so rapid in the rat - it tends to bury the activity within a couple of days, so you ' re giving the surface target cell each time with a different dose, so we are giving350nano curies with one exposure o f ? ns no curies to a shot,at10exposures,I think it chronic exposure for alpha emitters in the bone i s worse, andit doesn ' t appear to be in the lung. That might be interesting ; that might very well show the So that ' s an interesting area We've done the work with morphometry now. W e heve,of that - and that kind of intrigued me asto why not ? Some invest i - g ation indicated,tome that the pathological criteria for tumors used by the people in John Little ' s group at John Hopkins with polonium210 were dj ffe rent because I sent some slides over t o th-,and they read them completely differently than the path o los is t here did. So they called them tumors,znd Isent10slides, and they c zl led seven of them tumors. here, and they c zl led two of them tumors,and Jerry Dagle and Bob I called one o r two of them tun or s Bush read them,end they only called one of them tumors. Then w e talked to a guy at Washington State Llniversity,anc2 h e looked et them, and we agreed(he ' s an expert in hamster pathology)...he agreed with our path o loa y so.... One of the problems that they hzZ that we didn ' t have, they had in their experimental design was (they were consistent about it, this is not a criticism)they were calling things

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response we were calling those tumors. One of the flies in the ointment WZS that they managed. to transplant them into the cheek pouch of hamsters,and1looked at them, and they were really wild malignant tumors. So w e repeated that experiment - a thousand hamsters,and transplanted to the cheek pouch and got absolutely nothing. You couldn ' tget them t o grow there either, so we are kind of at an impass right now. We have gotten some of the tumors to grow in mice,so it could be that they are malignant, whereas the normal hamster won't do anything. So there could be something there.. STANNARD: Do you think there is some sort of cell factor lacking, i n some cases and not in others. SANDERS: What Kathy Roach did, she's got her Master's Deqree, s h e d i d 'a morph ome try study,and she. showed that morph o metrically in Wei bel ' s techniques that the rat and the hamster are nc different. There are few differences, but they are really minor - nothing to explain why they are reacting that way. auto radio graph y of the hamster lung and the rat lung and divided it up into sub pleural peri bronchial,peri vascular,and so forth. Little cl dims that intra tracheal iron oxide and polonium is the optimum way to get tumors in hamsters.He ' s giving c once n - t ration in the peri bronchi ola rare as,which he claims the tumors are coming from.Well, when Kathy did the quantitative auto radio graph y, she found there was -no activity !'n the rat in the peri bronchial peri vascular areas,the areas that he claimed were getting tumors (excuse me, in the rat or in the ? ) . She found concentrations of plutonium particles in the rat,peri bronchi ally, of course,sub pleural y,and she quant it a ted that. Whereas, in the hamster,she fog nd there was nothing peri bronchi ally or Then she did a quantitative

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peri vascular ly,so that could explain,in part, why our inhalation doesn ' tgive us tumors,whereas the intra tracheal polonium did. Now they re pez ted that study in Lovelace and found. not as many tumors as w e found, but certainly a lot more thanI would have expected, so I think there i s something to that distribution being important in the models that we use for induction of tumors. STANNARD: Now you are getting more into chemical toxicology ? SANDERS: Ididn ' - t really answer your question there because I was thinking about something else.I think I kind of wanted to avoid answering that question. Number one, yeah,we should come t o an end. The doggy work tome is not a way to use the ' taxpayers ' money. I think what i t ' s going to show is that the dog data is going t o be similar to the rat data. I think there will b e some obvious differences,but I think when you come right down to the nitty - gritty,you are going to find a tumor response to2 low dose,and it is going to be similar between the dog and the rat.I think the interpretation of the data is going to be similar. When i t comes right down to 7why, we don ' t know yet.I base this upon what Jim has talked to me about.In the dogs you are getting tumors now at some pretty low doses.. The work with the bone tumors in dogs in Salt Lake City,in Utah, which is really quite similar to what we are getting in our rats. They get a much better dose response curve than we do.Our bone tumors in rodents tend to increase20to30%and then they just plateau, no matter how much dose you give them. Then you have a very shallow dose response curve from there,but you do get the tumors a t low doses,like the doo s.It ' s interesting.