Interview with P L Hackett and B J Mcclanahan

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Early work and training experiment with miniature pigs - at 125 u Ci level where saw much Pig-shows fewer changes in chromosomes than cells of man after irradiation - more sensitive to chemicals Exposures to electric fields - beginning of work Did not do much on bone pathology or biochemistry Did Clinical Chemistry and Hematology in the Sr-90 pig experiment later on Started with Kornberg in 200 West and did many things - To Leo Bustad iodine study Clinical studies with the dogs in Jim Park's show on Pu Made a clean break and went to fetal toxicology with Me1 Sikov - both radiation and chemistry LMFBR aerosol in dogs Effect of particle size on intake of several things by fetus and juvenile mammals Similarities and differences between chemical toxicology and radiation toxicology problems and programs Should not focus on one route.of administration of materials

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Importance of chemical form Chemical formmakes more difference for chemical effects than for radiation effects - e.g. nickel carbonyl is highly malignant while other nickel compounds are not in chemical toxicology (until recently) Most important projects at Hanford, BNW, PNL Fetal and juvenile mammal Pu on skin and in wounds - important but very difficult and not much emphasized Lack of effect on reproduction in these experiments is Difference in attitudes toward chemical effects and hazards of Improvements in work and,conceptsover the years Few AEC labs were fully basic - perhaps Biology Division at Can now work with purer things and much better equipment Too single minded in what we look for? Need for behavioral studies?

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Connection to fetal and juvenile mamma1 work jtexnember radioisotopes concentrate in the yolk sac

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abaut 1960; then I went back t o school and came back t o biology in 1962. man then on, I've been function bg as a biologist, although doing sane work on zinc and ca6miUm. Plad then plutonium in wounds. I fiyuxec5 I was a chemist and worked as a chanist until xot so rmch the skin, but actual wounds. cy togae tics and the strontium-90 program. Well, a lot of miscellaneous Then I was getting into work we're doing here. Us0 currently I am split betmen cytogenetics and the bne STWNARD: What is the cytogenetics? McCUW%Ah 1: ment ly ? on the strontium-90 animals, it was primzcily when we had *he high leukemia incidence in the 125 micrcxurie animals, and bear in mind, t h i s was in the middle 1960's when cytogenetics was quite a big play in a l l sorts of places. STANNARD: Pigs, the miniature pigs? Yes. The idea was t o see i f we could find any kind of a sanething on the omer of the Philafielphia & mse,scm so,- of abnormality in the leukemic &l. Well, unfortunately, by the t h we mlity all right, but it certainly wzsn ' t consistent from animal to animal. it wasn't even consistent w i t h i n an anim.1 or; the hsis of chrmscane survey.

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In the process I beczme axare of the fact that1 ~ 2 ~s eeing relatively So I did a little bit on actually ir rac i atf ng, comparing human versus 719 using in vitro x-radiation. Ani deed,the pig doesn't form the number of aberrati0.m that the human chra~~scrresdo. blCCLANAHAN: Yes,it really seems t o be more resistant.Currently what I ' m doing on cytogenetics is looking at the sister chromatid exchanges. They have been found to he extremly sensitive, much mre so than the mnventional aberrations as far as chemical acjents are concerned. In fact, they probably represent a different type of biological event because they aren ' t as sensitive from the standpoint of radiation as the conventional aberrations are,but they ' r e more sensitive to chemicals than the conventional aberrations are. So w e ' re looking st those with regard to electric field exposures and some chemicals. STAKTARD: Electric field exposures? You mean the high tension lines? so I'm looking at it in pigs right now, 2nd we're going toget going on rodents this y ez r.Idon ' t really expect t o see anything. I ' m just i oo king at the animal a s he i s exposed to the fi el2,and then I take his cells znd then zlso expose them toa chemical muzagen tosee If rrq-be they might be sensitized by exposure to the electric field.I ' v e been doing that for a couple months now. So far,nothing startling bas come up. I vo ul dn ' t real iy expect itto. And then I'm also doing some bones in the Funds being what they areI ' m doing 2little bit of bone

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and strontium that the bone work weuld just never stop. ? lCCMm ' : No, the bone work never really got going. You mean like Utah? Nothing like that, no. We analyze to see hov much is in the bone, but that ' s about all ve know. STANKARD: Were you concerned with the strontium ingestion experiments ? M CCM AHAN : Yes, those were the ones with the pigs we were doing. Dr. Hackett was involved in that also in the clinical chemistry and hematology initially. STIUXARD: Ptaybe I should know more about what you ' v e done, Dr. Hackett. HXCKETT : Well, I started out with Harry Kornberg when we first got our laboratory over in 200 West. That was kind of a hodge-podge. We were binge very tag frm inhalation q sure s to looking at jack rakbit thyroids aut in the desert. I then went with Leo Bustad on the chronic idhe study that leste d for z number of .years. And then on to the chronic strontium study.Iwas mzinly involved with hm to loz and clinical chemistry. And then,let ' s see, Iv as involved in an awful lot of clinical chef is try ' in all these chronic studies with the d qs, e.5. Jim Pxk ' s plutonium dogs. About two years ago I made a really clean break and went to fetal toxicology that's what I ' m involve3 in p z j m xi ly nay with several ~ tals ,tran..s@utorics, transfer of metal. bith soiium fuel aerosol in dogs and rats. tri th the field studies vith lea2,and then in Nel ' s charter we were also m d then &so I'm doing a UEER aerosol study h' I got into inhalation neas u ring the differences th z t particle size u o ul6 nake on uptake i n fetal and jwerule cme5to asult luncs. iad then I so,* of evolved

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rn to this sodium i uci study L-hich is zi so very in ceres c ing. emphasize the time between 19LO when thE Nanhattan Engineer District started and ' 75. I'n sure I'll have t o run a little bit h to prtents for the future. One of the things I wanted t o emphasize and I hope I can get the message across, hob? much the radiation a ~ 2r a dio isotope vor k is similar tothe problems that the chemical toxicologists are nou facing. And i f something can be done t o save them some tine and trouble and learn some lessons from what wedid,I ' d like to keep them from having to relive the history of the whole radi arion program. You are shifting wer,and the laboratory is shifting wer t o chemical toxicology. Do you see ways i n which the experience of the radiation work czn be brought to bear and maybe make it easier for the toxicology people to not have tocut and try in qite so many different ways? NCCT.JdiM : Well, for ezch chemical you ' r e going t o have t o deterriiine what is the target organ. You're going to have t o look at both an acute exposure from the industrial accident w d also going to have to be concerned with long-term chronic exposure to general populations.In. the case of met sls, you mighr be able to use some of the,no,there ' s enough known about the metabolism of the regular nonradioactive chen ical s tiACI;ETT : I think,well, one bit of advice the tI would have t o them is,we had a tendency to focus on one route, and v e have found that we cannot do that.In order to res ll y make 8 model for a metal ve have t o do htravenous, gavage, an2 inhaled. i mean w e have to do it. hk would, fuss around r-ich, sap, sozebody would be doing intravenous over here,

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somebody would be doing in hala ci on and nc t get the group together. sir : liar's a good point.I think the to xico log is z s in general have traditionally looked at all routes of a dni nist ration in their first screening to a larger extent than we did in the radiation field.I think LE t&ed because the techniques were so specialized, like for inhalation, to build a whole labzstoAqaround Jnh2lation expsures. There might be even a totally different organization and a differ enc place than the people doing other routes of administration. I guess the strontium experiment is a good example. And the inhalation work was being done elsewfiere. HACKETT: Yes. That was the best guess.. ... MCCLANAHAN: Something else too,I think,that has to be considered is It was all ingestion. MC CLAN W ' : I think about a11 you could do would be to set up a basic program which would involve your acute/chronic, I ' m still not convinced p rococo l which would involve all those things. There isn ' t an easy answer. STANNARD: No, there certainly isn ' t.If there was, we'd have i t done M CC LAi ' i ' : I think that would be the most useful thing to come out of all the radio nuclide work. You know, okay, you I.V. inject a citrate prepared under very carefully controlled conditions. We have rhe s o - c zl led You have t o hav; it to calculate how much if it gets in there ... I mean you would just have t o set up as rand ard

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miy people are going toget it? iodine injection of a monomeric how it behzves, practically speaking,you ’ re not going to get the spec tm. HACETT : Pra czi cd lp speaking, =hen you have aa in hala ci on exposure, you also have a gut ro intestinal exposure. But the metal,that ’ s one reason I think I ’ m so fascinated by metals now, areso similar t o - the studies like, I’m doing lead,and plutonium and lead are just ... STANNARD: Plutonium moreover is a little different.A little harder Your par zi cle diameters on in hz la tion vh ich markedly influence HACKETT : Yes, you bet. But the manifestations that ’ s the only thing that is different. STANNARD: Thar ’ s an inter es ring point. You th kk the chemical form makes more difference when you ’ r e working with chemical toxicity th zn with the radiation toxicity ? chemical toxicologist quite2lot harder than we had it. KC TANAH AN : Yes, I mean like nickel carbonyl is highly mzlignant,but alot of other nickel salts aren ’ t . But i t .would be 2 tremendous job. Nickel alone could go through in half the tests. If you were starting out bdth no information now, t o have t o go through and test all these various compounds of nfckel. STANNARD : Well, the strong tendency with radioisotopes is to just divide them into soluble and insoluble land let it go at that.I guess there are not nearly as many examples like the nickel. carbonyl one where I would have said so, although ... That makes the job of the

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the natcre of t h e anion makes all the &fference i n whe+ber or not It does sw-thulc. The ra&ation AS there, and t h a t presm&ly is the cause of the damage,& the rest of it is determininq metabolic behavior along the way. BACKETT : Well, the one thin & . I ' ve noticed on new toxicologists coning in,the difficulty they have inthe concept of a target organ, particularly the skeleton,they ' r e used to dealing with compounds that are distributed all over the body. And that is one place that the old AEC people have a better feel or could guide in that di iec tip n. sIIAM.JARD: There's no question, the toxicologists never worried about dose to a target organ. field that we went through alot of this shenanigiln of trying t o determine [They do nm!] If they injected so many milligrams per It was only in the radiation h m much wzs in a given organ. I ' d like to aska kind of.genera1question. You've seen the outline of the book. You've seen2lot of evolution of the work here extremely important to be sure to get in the book? - 1I What, as you knaw the work here, would you think wuld be I think I know the work here pretty well, and yetI find every place I go, there were things Ididn ' t know about. MC CUNA HAN : Well,Ithkk probably the big major project would be rhe of effort went into that. but I think the strontium-90 pigs. A lot HACKETT : Well, what about our iodine ? MCCLANAHAN: That's wha: I was going t o say, alot of ef for r went kt0 that, too. And Leo Buesrad saved some necks afew rimes with thar. Okay the plutonium

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an area that probably vi11 never be.solved. Bow do you make a standard vound and all this sort OL eking. That was one of the six areas that Xerb Parker said that, he note down during the war years as a thing that had t o be settled MCCLANAEAN: And it hasn ' t been yet, and I really don ' t think it ever will be.I suppose the simplest thing is to cut it out. That was sort of our conclusion. Leo Bustad had s m of the A i r Force veterinarians going through here taking the intra dermal injections.I on that. Because there really should be -thing (malignancies) perhaps we didn ' t have enough animals to get a really good answer showing up. Those tre the big ones. There are alot of smaller projects that are probably just. as meaningful. You probably know more about them HACKEIT: I was thinking what is mre significant. Part of the dermal or will be talking tohim on his gut absorption work. Those are difficult studies t o Perform, terrible. Actually the most interesting one tome personally was the hematopoetic effects fran the strontium-90. It also maee me wonder h m he [Bustad] could n i …