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TEE UNIVERSITY OF ROC HILT IR SCHOOL OF MEDICINE AND DENTISTRY The only strong conviction I have about the Davis experiment I s that and appro= I vould be glad t o drop out and l e t them present a unanimous If the others tm the camnittee do understand it The reason I don't understend the plan l e not necessarlly a canment on its merits but rather on my mesger cmpettnce In this field and m the fact thatI was not present at the original planning reseions for the Utah experiment8 where the present pattern was established. Firet of all 180)not clear ðer this Is Intended t o be a rsdioblological investigation or 8toxicity experlemnt t o ertimate a maxim u pcrmi88ibh level. In the farmer anything goes but i n the latter it Is fairly camon practlve to concentrate on a range knm to be only moderately toxic and t o armame linearity fran t h i s range dovnward. It was m y Lmprerslon that an M.P.C. In a long-lived animal MI8 being sought. For M.P.C. one would not bother vith levels such as t h e 5 far example, because the results are not relevant. a dose is of academic ln terer t, only, because, presumably, no slgnfflcsnt number vould be so exposed again intentionally. The fact that a m ~ l lmay have bad such Also I m not clear that there I s any sense l n determining the ratio Of o= the toxicity of me substance t o another except in retrospect. wan lng ful only vhen both agents produce the eeme cf fec tr. providing It doesn't lead toa plan which falls t o get adequate InfO ~ tiOn In this regard most of the older experiments on rodent6 covered a Vide Agbg without i.L +.specific disease may be the only effect which different radiations produce at levelr of practical interest. range of doses and mve rise t o extensive dose-effect CUITCB, of these curves for setting of H.P.C. was usually weakened by the failure to Use enough snW1sto determine accurately thoec points of lov effect from On the other hand there l e no objection to dctcrmining this ratio
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which extrapolation toward zero or t o the ever postulated real or fic t ltl we threshold might reasonably be made. I don't detract iran the value of these curvea f o r general radiobiological Informstion. do rni6e the question a~ t o whether it Is better to determine a few low lewls vel1 when looking for an M.P.C. in a long-lived animal rather than examining an extended range especially when rodents can be ured relatively cheaply t o study such a range. Another point along th ie line 18 that one reldcm examines the M.P.C. itself if he is fairly convinced of i t s order of magnitude. hen is that the M.P.C. presumably produces no eignlffcant injury or a significant inJury in only u3 i n ~ lg n if i can tnumber o f caeer. the performance of long-lived aninrsl ex per bent because a definitive answer requires an imposeibly large number of individuals . Another thing that bothers me ie thatI am not aware of the opinions Of the cam it tee on how the Davis program is related to existing data on Sr and may not be relevant. The following data are available: An example of what I mean concerns l i f e span which may or Element LD50 30 Dose t o Shorten A couple of tetimatcs of l i f e shortening i n the dog can be made on the assumption that the ratio of the acute lethal dose t o that dose which rhortens life by one-half i r similar for different elements. Because Sr9O I s more like Ra than PCJ or PU inits distribution, the ratio In anLppals of longer life span If 60 his dose f o r 508 life ehortening would be 1/40 or 1 50 of 1 p c / g I of dose f o r SO$ life shortening t o acute dose i n the rhort-lived animal6 probably would be eimllar to that of Ra, i.e.,1to 20. this ratio should probably be decreased. dog. Poesibly 1/40 is appro rlate t o the The other method depends on relating Sr9' to existing data on Sr89. F. F:: sr@ cauBe8 SO& l i f e shortening in mice with atwt 12pc/g i n divided doses E 9 and about 6 pc/g in single doses. the material retafned by t h e animal vi11 have exerted I t a radiological effect M ng to its ehort half-life, 54 bye, most of 0
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during 50$ of i t s normal life span. tissuee because Sr is essentially all excreted or lodged in the bone vith in Pure SrgG in equal )IC dosage would deliver about l / 3 as much energy t o the !soft tissues on its way t o bone owing t o the lower energy of its 0 emlesion, 0.54 MeV compared to 1.48 MeV. Within the bone it will continue to Irradiate durlllg sane 300 bye, However, Not much of this Is ebeorbed by soft at essentially its initial of a mouse, i.e., Because the elements are the same chemically it will be sufficient to calculate the relative doses from 1p2in 300 days i n order t o canpare their For 90 the corresponding cal cula tig after correcting for energy I s For 89 dose .78 approx. In p c days. If YW 1 s retained i n bone 8s is Srgo (and probably it 18 approx.) then t h i s On t h i s basis one would expect the dose f o r half-llfe shortening of Sr9' - ~o figure should be increased by about 5 fold t o say 5 5 0 p c days. t o be 78/550 that of Sr@ . this figure mhouz be reduced by 7 or 8fold to say 140 pc/kg for the dog. For single doses in the mouse this vould be 78/550 X (xring t o 19 30 d ~ y sbeing 7to8 times as great in the mouoe 81 the dog Owing to the exposure being longer during the dogs so& life span, this should be decreased by 7 or 8 t o 15 or 2Opclkg. r i g h t life shortening would be expected about a8 follows If the normal life span of the dog i s 15 yeare end If shortening is proportional t o dose. appears t o be too low perhaps for the Argonne 100 rc/kg dog who has l i v e d 9 years. These two methods lead t o about the same result. If the guessing is about Dose yc/ka Fraction Shortened Time Shortened Years me experiment is ObvIGuely not vtll planned for life-apan studiee only, because the effects of the three lower leveie wculd be undetectable. If lifc - shortening is not an important datum t h i s doesn't matter. t o me that the plan is any better adapted t o the determination of other criteria without also wasting erne levela. However, it i s not clear Perhaps other members crf the committee can guess where significant bone changes or cancer would appear and whether the plan is appropriate t o deal with t h e i r
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Another factor with vhich I sm not well acquainted I s the work In progress or planned elsewhere on Sr and vhat effect I t should have on the planning a t For r e ~ son 8such as thooe mtated I don't feel that I have a reasonable basis at thir time to t it her approve or disapprove the Davis plan. whole 6s you know I have misgivings about It and In particular I should not like to eaddle Davis perronnel and the Cammission'vith another experiment lfke the external radiation one vhich In retroepect, at leaot, l e , I think, not going to yield nearly ae much Information as It could have. othemdse, the data likely t o arise from the Davis experiment could have been obtained much less expensively. Or, t o put It . Because I have no reason t o suppose that the other members of the meet wain. If they think the program could be dlscus6ed again prof itably appropriate arrangement8 can be made at that time. my misgiving e vhy don't we find thle out before planning t o If ttley favor the plan 1'11 ask Walter Claue t o fire me.