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THE UNIVERSITY OF ROCHESTER SCHOOL OF MEDICINE AND DENTISTRY As I stated at our recent meeting I think it lmight be profitable t o consider the x-redistion program a t Davis in relation t o our present knowleQe of the subject. I n the program appended it vi11 be seen that 140 dog8 received 100 r various ways. With the possible exception of t h a t group which got a single dose, it would be our present expectation that a l l would be affected the seme way and that their life expectancies would be reduced by about it wont be. animals 8 8 i n the controls. 100 r exposure entails no significant consequences. By luck this difference might be obeerved but there’s 8 fair cbance Specific diseases should be about the same l a the exposed The principal conclueion wIU. probably be that The figure 18 above and those eetimstes which follow perhope should be raised by the r a t i o of Lbw’in rodent and dog, 1 . e . by about 2. We don’t yet know wbether absolute dose or doee relative t o LDy) %E the proptr It is t o be expected also that the 60 dogs in the groupr I, J and K exposed t o 300 r will euffer the #me effects and lore about 3s of their life spans, an amount perhaps dlscernlble but not vlth high percentThe 60 dog6 L, M and Ip Vi11 probably again be alike but they may be unlike I, J and K because of the as yet uneqtlalned phtncarenon that high brief single doses caum more mfter efrect per roentgen than rsasU doree. A high single dose, In thio eenre, i n the mouse is smething e eat cr than 120 r but it may be lover in the dog because his LDw i r lower. The rur vivo re of 300 r in a single dose may euifcr 20$ or more life - shortening but this experiwnt is not comf?arable becaure many of the original group, perhaps those most susceptible, died acute deaths. ’. Altogether there cue four experimental groupr, two of which A to B and ItoK are comparable but which arc not likely t o be highly accurate.
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Nevertheless they will probably give samc Ides of the shortening of life per roentgen for small doses. data of 6cme Interest but since they ere not simply related t o each other o r t o the other two sets they vi11 not form part of a curve from which interpolation or extrapolation vi11 be possible. Rochester st low levels 5 days per week for lifetime. The other tvo groups L t o 19 and 0 vi11 be expected t o yleld isolated As you know, there ie B group of beagles being irnsdisted here In The dosage schedule No. Doge Dosage 10 Year Dose Because the prim purpose of this experiment leto determine fertility changes, the numbers of animalo are rather -11 for life-time (presumably about 20$ l i f e shortening) t o go with the tvo lavest dosage groups at Dgvis. doeage plan 6t Davis gives the same results as daily exposure In the 100 ~eV'ertheles8the 3 r per week @wup w i l l give another point The other two groups will perhaps be indicative of' whether the The highest dosage Rochester group has accumulated t o t a l dose of My first tendency with respect t o the Davis plan vas t o suggest that the 100 r group be cut down t o 60 or less and that the remaining dogs be loaded up a t 25 r or 50 r per dose to a couple of higher levels which vould give definitive data. m e r e is an objective to this, however, in that a8 far as we know, although it is unlikely, and an experiment In which 100 r given a t one time followed by addftlonal dosee sQne y e a r s later may be a special case. Because of t h l s the data might be not very useful unless the vhole problem was studied In rodents I n advance in order t o develop a useful plan. In consequence, I 8m reconciled t o the program as It le. However, with this example In front of us I think we should attempt t o be highly astute about the new program on internal emitters and t h i s one 88 planned makes me very uneasy.
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the Radium propooal No. of Dogs This, as I understand it, is proposed t o give a comparison of the effects of Dingle doses and 4 or 5 doses given over a 6 month period b e g i a n g fa adult animals at 18 months of age. A8 I see it, there can be two basic differences bctveen single and divided doses 1) retention and 2) distribution of Ra i n bone with possibly consequent diflerencce i n toxicity. counting or sacrifice. require more than 1 level vitha plan such a s Retention can be rtudlcd by whole body I don't ace how the other questions cea possibly 3 .27 15 or 20+ a few for sacrifice Granted the high level dogs vith different doeage mlght possibly have dlfferent gross bone pathology because of different distribution but any practical informatian about this point should 6pp ~equally well from a oinglc level not overwhelmingly toxic. I am similarly disturbed about the S r w propoeal. My concern can perhap8 be illustrated best In relation t o camon procedure in toxicology To test a probably valid M.P.C. the usual prsctice vould be t o expose 8emral species t o 100 times this M.P.C. positive finding8 i n 8ormc or all of the species this would coniinn the M.P..C. because a factor of 10 i s usually used t o allw for different rpecics 8USC~ptlbllltl1?8on the grwnd that man might be relatively highly 8usccptible md soother factor of 10 I s ured for rick children and aged college professors on the ground that they might also be highly sueceptible relative t o healthy truck drivers. If there vcrc minimal If the M.P.C. were not indicated at sll vell, u r u a l practice wwld be to teat a cheap species a t 10, 100 and lo00 times the beet guess for
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Dr. Robley Eoans July 1, 1957-4orientation, then do the previous experiment on a number of species. Thio method, of course, is of no use far intarpolation or extrapolation so it may not kh dic a ted for 3-90. may be employable. Nevertheleor sane of the principles For exmaple, If the suggested M.P.C. of 1 p c i 8 valid in the usual eense studying it in a na6onably .mall number of animals vould not 81iniarmation 011 toxic effects. such level6 are warranted. A l s o very high levels do not give more then quOllbtitrr Consequently no large numbers of animal o at Thin suggests a plan eamething like IievCl Retained b e No. of Dog s- 10 Ten high level dogs ohould be quite sufficient t o campare vlth the Utah eerie6 using other elements. Twenty dog6 per level w i l l give almost a8 much informstion a6 30 aab you would hive to go to 9 t o 80 t o increase the inionnation aubstantiallY. For R,226 and 8r90 together these propoealr reduce the number Of doge to about 1/2 vith considerable reduction in cost and I don't think much reduction in probably useful information. I advance these proposal6 only as a basis for further biscueolon. mty haw not been revlewd by 8stat irt ici an. there is a cattpetent experimental planning group at Davis headed by Dr. Baker. Thla group m i g h t be villing t o advise on animal numbers and the In this regard I undtretand What I would urge mainly I6 taking a r e a l 4 hard look at thir progrlrar before it I s put into effect. If we put uanecteoary money and manpower i n t o currently popular item going to get caught short i n the future. CC:Ikr. Anderson, Brues, Claus, Lmghan, Pearson, hmham, Col. Pm, MaP32308.own
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