Broerse, J. J.

Gerber, G. B.

Kellerer, Albrecht M.

English

Universität München: Elektronischen Publikationen

Summary of the discussion on mammary carcinogenesis in the rat

Open Access LMU

Commission of the European Communities Neutron carcinogenesis J.J. Broerse (TNO) G.B. Gerber (CEC) Directorate-General Science, Research and Developmmt I I I NEUTRON CARCINOGENESIS = TABLE OF CONTENTS = Introduction J . J , Broerse G.B. Gerber Neutron carcinogenesis and radiological protection: a h i s t o r i c a l perspective. Induction of myeloid leukaemia and other tumours i n mice by i r r a d i a t i o n with f i s s i o n neutrons. J.A. Dennis R.H. Mole J.A.G. Davids Lung tumor induction i n mice: neutron RBE at low doses. R.L. U l l r i c h Cancer induction i n rat s after f i s s i o n neutron i r r a d i a t i o n with special emphasis on lung cancers. J . Lafuma M. Morin R. Masse RBE of f i s s i o n neutrons for l i f e shortening and tumorigenesis. J.F. Thomson L.S. Lombard D. Grahn F.S. Williamson T.E. F r i t z Summary of the discussion on tumour induction i n diffe r e n t organs. J . J . Broerse Mammary carcinogenesis i n r a t s : basic facts and recent r e s u l t s i n Brookhaven. C.J. Shellabarger J.P. Stone S. Holtzman Pathological aspects of mammary carcinogenesis i n r a t s . M.J. van Zwieten J . J . Broerse C.F. Hollander Mammary neoplasia i n Sprague-Dawley r a t s following acute and protracted i r r a d i a t i o n Mammary carcinogenesis i n diffe r e n t r a t s t r a i n s after single and fractionated i r r a d i a t i o n s H.H. Vogel H.W. Dickson J . J . Broerse L.A. Hennen M.J. van Zwieten C.F. Hollander Mammary carcinogenesis i n Sprague-Dawley r a t s Estimation of r i s k of breast cancer following low l e v e l s of neutron i r r a d i a t i o n : some possible problems. Carcinogenesis studies i n rhesus monkeys after f i s s i o n neutron and X-irradiation J.L. Montour M.N. Gould C.F. Hollander M.J. van Zwieten J . J . Broerse IV Page Late e f f e c t s i n mice following whole-body exposure to d(50)-Be neutrons and gamma rays. J.R. Maisin A. Wambersie G.B. Gerber J . Gueulette G. Mattelin M. Lambiet-Collier 187 L i f e shortening i n mice exposed to f a s t neutrons at different ages. RBE for reduction i n latency of C^H mouse mammary tumours of d(16)+Be neutrons r e l a t i v e to 250 kV X rays. Summary of the discussion on mammary carcinogenesis i n the r a t . V. C o v e l l i V. Di Majo P. Metalli S. Hornsey A.M. Kellerer 191 199 203 Analysis of tumor rates and incidences - a survey of concepts and methods -A review of the revisions i n the dosimetry of the atomic bomb survivors. A.M. Kellerer D. Chmelevsky W.K. S i n c l a i r 209 233 Organ doses and r i s k s from neutron exposure G. Burger G. Wittmann 255 Low-LET r i s k values and the importance of neutron A. Mi l l and high-LET ra d i a t i o n s . M. Charles Cancer r i s k s and neutron RBE 1s from Hiroshima and Nagasaki. Summary of the discussion on mathematical a n a l y s i s , neutron doses and epidemiology. RBE of neutrons for genetic e f f e c t s . Qualitative differences i n the mutagenic action of neutrons and X-rays. RBE of neutrons for induction of c e l l reproductive death and chromosome aberrations i n three c e l l l i n e s . R.L. Dobson T. Straume J.A. Dennis J.R.K. Savage B. Leigh Neutron effectiveness at low dose l e v e l s for other M. Coppola endpoints. J . Zoetelief G.W. Barendsen 275 279 301 307 333 343 357 RBE and dose e f f e c t r e l a t i o n s h i p s i n mammalian somatic and germ c e l l s . Summary of the discussion on non-carcinogenic e f f e c t s . A. Leonard G.B. Gerber G.B. Gerber 361 365 The role of neutrons i n c e l l transformation research H.H. Rossi I. Theory E . J . Hall M. Zaider 371 ν The role of neutrons i n c e l l transformation research I I . Experimental Neoplastic transformation in_ v i t r o : dose rate dependence of the r e l a t i v e e f f e c t i v e n e s s of fission-spectrum neutrons versus Co y-rays. Quantitative r e l a t i o n s between e f f e c t i v e and sub-ef f e c t i v e c e l l u l a r l e s i o n s i n rad i a t i o n carcinogenesis. Dose-effect-time re l a t i o n s for l a t e somatic e f f e c t s . Summary of the discussion on c e l l transformation. Summary of round table discussion on neutron carcino-genesis and implications for rad i a t i o n protection E.J . Hall H.H. Rossi M. Zaider R.C. Miller C. Borek C.K. H i l l M.M. Elkind G. W. Barendsen H. G. Paretzke M. Coppola G.W. Barendsen Page 381 397 407 419 437 445 L i s t of p a r t i c i p a n t s . 455 - 203 -SUMMARY OF THE DISCUSSION ON MAMMARY CARCINOGENESIS IN THE RAT A.M.Kel1erer, University of Würzburg, Germany The discussion l e f t no doubt t h a t , even in t h i s specialized f i e l d of investiga­ti o n s , there is no lack of experiments s t i l l to be performed, and no shortage of controversional i n t e r p r e t a t i o n and application of those results that are ava i1able. The f i r s t part was focussed on technical aspects, although the technical questions did largely r e f l e c t essential differences in approach and inter­pre t a t i o n . Major topics were the problem of m u l t i p l i c i t y of mammary neoplasms and the decision to score f i r s t tumors only or a l l tumors in an animal. Closely related is the choice of the strategy either to remove a l l palpable lesions or to leave them in the animal for lat e r pathological assessment at necropsy. A further related point concerned the not uncommon observation of p a r t i a l and even complete regression of mammary neoplasms. This, in t u r n , led to the question, whether the pathological c l a s s i f i c a t i o n s have d i s t i n c t i n d i v i d u a l i t y or whether they are mere labels a f f i x e d to largely t r a n s i t i o n a l types of neoplasms. The second part of the discussion started out with considerations of terminology and of t e c h n i c a l i t i e s in the mathematical analysis. I t then addressed the wider question of the relevance of animal data to considerations of breast cancer in humans. The considerations were focussed on the r e l a t i v e biological effectiveness of neutrons at d i f f e r e n t dose levels and in rat strains of d i f f e r e n t spontaneous incidence. Particular a t t e n t i o n was given to the p o s s i b i l i t y that low incidences are associated with low neutron RBE and high spontaneous inci­dences with high RBE. The subsequent resume aims at those points that found particular i n t e r e s t . - 204 -F i r s t part: The discussion started on an appropriate keynote with b r i e f inquiries exemplifying the nearly unlimited range of parameters to be varied, and ultimately to be understood, in radiation induced mammary neoplasia. Broerse pointed at the possible e f f e c t of a temporal reversal of DES-implantat ion and i r r a d i a t i o n ; Shellabarger reported that such reversal has indeed been studied in AC I rats and that certain effects - although no dramatic changes - have been seen. Paretzke emphazised the d e s i r a b i l i t y of information on the temporal dependence of tumor-growth rates and the interest in any variations with dose level or radiation q u a l i t y ; van Zwieten responded that the importance of the question had been appreciated in the experiment at TNO, but added that the analysis of the extensive data on tumor volumes was far from complete. A f a m i l i a r and recurrent topic in the study of mammary tumorigenesis in the rat was then considered. Gould posed the question whether f i r s t tumors only should be scored, in view of the common observation that animals with a previous neoplasm have a higher p r o b a b i l i t y for mammary tumors than animals without previous neoplasms. Van Zwieten concurred that the group at TNO derives actuarian incidences based on animals with tumor, regardless of the number of tumors. He added that multiple tumors, too, are registered and that their numbers are evaluated. There appeared to be agreement with the further state­ment, that the increased pr o b a b i l i t y for subsequent tumors need not be caused by the f i r s t tumor; variations of inherent tumor rates within the s t r a i n , due for example to d i f f e r e n t hormonal status, would lead to the same r e s u l t . I f , however, the non-Poissonian d i s t r i b u t i o n of mammary fibromas or carcinomas is a r e f l e c t i o n of biological v a r i a b i l i t y among the s t r a i n , accounting for f i r s t tumors only would bias the investigation towards the lower tumor rates in the less susceptible i n d i v i d u a l s . Both the incidence based on f i r s t tumors only, and the cumulative tumor rate based on a l l tumors are therefore quantities of i nterest. This led to deliberations on the merits or disadvantages of removing pal­pable lesions or leaving them in the animal u n t i l they reach a certain size or the animal dies. There was agreement that neither approach could provide a l l information. But there is also evident disagreement, as the large labora­tories have chosen opposite approaches. - 205 -Van Zwieten commented on the procedure adopted at TNO not to remove a l l palpable lesions. This conservative procedure leads doubtlessly to a certain increase in the complexity of bookkeeping in a large experiment. The advantage is added information on tumor growth, and several participants of the dis­cussion were intrigued by the not uncommonly observed regression or dis­appearance of mammary carcinomas. In the current radiation experiments l i t t l e hard information on this point is obtained, and most of the regressing lesions could well be cysts. However, as Shellabarger emphasized, there is well estab­lished evidence for regression of mammary adenocarcinomas a f t e r chemical car­cinogenesis in the r a t . Adenocarcinomas tend to appear e a r l i e r then adeno-fibromas, although averaged ever total l i f e time, t h e i r frequency is low. In pregnancy carcinomas tend to grow f a s t e r , but they frequently stop a f t e r lac-tat i on. Barendsen raised the related point whether observed mammary neoplasms are pathologically d i s t i n c t , or whether they tend to be t r a n s i t i o n a l in type. He added the more general question whether transforming events are to be thought of as sp e c i f i c . Van Zwieten commented that there were c e r t a i n l y predominant patterns, but no clear-cut,stable types. Anaplastic tumors remain anaplastic, but most tumors dedifferentiate after repeated transplantation. A f i n a l point of interest was uniformity or non-uniformity of the frequency of tumors in d i f f e r e n t parts of the mammary tissue. With chemically induced adenocarcinomas there can be a substantially higher incidence in the anterior part of the mammary tissue. No similar observation has been made a f t e r uni­form i r r a d i a t i o n . Shellabarger had ea r l i e r demonstrated the lack of an ab-scopal e f f e c t ; an increased tumor incidence was found only in the irradiated mammary tissue of Sprague-Dawley r a t s , no change of the spontaneous incidences was observed in the shielded areas. Montour emphasized the d e s i r a b i l i t y and the potential of studies that would u t i l i z e heavy ions of properly chosen range and stopping power. Such studies could elucidate a number of factors that are not controlled in experiments with x-rays or neutrons. Second part: The discussion continued with considerations on terminology in the analysis of radiation carcinogenesis. There was consensus that competing risk corrected quantities had to be employed, but there appeared to be less - 206 -agreement on terminology. One proposal was to use the term nominal incidence for the competing ri s k corrected cumulative incidence up to a specified time. Another proposal, approved by several pa r t i c i p a n t s , was to u t i l i z e the term actuarian incidence. The considerations then turned to the more general aspects of s t a t i s t i c a l methodology. The ongoing study of mammary neoplasms at TNO permits, at present, only a p a r t i a l analysis, because the rats have longer tumor free l i f e spans than, for example, the Sprague-Dawley rats used by Shellabarger or by Vogel in the US. The attempt to draw meaningful conclusions from p a r t i a l results necessi­tates the use of j o i n t f i t s to the various dose groups. As reported by Broerse, the notion of a forward s h i f t in time of the tumor incidences with increasing dose agrees well with the data. This is in line with previous findings of Shellabarger in Sprague-Dawley r a t s . Adequate f i t s were obtained by postulating power function in time for the tumor rates, and i t was emphasized that even such comparatively simple parametric solutions require computer analysis rather than visual f i t s . There is l i t t l e evidence from available observations that variation of more than one parameter is needed to represent the change in temporal dependencies of tumor rates after d i f f e r e n t doses of d i f f e r e n t radiations. Evidently this may be a matter of i n s u f f i c i e n t data. The question is therefore open. That i t has importance beyond the mere te c h n i c a l i t i e s of curve f i t t i n g was exem­p l i f i e d by two further considerations in the discussion: - Mole stated that RBE values may well depend on the method of analysis, and could d i f f e r whether one asked for equal cumulative incidence up to a certain time, or for equality of the temporal d i s t r i b u t i o n of tumors. I f the change in temporal patterns a f t e r i r r a d i a t i o n is described by one single parameter modifying the response curves, equality of the parameter would imply equality of the entire response. One would then expect the same RBE values, regardless of the c r i t e r i o n chosen. I f , on the other hand, the radiation induced change is more complex, and requires the description by several parameters that may be affected d i f f e r e n t l y by d i f f e r e n t radiation q u a l i t i e s , the very concept of RBE would begin to be of doubtful a p p l i c a b i l i t y . - Gould emphasized that one must distinguish between mere changes in latency time, on the one hand, and actual increases of incidences, on the other hand. - 207 -I t appears that better information w i l l be required to judge whether an acceleration in time, a forward s h i f t in time, or a time independent increase of tumor rates is the most suitable approximation to experimental observa­ti o n s . I t was, furthermore, pointed out that tumor rates may vary as a power of time and t h a t , under this particular condition, an acceleration in time can not be distinguished from an increase of the tumor rates by a time inde­pendent constant fa c t o r . Paretzke pointed out that a reasonably modest approach would focus on tumor incidences integrated over the l i f e span. However, he added, in agreement with Dennis and Mole, that the loss of l i f e time or of cancer free l i f e time is ultimately the more meaningful parameter for radiation protection. The more sophisticated considerations aimed at a qu a n t i f i c a t i o n of detriment are given particular attention in present investigations at GSF. Experimental studies in the rat and the mouse can, as reiterated by several p a r t i c i p a n t s , not be d i r e c t l y relevant to radiation protection and risk de­termination in the sense of providing actual numerical values. Their potential value, as that of a l l animal studies, lies in the i d e n t i f i c a t i o n of recurrent t r a i t s and common characteristics of responses to d i f f e r e n t types of radiation and to d i f f e r e n t absorbed doses. The comparative study of d i f f e r e n t strains or stocks of animals was therefore an obvious focus of the discussion. No conclusion was reached on the cause of the s t r i k i n g difference in appearance times of tumors for the Sprague-Dawley rats used in the United States and in the Netherlands. A comparative study that included keeping the Dutch Sprague-Dawley rats at Brookhaven, resulted in the same late appearance of tumors as observed at TNO. Van Bekkum pointed out that the later appearance of the mammary tumors is in line with a somewhat longer l i f e span of the Dutch stock. Greatly d i f f e r e n t values of the RBE of neutrons are found in d i f f e r e n t strains and even in the same strain with and without estrogen treatment. Various par­ticipants expressed the opinion that high values of the RBE of neutrons are observed for adenofibromas, and generally for tumors with high spontaneous incidence. With low incidence of tumors - th i s was presumed to be the 'physiological 1 condition - the RBE of neutrons tends to be low. - 208 -There was agreement that this is a question - i f not the question - of interest in the studies of mammary neoplasia in the r a t . But i t was pointed out that the association of high incidences with high neutron RBE and of low incidences with low RBE need not be inherent, although i t is commonly encountered. Animals with low incidence are generally less sensitive and require higher doses of any ionizing radiation for s t a t i s t i c a l l y meaningful results. At high neutron doses, however, the RBE is low, for fundamental biophysical reasons emphasized by Rossi. In animals with high incidence one can investigate small neutron doses, and the high RBE values reported by Vogel and by Shellabarger were ob­tained under these conditions. In a recent experiment by Shellabarger on AC I r a t s , preimplanted with a r e l a t i v e l y high dose of DES, high incidences of adenocarcinomas were observed and the RBE of 430 keV neutrons was in excess of 100 at 0.01 Gy. At larger doses the RBE decreases, but at 0.09 Gy i t is s t i l l substantially larger than 10. On the other hand, the Sprague-Dawley rats with their high spontaneous incidence and their high RBE values at low doses show the same RBE of about 10 at doses close to 0.1 Gy as the non-DES treated AC I rats and other strains with low spontaneous incidence. Rossi expressed the opinion that meaningful differences in RBE for d i f f e r e n t strains can only be established on the basis of additional data. Many of the data reported at this conference were of preliminary nature, without the adequate error analysis that is required for d e f i n i t i v e conclusions. Based on available evidence the differences of RBE for mammary carcinogenesis at specified neutron energy and dose may well be within a factor of 2 in d i f f e r e n t s t r a i n s . He made the further point, that radiobiological observations are generally obtained at doses and at incidences beyond the acceptable levels in radiation protection. There is therefore every reason to expect that RBE values relevant to radiation protection w i l l be at least as large, and possibly much larger, than the values obtained in animal experiments with neutrons. Shellabarger concluded with the comment that the rat may, in many ways, be a poor model for man, but that differences between humans are equally s t r i k i n g . As Metalli cautioned, we do not know how relevant the studies on the rat are for risk estimates, but we know that comparative research is indispensable, and that i t must include animal experiments as well as human epidemiology. 

https://epub.ub.uni-muenchen.de/8717/1/8717.pdf

Summary of the discussion on mammary carcinogenesis in the rat

Abstract

Similar works

Full text

Available Versions

Universität München: Elektronischen Publikationen

Open Access LMU