oli $ . 1 .. I OF I ORNL P 2407 : i . : F + + I i * . . LLIST : . NE.. $150 PREFE . ITE MICROCOPY RESOLUTION TEST CHART NATIONAL BUREAU OF STANDARDS -1963 .- ORNL -P- 2407 Conf-660917-3. 9h22 19th MASTER Gastrointestinal lesions in Aged Conventional and Germfree Mice Exposed to Radiation as Young Adults. * G. E. Cosgrove, H. E. Walburg, Jr., and A. C. Upton · Biology Division, Oak Ridge National laboratory . .W. Oak Ridge, Tennessee CFSTI PRICES RELEASED FOR ANNOUNCEMENT IN NUCLEAR SCIENCE ABSTRACTS ABSTRACT HC. $ 1.00; MN 5 Life span and disease incidence studies on a large number of mice . irradiated with single or fractionated exposures with or without treatment : and their unirrađiated controls have been completed. Sources of irradia- . - . . . . tion have been 250-300 kvp X-ray machines for X-ray, atomic bomb or Co® . . . . . . sources for gamma rays, and atomic bomb, reactor, Cockroft-Walton, or Po-Be sources for neutrons. Several smaller groups treated with radiomimetics or . . . . . radiostrontium, or that were irradiated and maintained in the germfree state . . -. were also studied. -. - The records of 9634 RF, 5185 LAF,, and 2507 103F, mice were (GI) examined, and primary gastrointestinal,desions were found in 3.7%, 7.2%, and 2.9%, respectively. The chief categories were inflammatory (average 3.2%), non-inflammatory (3.4%), or neoplastic (1%). Comparisons made between .. .. . -.. . - . controls and treated groups in each strain and also between strains, and by ... - - --... - . . . .type of radiation reveal that with the exception of primary GI neoplasms, GI lesions were less frequent in irradiated than in unirradiated mice. The - . . ... . . - . principal increase in primary GI neoplasms was in neutron-irradiated mice of - . - - - . the LAF1 strain. There were mouse strain differences in the type of primary . GI. lesions both in the control and irradiated groups. . . . . Research sponsored by the U.S. Atomic Energy Commission under contract with the Union Carbide Corporation : The GI tract was secondarily involved in more generalized diseases such as amyloidosis, leukemia/lymphoma, and polyarteritis. Strain differ- ences were observed. The number of cases of GI involvement in the generalized diseases varied depending on the effect of the treatment on the incidence of the disease in question. INTRODUCTION Surveys of spontaneous alimentary tract lesions in mice (Cloudman, 1941; Dunn, unpublished; Horn and Stewart, 1952; Slye et al., 1917; and Wells, et al, 1938); in rats (Bullock and Curtis, 1939; and in several species of laboratory rodents (Dobberstein and Tamaschke, 1958; Guerin, 1954; Schulte, 1958; and Temaschke, 1955) have been published as have surveys in long-term rat and mouse survivors of various types of irradiation. . - - - - - ... - There has likewise been considerable interest in the experimental induction of alimentary tract lesions in laboratory rodents by various means other than irradiation. Klein and Palmer (1940) reviewed the sub- .-- ject up to that time. Some of the factors mentioned by Klein and Palmer - -- have been studied further (e.g. diet - Peacock et al. 1953; diet and parasitism - Hitchcock and Bell, 1952; and carcinogens - Horava and von - - - .. . - - - . .. - - - . The use of large numbers of mice of several strains in long-term . . . survival experiments after irradiation in our laboratory has given us the . 5 opportunity to accumulate considerable information on the incidence and types of gastrointestinal lesions in both controls and irradiated groups and a review of the data is presented here. LEGAL NOTICE This report was prepared as an account of Government sponsored work. Neither the United States, oor the Commission, nor any por son acting on behall of the Commission: A. Makes any warranty or representation, expressed or impliod, with rospace to the accu- racy, completeness, or usefulness of the information contained in this roport, or that the wo of way information, apparatus, method, or process dlocloved in this roport may not infringo privately owned righls; or B. Assumes any liabilities with respect to the use of, or for damages resulting from the use of any information, apparatus, motbod, or procons disclosed in this roport As used in the above, "person acting on behalf of the Commission" lacludos iny on- such employee or contractor of the Commission, or omploys of much contractor preparos, with the Commission, or No omployment with such contractor, Materials and Methods The principal portion of the study was the regiew, of necropsy - ILAFI and 2507 (101/com X C3H/a records of 9634 RF/La (RF), 5185 (C7 L x A/He)F, T1c3F1) nice used in unirigit na led long-term radiation survival studies either as controis' or irradiated mice (Tables 1,2,3,4,5). The experiments took place over a period of approxi- mately 12 years and were performed in different ways. Unirradiated con- trols were set up with each experiment. Of the 13,318 irradiated mice, 5083 were exposed to x-rays, 3821 to y-rays, and 4414 to neutrons. Table i contains a summary of the experiments from which groups of surveyed mice were derived. In general, radiation exposures were given to mice of either operated at 250 or 300 Kvp., TSD 93-97 cm, 30 Ma, half-value layer 0.55 mm Cu and duse rates of approximately 80-90 R/min. (Cosgrove et al., 1964, 1965; Upton et al., 1954, 1956). In some of the x-ray experiments, groups of mice were given protective or recovery treatment, consisting of partial body shielding, injection of AET, or injection of hemopoietic cells (Cosgrove and Upton, 1961, Cosgrove et al., 1964, 1965). Gamma rays were from a co source at 10.6 cm distance, dose rate 10-15 rad/min (Upton et al., 1956 a,b) or from an atomic detonation (total doses 192-749 rads) (Upton et al., 1960), or from daily exposure at a rate of 13–100 rad/day (total doses of 300-5122 rads) from a 60co source. Fast neutrons (approximately 1 Mev) were generated by a cyclo- tron at doses of 130-450 rads (Conger et al., 1958, Upton et al. 1956). Thermal neutrons with gamma contamination were from a reactor, (Upton et al 11 * . 1954). Exposure to fission neutrons from an experimental atom bomb explosion resulted in doses of 28-250 rads. (Upton et al., 1960). Exposure to 14 Mev neutrons at doses of 50-400 rads was done in a Cockroft-Walton device. Chronic daily exposure to neutrons from a pologium-beryllium source resulted in doses of .06-4.5 rad/day (16-461 rad total doses). (Randolph et al, unpubl.). Mice from a number of smaller experiments were surveyed separately. These included survivors of radiostrontium injection (Cosgrove and Upton, 1962); survivors of injection of radiomimetic chemicals (nitrogen mustard (HN2); triethylene melamine (TEM]); Myleran; or 34- p-dimethyl (aminostyryl) quinoline [4M20])/(Conklin et al. 1963, 1965; Cosgrove et al., 1965). It also included long term survivors of 2 strains of mice maintained in the germfree state with and without irradiation and young adults After exposure or treatment mice were maintained in the colony until natural death. A necropsy was performed and all lesions recorded. No special dealth. An . . 15-12wko) attempt was made to examine the GI tract and it was not opened from end to end. Histologic preparations were made from 10-30% of the mice that wered decomposed in various experiments. For this review, all mice with GI diagnoses in the selected experiments were considerea. Much of the retrieval was done by IBM machine techniques after previous coding and storage. A wide range of GI diagnoses was encountered. The incidence was usually low in any given experiment necessitating pooling for an approach to meaningful resu?ts. Diagnoses fell into 4 main categories, i.e., inflammatory, non-inflammatory, primary neoplastic, and coincidental involvement in more generalized diseases (Table 6). Pesults Incidence of gastrointestinal lesions. In 4008 control mice of the 3 principal strains used there was a 7.3% incidence of GI lesions : - whereas in 13556 irradiated mice of the same three strains the incidence of GI lesions was 4.0% (Tab.e 2). Pooled information from control and irradiated mice by strain revealed a 3.7%, 7.2, and 2.9% incidence of GI lesions in RF, LAFI, and 103F1 mice respectively (Table 2). Types of gastrointestinal lesions. Non-inflammatory lesions were the most common (Table 3) in both pooled controls and pooled irradiated groups. Inflammatory lesions were almost as common while primary neo- plastic lesions were less frequent. There were differences in incidence of lesions in each of the three major categories between pooled control frequent in controls while primary neoplasms were more frequent in irradiated mice. lesions. In the LAFI and RF strains fairly large groups of mice were exposed to x-ray, gamma, or neutron irradiation allowing a comparison in incidence of GI lesions by radiation type (table 4). This table - .- .-- . .. - ..- : * indicates little difference in incidence for types of GI lesions except - -. - for primary: neoplasia which occurred in approximately 1.5% of neutron - - .. . - the frequency in gamma irradiated mice was intermediate. However, when the incidence is examined by mouse strain the RF had a fairly uniform incidence with each type of radiation while the LAFI had the differing incidences. Effect of mouse strain on the incidence of GI lesions. Unirradiated RF and LAF1 mice had about twice as many GI lesions as 1C3F1 mice (Table 5). The bulk of the difference was in the very low incidence of inflammatory GI lesions in the 1c3F1. In 2503 RF control mice, there were no primary GI neoplasms. The incidence of GI lesions in irradiated LAFI mice was about twice that in RF and 103F1 strians. Irradiated LAF1 mice had more inflammatory, and neoplastic lesions than irradiated mice of the other two strains. - GI involvement in more generalized diseases. Total incidence of leukemia/lymphoma was about 55% in RF, 38% in LAFI and 9% in 1C3F1 mice. The three major types of leukemia/lymphoma found in our strains of mice differ in incidence following irradiation, with increases in thymic lymphoma and myeloid leukemia after certain levels of radiation exposure while reticulum cell sarcomas remain unchanged or decrease in incidence. In each of these three forms of leukemia/lymphoma where iuvolvement was widespread over 50% of the involved animals had invasion of intestinal wall and/or intestinal lymphatic nodules (Peyers' patches). The GI tract was involved Diliconia in various forms of leukemia/lymphoma in all 3 strains of mice, always as - - a part of more widespread disease. -- - - - - * - - - . The incidence of secondary amyloidosis varied with strain, being more common in LAF1 (0+ • 23%, f“ 2%) than in RF, or 103F1 (* 1%). When amyloidosis was present there was variable intestinal mucosal involvement ranging from 28% in LAF2 males to º 2% in RF females. Amyloidosis did not seem to be related to radiation but was related to age, appearing in older animals. GI tract in a few mice, principally of the RF strain. It was usually associated with periarteritis in several other areas. The cause has not been determined. Lesions in smaller experimen al groups. The information from germfree mice is not included in the general survey but will be mentioned here. Strains studied were the ICR and RF. The very large cecum common in germfree mice was noted in both strains. In the ICR mice cecal volvulus occurred in 26%, while the RF mice had no occurrence of volvulus. Inflammatory lesions of the GI tract were absent. There were a number of primary neoplasms including squamous cell carcinoma of the stomach and adenocarcinomas of stomach and intestines. These primary neoplasms occurred in both control and irradiated mice. 6 I livolvement in Meckle Offeratele horaseo also recurred in gerinfuce nice with leukemia/exrapiloman in the RF and are advisering in the ICR benin the must conamesir A survey of GI lesions in RF mice receiving systemic radiomimetic chemicals did not reveal any definite differences in incidence and types of lesions when compared to RF mice in the major experiments. In one experiment RF male mice (258) received radiostrontium injections. The GI lesions found in the injected mice were similar in incidence and type to those in the controls. Mouse strain differences in disease distribution. A few diseases radiation did not markedly alter the incidence of most of these diseases. and 103F1 controls. The LAFI mice had a considerable incidence of rectal prolapse and fecal impaction (4% in pooled sexes, 15% in males). LAFI males with amyloidosis had intestinal amyloid in 23%. Intussusception was more common in 1c3F1 mice (1.6%). RF mice developed much more thymic lymphoma and myeloid leukemia after irradiation than did mice of the other two strains. Primary GI neoplasms. The location and types (where known) of 109 primary GI neoplasms are indicated in talle 7. Tumors of the stomach were most common and the great majority of them were squamous cell carcinomas of the forestomach. Occasionally metastases occurred in liver, lung, and peritoneum. Intestinal tumors were principally adenocarcinomas many of which were composed of mucin forming cells. There were seven sarcomas, most apparently of smooth muscle origin. There were three benign tumors; 2 adenomatous polyps of the stomach and one leiomyoma of the colon. The stomach was the site of metastatic osteosarcoma from pelvic bones in one mouse. Discussion Since primary GI lesions occur in rather low incidence in the mouse strains used in our experiments it is difficult to detect signifi- cant differences in occurrence of the various types of lesions between subgroups of an experiment. This necessitated the pooling of large numbers of mice from different experiments for adequate review of the occurrence of GI lesions. Such pooling probably gives an inaccurate picture and can only indicate general trends in incidence and types of GI lesions under various experimental conditions. It would be much better to do a very large experiment with one strain of mice exposed to varying conditions to more accurately determine the true effect of such conditions on the presence 9 of GI. lesions. The largest mouse radiation experiments with extensive listing of GI lesions are those of Cottier (1961) and Upton et al (1960). The component parts of the mouse gastrointestinal tract are small and it is not usually profitable to do the thorough type of necropsy examination that is performed on the GI tract of larger animals and man. Many sinall and early lesions are certainly overlooked in routine mouse necropsies. The reason for the general decrease in GI lesions in irradiated mouse groups is not obvious. The decrease mainly occurs in the general categories of inflammatory and non-inflammatory lesions while neoplasms may be more common in irradiated mice. Some of the difference may be explained by life shortening. The type of irradiation affected the incidence of primary GI neoplasms with neutrons inducing more, x-rays the fewest, and gamma rays intermediate in one strain of mouse (LAF1) but not in another (RF) in our experiment. Similar differences were noted by Nowell and associates (Nowell et al., 1956, Nowell et al, 1958, and Nowell and Cole, 1959). Other reports indicating an increase in GI tumors after irradiation are those of Bond et al (1952), Brecher et al, (1953), Lisco, et al (1947), ană Osborne et al (1963) in rats; Cosgrove eü al (1964), ard Upton et al (1960) in mice and Cottier (1961)-in mice. Lushbaugh (1962) reported hyperplastic gastric lesions in mice exposed to neutrons from an atomic bomb. The effect of sex of mice and genetic constitution of the various strains used is manifested by differing incidences of various types of lesions in untreated controls. Noteworthy in this respect is the variabłe 10 10 occurrence oť intestinal amyloidosis, rectal prolapse, and fecal impaction as well as strain differences in GI neoplasm incidence. Similar findings were noted by Lesher, et al (1965) for intestinal amyloidosis and from groups used in the present experiment reported previously (Cosgrove et al. (1965) and Upton et al. (1960)].). Stewart (1941, Strong and associates (Strong, 1947: McPeak and Warren, 1947; and Kaplan, 1949); Hare and Stewart (1956), and Miller and Pybus (1956) reported on strains of mice with high incidences of alimentary tract lesions. Some of the reports indicated that carcinogens increase the incidence further. Some of the new labora- tory rodents ma;y be similarly prone to alimentary tract disease; e.g.) the multimammate rathMastomys) (Oettle, 1957). 1 The relation of the late appearing effects of radiation to the very marked early radiation effects in the GI tract is not apparent from this review but may be indicated by the late post-irradiation atrophy and sclerosis of the gastric and intestinal mucosa seen in rats by Zayrat' yants (1960). ~ . олара, dean da Y Cranylight алия али труда велого) о г aborda a mintind flera lefoonca, ??? . ... . 1 . The atteration of the intestinal esteroflora and, Jaunos as seen in the gennufue environment influences the development of intestiral neophoems and secondaing generalged degenerature danse weetle if at all. On the other hand the incidence of inflammaton leasino is reduced and the incidence of volualus in merased by the absence of a normal mucoflora. - - - * - - - - - - - :-..... . . . . .. . . . . . .... ... 4R ......- .- -... - ** ** m ett..", BLE 1: Summary of experimental groups of mice. ME OF PERIMENT STRAIN OF MOUSE, SEX* 1; NUMBER OF SOURCE OF MICE IN MICE † | EXPERIMENTE IRRADIATION AND OTHER TREATMENT REFERENCE ORNL RF random bred, MF 995 (1) 14.1 Mev neutrons (Cockroft-Walton): dose 100 Upton et al., 1954. -450 rad. (2) “ 1 Mev neutrons (Cyclotron): dose 130-450 Upton et al., 1956. rad. (3) Thermal neutrons with y contamination, reacto: - 5 Mev neutrons (Po-Be source): dose 16-461 Randolph et al., in manuscrip. rad 1.06-4.6 rad/day). ", F ORNL 1760 ORNL 1724 14.1 Mev Neutrons (Cockroft-Walton): dose 50-400 Darden et al., in manuscript. rad. ORNL 1653 852 ORNL ORNL 593 bºco y at 13-100 rad/day: dose 300-5122 rad 250 Kvp X-ray: 25–450 R : 300 R .04-0.2 mc90 Sr or 0.51 mc 89sr I.v. (1) .10-.12 mg HN2 or (2) 3-4 mg TEM or (3) 250 Kvp X-rays : 500-600 R Randolph et al., in manuscrip, Upton et al., 1958 Cosgrove and Upton, 1961. Cosgrove and Upton, 1962 Conklin et al, 1963. ORNL 324 ORNL 660 ORNL 450 (1) .24 mg HN2 or (2) 6 my TEM or |(3) 0.3 mg ryleran Conklin et al., 1965. !", F ORNL 198 2-4 mg 4M20 Cosgrove, et al., 1965. enhouse LAFI, MF NMRI 3064 Experim. nuclear detonation y dose 223-697 rad N dose 28-250 rad Upton et al., 1960. LAF1, F Jax 346 1 250 Kvp X-ray: 300 K Cosgrove, et al., 1965. AF Jax 484 : 600-900 R with or without hemopoietic cell injection 250 kvp x-ray whole-or : 500-1200 R partial-body with or without AET ", MF Jax 1360 Cosgrove et al., 1965. * * -- - - - - - * * 5. - .-* -!. ;*: *** * ****** ** v . .:- . . i . .. . ----TABLE I------ continued 103F1,F : CUM 1447 250 Kvp X-ray with or without / 350-1800 R Isogenic bone marrow or AET. Cosgrove et al., 1964, ", MF CUM 568 limaerism 250 Kvp x-ray, with or :400-900 R rithout hemopoietic cell injection. T v -Ay ", MF ORNL 463 None ;-By imfree ICR, MKV RF,MF ORNL ORNE } 300 Kvp X-ray: with a without Germfee 1. Conditions M = nale F = female ORNL = Biology Division, Oak Ridge National Laboratory; NMRI = Naval Med. Research Inst,; Jax = Jackson Laboratories, Bar Harbor, Maine; CUM = Cumberland View Farms, Clinton, Tennessee. Not all of the mice in each experiment were used in the present survey of GI lesions. - - - . . . i = :- * * : . --* - * ' * ** - * RI" * * : T * r V ., A TABLE 2: Comparative incidence of primary gastrointestinal lesions in 17,564 mice of the RF, LAFI, and 103F1 strains. Incidence of GI lesions % * No. A. Unirradiated 4008 7.3 + :41 4.0 + .17 Irradiated 13,318 B. All RF mice 9634 All LAFI mice 5185 3.7 1 .19 7.2 + .36 2.9 + .33 All.103F1 mice 2507 * 1 standard error of the mean. TABLE 3: Incidence (%) of primary gastrointestinal lesions in mice by major categories of diagnosis. Control Irradiated Number of mice 4008 13318 (3 strains pooled) to Type ) Non-inflammatory C ) Inflammatory Lesion ) Primary neoplasm : ww 1+1+1+ 1.6 + .ll 1.6 1.11 .83 F .08 Total incidence of primary GI lesions 7.3 + .41 4.0 + .17 - . TABLE 4: Incidence of primary gastrointestinal lesions in RF and LAF1 mice as influenced by type of radiation. Type of radiation X-ray gamma neutron 1920 282 LAFI RF 2168 1653 1346 4132 Total : 3821 ܛܐܐܛܐܛܐ Type of Lesion Non-inflammatory Inflammatory 1.7 + .23 2.3 + .26 .79 + .15 1.7 + :21 1.5 + .18 2.0 + .23 2.3 + .23 .99 + .16 1.5 + .18 Primary neoplasm Total incidence of primary GI lesions 4.8 + .35 4.7 + .34 5.3 + .39 TABLE 5: Incidence (%) of major types of primary gastrointestinal lesions in unirradiated and irradiated mice of 3 strains. Strain RF LAF1 LAF1 103F1 203F1 Unirradiated Number of Mice 2503 815 690 Type of lesion: inflammatory non-inflammatory primary neoplasm · 5.9 + .47 3.3 + .36 3.4 4..63 3.9 + .68 1.6 + .44 .3 .21 3.1 1.66 55 primary GI lesions 9.2 + .58 8.9 + 1.0 3.9 + 73 Irradiated Number of Mice 7131 7131 4370 4370 1817 1817 Type or lesion: inflammatory non-inflammatory primary neoplasm 1.7 + .15 .8 t .11 .2 + .05 2.4 + .23 2.6 + .24 1.7 + .19 7 + .19 1.5 + .29 6 + .18 Total incidence of primary GI lesions . 2.8 +.19 6.9 + .38 2.5 + .37 . : . - . . . . E t = * 7 ir 12* * * * i - - . . - - - -- -- - - - : - - - . . Table 6: Diagnoses included in each major category. . - Inflammatory Gastritis Enteritis Colitis Abscess Ulcer Necrosis Volvulus Intussusception Fecal Impaction Prolapse Perforation HD fa un i Adhesion Distention Hemorrhage Infarct Maifoimation Primary Neoplastic Benign Malignant Involvement in Widespread disease Leukemia/lymphoma Amyloidosis Periarteritis/arteriosclerosis Edema Table . Location and types of primary GI neoplasms . . Location Number . ...1 1 I . Sarcoma Type Carcinoma Squamous cell adeno Stomach 37 Small intestine Large Intestine Anal Total - AI THI. nequences 1952 ✓ Bond, V. P., M. N. Swift, C. A. Tobias, G. Brecher ,' Bowel lesions folliwng single dexteron irradiation Fed. Proc. 11:408-9. i Brecher, G., Cronkite, E.P. and. Peers, J. H., 1953 Jour. Nat.l. Cancer Inst. 14:159-175 Neoplasms in rats protected against lethal doses of irradiation by parabiosis or para-amino proprio phenone. Bullock, G. D. and M. R. Curtis, 1930. Spontaneous tumors. of the rat J. Cancer Res. 14:1-115. Cloudman, A.M. 1941 Spontaenous neoplasms in mice, PP. 168-233, Chap. 4 in Biology of the laboratory mouse, ed. Snell, G. D., Dover, N. Y. 1 1 1 . .. - - - - - Conger, A. D., M. L. Randolph, C..W. Sheppard, and H. J. Luippold 1958 - - . Quantitative relation of RBE in Tradescantia and average LET of gamma- . rays, X-rays, and 1.3-, 2.5-, and 14.1- meX i'ast neutrons Radiat. Res. 9:525-547. -.-. -.- . . .. . . Conklin, J. W., A. C. Upton, K. W. Christenberry, und T. P. McDonald 1963 Comparative late somatic effects of some radiomimetic agents and X-rays Radiation Res. 19:156-158. Conklin, J. W., A. C. Upton, and K. W. Christenberry 1965 Further observations on late somatic effects of radiomimetic chemicals and x-rays in mice. Cancer Res. 25:20-28. - . . . . . . --- ✓ Cosgrove, G. E. and A. C. Upton 1961 Some delayed effects of partial-body irradiation in mice of the RF strain Internat. J. Radiat. Biol. 4: 97-103. v Cosgrove, G. E. and A. C. Upton 1962 Some late effects of radiostrontium in RF male mice J. Nuclear Med. 3: 293-299. Cosgrove, G. E., Upton, A. C. Consdon 6.C. Doherty, D. G. P . Christenberry, K.W. and D. G. Gosslee, 1964. Radiat. Res. 21:550-574 Late Somatic effects of X-radiation in mice treated with AET and isologous bone marrow. .... . | | -- ✓ Cosgrove, G., E., M. L. Davis, and M. Asano 1965a Oncogenic effects of 4-fp- dimethylaminostyryl)quinoline (4M20) in mice Cancer Res. 25:938–945. Cosgrove, G. E., ... .c. Upton, L. H. Smith 19656 Radiat. Res. 25:725-735 - . . Radiation flomerulosclerosis and other late effects: influence of radiological factors and AET. ✓ Cottier, H. 1961 Strahlenbedingte Lebensgerkurzong, Springerçverlag, Berlin 462 p. - X Dar Darden, E. B., G. E. Cosgrove, A. C. upton, K. W. Christenberry, J. W. Conklin, M. L. Davis, M. E. Kastenbaum, and D. G. Gosslee, Late Somatic effects in female RF mice irradiated with 14.1 Mev neutrons Unpublished. V Dobbersteán, J. and C. Tamaschke,1958 Tumoren, P. 470-598 in Pathologie der labora- toriumstiere, by Cohrs, P., R. Jaffe, and H. Meesen, Springer, Berlin - Dunn, T. B. Publication on the normal and pathologic anatomy of laboratory mice (excluding neoplasms). Unpublished Laingtori, Ü. W. ana i. i. Gandoipn iyo da comparisch. c† the relative effect- iveness of radiations of different average linear energy transfer on the induction of dominant and recessive lethals in Drosophila , Genetics 43: - - 715-727. - - - - - - - -- - -- - Guerin, M. 1954 Tumeurs spontanees des animaux de laboratoire, amedie legrand - - - & Cie., Paris, 211p. - Hare, W. V., and H. L. Stewart 1956, Jour. Natl. Cancer Inst. 16:889-911 Chronic gastritis of the glandular stomach, adenomatous polyps of the duodenum, and calcareous pericarditis in strain DBA mice. ... .. - 12:1345- Hitchcock, C. R. and E.T. Bell, 1952, Jour. Natl. Canc. Inst. Studies on the nematode parasite, Gongylonema Xeoplasticăm (Spiroptereě neoplasticom), and avitaminosis A in the fore stomach of rats: Comparison with Fibigers' results. Horara, A, and Ei von Haam, 1958, Experimentel carcinoma of the colon, Cancer Res. 181764-767 ✓ Horie, A., S. Kohchi, and Mikuret sune, 1965. Carcinogenesis in the esophagus. II, Experimental production of esophageal cancer by administration of ethanolic solution of carcinogens, Gann 56: 429-441 . . . .. . . V Horn, H. A. and H. I. Stewart, 1952, Jour. Natl. Canc. Inst. 13:591-603 A review of some spontaneous tumors in noninbred mice Keplan, H. S. 1949 Jour. Natl. Canc. Inst. 10:407-421 Lesions of the gastric mucosa in strong strain NHOR mice. : V Klein, A. J. and W. L. Palmer, 1940, Arch. Path. 29:814–844 Experimental gastric carcinome, A critical review with comments on the criteria of induced imaliouancy, Lesher, Spottet, G. A. Sacher, D. Grahn, K. Hamilton, and Arthroty Sallese, Survival of mice under duration-of-life exposure to gamma rays. II. Pathologic effects Radiation Res., 24:239-277, 1965. Februaryt. Lisco, H., M. P. Finkeil, and A. M. Brues, 1947. Radiology 49: 361-363 Carcinogenic properties of radioactive Dision products and of plutonium. Lushbaugh, C. C., 1962, Arch. Path. 74: 279–303. A fatal hyperplastic inflammatory lesion of the stomach of mice exposed to neutrons from an atomic bomb. „ McPeak, E. and S. Warren 1947 Jour. Nat. Canc. Inst. 7:309-321 The pathology of gastric carcinoma in mice. v Miller, E. W. and Pybus, F. C., 1956, Hyperplastic and neoplastic lesions of the glandular stomach and intestine in two inbred strains of mice and their reciproca: hybrids. Brit. Jour. Cancer 10:89-109. 1956 Nowell , P. C., Cole, 1. J. and Ellis, M. E. Cancer Res. 16:873-879 Induction of intestinal carcinoma in the mouse by whole-body fast-neutron irradiation. Nowell, P. C., Cole, L.J. and M. E. Ellis, 1958, Neoplasms of the glandular stomach in mice irradiated with x-rays or fast neutrons Canc. Res. 18:257-260 1951. Nowell, P. C. and L. J. Cole, Late effects of fast neutrons versus x-rays in . mice: Nephrosclerosis, tumors, longevity. Radiat. Res. 11:545-556. Oettle, A. G. 1957 Spontaneous carcinoma of the glandular stomach in Rattus (Mastomys) natalensis, an African rodent. Brit. J. Cancer 11: 415-433 lom v . il- .. Osborne, J. W., D. P. Nicholson, K. N. Prasad 1963, Radiation Res. 18:76-85 Induction of intestinal. carcinona in the rat by x-irradiation of the small intestine. -- . . --- 13:931-947. ✓ Peacock, P. R. S. Beck, J. G. Chalmers 1953 Jour. Nath. Canc. Inst. Gastric Cancer: Possible dietary carcinogens v L Randolph, M. L., A. C. 'Upton, and others 1966 Dosimetry for chronic irradiations. in manuscript. Trail TITI L . Pag-130 Schulte, F. 1958 Speiseröhre, Magen, Daren und Bauchfell in Pathologie der Laboratoriumstiere, Vol. 1, by Cohrs, P., R. Jaffe, and H. Meessen; Springer, Berlin v Slye, M., H. F. Holmes, H. G. Wells, 1917. J. Cancer Res. 6:10.1-425 Comparctive paizology of cancer of the stomach with particular reference to the primary spontaneous malignant tumors of the alimentary canal in mice. -stronc, Loc, 1947 Jour, nath, cauc. Inst, 7: 305-308, 489-502 Hyperplastic and neoplastic Stewart, H. L. 1948 Jour. Natl. Canc. Inst. 9:3050308 Further observations on ✓ Tamaschile, C. 1955 stanienstherapie 96: 150-168 Die spontantumoren der Kleinen Laboratoriumsauger in ihrer bedeutung fur die experimentelle onkologie ions of the stomach in mice. . . .. en el considerateri m .. - .. --... : ✓ Upton, A. C., J. Furth, and K. W. Christenberry, 1954 Late effects of thermal neutron irradiation in mice Cancer Res. 14: 682-690. ........ ......... . i LCD Upton, A. C., F. F. Wolff, J. Furth, and A. W. Kimbell 1958 A comparison of the induction of myeloid and lymphoid leukemias in x-radiated. RF mice Cancer Res. 18:842-848. in Upton, A. C., K. W. Christenberry, G. S. Melville, J. Furth, and G. S. Hurst 1956 x The relative biological effectiveness of neutrons, x-rays, and ganma rays for the production of lens opacities: Observations on mice, rats, guinea pigs, and rabbits. Radiology 67: 686-696. v Upton, A. C., F. P. Conte, G. S. Hurst, and W. A. Mills, 1956). The relative biological effectiveness of fast neutrons, x-reys, and gamma-rays for acute lethality in mice Radiat. Res. 4: 117-131. Upton, A.C., A. W. Kimball, J. Furth, K. W. Chri:tenberry, and W. H. Benedict Cancer RZs. 20 (part 2) :1-6291960. Some delayed effects of atorn-bomb radiations in mice. ✓ Wells, H. G., M. Slye, H. F. Holmes, 1938. Amer. it. Camini :1707".4---43 Compartive pathology of cancer of the alimentary canal with report of cases in mice. Willis, R. A., 1935 J. Path. Bact. 40:187–188 Carcinoma of intestine in rats. Zayrat'yants, V. B. Pathonorphological changes in the gastrointestinal tract in chronic radiation sickness. Med. Radiol. USSR (English translation), 5: 82-99, 1960 t t t t t................... i END DATE FILMED 10/21 / 66 17 : . . . 4 . . . . :: N PINN CER L . .. "Via M . STO .. .SI TAM WWW. .