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FILE NAME Brakes BRK DATE 1983 DOC BRK084 DOCUMENT DESCRIPTION Journal Article - Mesothelioma in Pet Dogs with Exposure of Their Owners to Asbestos - Environmental Research investigation J. Soc een mutagenicity and g cancer in U.S. coal tion carcinogens and of nitrosomorpholine . J. Agr Food Chem Brit J. Ind Med 22 C. Sommer Ed Vol 5 Studies on in vivo tions in human saliva -18 . Ph.D. Dissertation ines formed by drug h incidence of gastric cinogens as mutagens 1. Sci USA 72 5135- 980 Hypothesis the 87-892 yurethane and alkyl- J. Natl Cancer Inst d in vivo occurrence agenicity of two coal -308 19 795-801 nines from secondary ol 7 301 307 hci ry diseases in 1940- Vales Brit J. Cancer aaah omnes on nitrite formation dneditsn rnal dosimetry of the Setaeh ad tion of in vivo nitro- ein-sas ia. tected wine ahha se s ee vm ENVIRONMENTAL RESEARCH 32 305-313 1983 #d PLAINTIFF'S Depo Ex No. Date 6/13/84 6/13/84 21 by JHL Mesothelioma in Pet Dogs Associated with Exposure of Their Owners to Asbestos LAWRENCE T. GLICKMAN LINDA M. DOMANSKI TOBI G. MAGUIRE* RICHARD R. DUBIELZIG AND ANDREW CHURG Department of Clinical Studies Section of Epidemiology and Department of Pathobiology University of Pennsylvania School of Veterinary Medicine Philadelphia Pennsylvania and Department of Pathology University of British Columbia Vancouver B.C. Canada Received July 29 1982 Pet dogs with spontaneous mesothelioma were used to identify environmental exposures that might increase their owner's risk of asbestos disease These animals share man's domicile environment yet do not indulge in activities e.g. smoking working which confound interpretation of epidemiologic studies Eighteen histologically confirmed canine mesotheliomas were diagnosed at the Veterinary Hospital of the University of Pennsylvania Philadelphia from April 1977 to December 1981. Sixteen owners of cases and 32 owners of age breed and matched controls were interviewed to determine their occupation and medical history and their dog's medical history life style diet and exposure to asbestos An asbestos occupation or hobby of a household member and use of flea repellents on the dog were significantly associated with mesothelioma In addition there was a trend indicating an increased risk of mesothelioma with an urban residence Lung tissue from three dogs with mesothelioma and one dog with squamous cell carcinoma of the lung had higher levels of chrysotile asbestos fibers than lung tissue from control dogs These findings indicate that designed epidemiological studies of spontaneous tumors in pet animals may provide insight into the role of environmental factors in human cancers and serve as a valuable sentinel model to identify environmental health hazards for humans INTRODUCTION Epidemiological evidence indicates that asbestos is a causal factor for human mesothelioma and lung cancer 1 2 The risk of tumor development appears to be influenced by the fiber type and by personal habits such as smoking 3 The latent period for tumor development following occupational exposure usually ex- ceeds 20 years with a marked increase in risk after 30 to 35 years 4 An increased risk of mesothelioma has also been reported for persons residing near industrial sources of asbestos and for spouses of workers in asbestos occupations 5 6 However up to 38 of individuals with mesothelioma have no documented history of exposure to asbestos 7 Pet animals have been a neglected resource for identifying environmental car- ' Presented at the annual meeting of the Society for Epidemiologic Research June 16-18 1982 Cincinnati Ohio 2 This project was supported in part by BRSG RR05464 awarded by the Biomedical Research Support Grant Program Division of Research Resources National Institute of Health 3 To whom correspondence should be addressed University of Pennsylvania School of Veterinary Medicine Department of Clinical Studies 3800 Spruce St. Philadelphia Pa 19104 305 0013-9351 3.00 Copyright '1983 by Academic Press Inc All rights of reproduction in any form reserved 306 GLICKMAN ET AL cinogens In the United States an estimated 40 million pet dogs 8 share their owner's domestic environment yet do not indulge in activities that could confound interpretation of epidemiologic studies e.g. smoking and working Given the Eighteen do relatively short lifespan of these animals the latent period for tumor development is decreased and accurate information regarding environmental history can be obtained In this study we used pet dogs as sentinels to identify environmental exposures that might increase their owners risk of mesothelioma and other as- diagnosis for e R.R.D. and Hospital Cent ck lioma and the bestos related pulmonary diseases PATIENT SELECTION AND METHODS The study group consisted of 18 dogs with histologically confirmed mesothelioma that were diagnosed between April 1977 and December 1981 at the Veterinary Hospital of the University of Pennsylvania VHUP The VHUP is a major veterinary referral center for the Northeast and Atlantic regions of the United States Each year there are approximately 17,000 admissions and visits CAPSASHER The distributio Fahy pleural five 2 The mean ag were male and a hospital popul * 6.4-97.3 Whe Mas greatest risk w ERIA 97.3 and in do to the VHUP and an additional 6000 submissions of biopsy specimens to the Pathology Department A cancer and noncancer control patient were selected from hospital records and matched to each mesothelioma case by age and date of diagnosis - year sex and breed Excluded from the noncancer control group were dogs with any respiratory disease or suspected malignancy Dogs with respiratory cancer were excluded from the cancer control group Owners were interviewed by telephone and questioned about their dog's medical history residences lifestyle management factors as well as the occupation and medical history of household mem- pationrst for purebreed difference was individual pure Bouvier des Fl CL95 1.4-9.6 The cancer a eases and conc of 16 of the 18 for suspected ! bers Occupations and hobbies of household members were classified as definite probable possible or unlikely according to the likelihood of asbestos exposure This classification was adapted from data published by McDonald and McDonald findings were s aces cancer or nonc a stronger asso 7 9 Occupations and hobbies with definite or probable asbestos exposure were considered to be asbestos related Residence was classified as urban population 100,000 or greater or rural and analyzed by the first longest or residence at whine RS noncancer con hobby was four edd using noncance Maya eee diagnosis Only residences and occupations for the time period prior to the date were used the ae of diagnosis of mesothelioma were considered Lung tissue from three meso- be relative risk for nt thelioma patients was analyzed using an electron microprobe for fiber content 10 state 1.1-11.0 Two For comparison lung tissue was also obtained at necropsy from three dogs with lung cancer and six older dogs with no recognized respiratory or neoplastic disease These comparison dogs were not included in the epidemiological study Because controls had been matched on age sex and breed these character- data time period the with him was e SE shipyard No o WE dog's lifetime istics for the cases were first compared to the entire canine hospital population The odds ratio OR an estimate of the relative risk of disease for each category fen workers are lik mesothelioma was determined using the Haenszel procedure 11 Age was controlled in sex comparisons and sex was controlled in age comparisons Location of re mesothelioma i Odds ratios for other risk factors were determined for matched pairs using the first longest a cancer and noncancer control groups separately 12 The control groups were increase the ris then combined and odds ratios calculated for matched triplets Using a 95 con- Table 2 No ot fidence interval the null hypothesis of an odds ratio equal to one was tested with the dog was fou computer programs developed by Rothman and Boice 13 Management exposed to envi + & ) share their uld confound ) Given the development story can be vironmental nd other as- A, agen! ed mesothe- we at the Veter- org. Tald JP is a major gions of the tripe ns and visits mens to the pital records s -year ogs with any cancer were y telephone vle manage- sehold mem- as definite os exposure d McDonald posure were i population residence at r to the date three mesocontent 10 ee dogs with oplastic discal study e character- population ch category is controlled irs using the groups were a 95 cons tested with CANINE MESOTHELIOMA AND ASBESTOS EXPOSURE RESULTS 307 Eighteen dogs with mesothelioma were identified from hospital records The diagnosis for each patient was confirmed histologically by a veterinary pathologist R.R.D. and by a physician pathologist Dr. Jacob Churg Barnert Memorial Hospital Center Paterson N.J. Characteristics of the patients with mesothe- lioma and the sources of asbestos exposure of their owners are listed in Table 1 The distribution of mesotheliomas by site was six 33 peritoneal five 28 pleural five 28 both peritoneal and pleural and two % pericardial The mean age -1 SD of the mesothelioma dogs was 8.0 -1.9 years 17 94 were male and 15 83 were purebreeds When compared to the entire canine hospital population males had a relative risk for mesothelioma of 16.6 CL95 6.4-97.3 When dogs 1 to 4 years of age were assigned a relative risk of 1.0 the greatest risk was observed in dogs 5 to 9 years of age OR = 25.0 CL95 6.497.3 and in dogs 10 years of age or older OR = 16.9 CL95 3.4-84.3 The risk for purebreed dogs when compared to dogs of mixed breeding was 1.7 but this difference was not statistically significant CL95 0.51-5.9 The relative risk for individual purebreeds represented by more than one dog with mesothelioma was Bouvier des Flandres OR = 124.3 CL95 62.6-246.7 Irish Setter OR = 5.3 CL95 1.4-9.6 and German Shepherd OR = 3.3 CL95 1.3-8.2 The cancer and noncancer control patients represented a wide variety of diseases and conditions not more than two dogs had the same diagnosis Owners of 16 of the 18 mesothelioma patients were contacted and interviewed The OR for suspected risk factors for canine mesothelioma are shown in Table 2. The findings were similar when mesothelioma patients were compared to either the cancer or noncancer control group However for 11 of the 14 risk factors studied a stronger association with mesothelioma was noted in the analysis using the noncancer controls Exposure of the owner to asbestos at work or through a hobby was found to be significantly associated with mesothelioma in the analysis using noncancer controls OR = 8.0 CL95 1.4-45.9 when cancer controls were used the odds ratio was 2.3 but was not significant CL95 0.6-8.7 The relative risk for mesothelioma with both control groups combined was 3.5 CL95 1.1-11.0 Two mesothelioma dog owners had worked in a shipyard during the time period they owned the pet and another who regularly took his dog to work with him was employed by a trucking company that was located adjacent to a shipyard No owners of control dogs reported working in a shipyard during the dog's lifetime Epidemiological studies in humans have shown that shipyard workers are likely to be exposed to asbestos and have an increased risk for mesothelioma Location of residence urban versus rural was not significantly associated with mesothelioma in the analysis with cancer or noncancer controls However for first longest and last residence living in an urban environment appeared to increase the risk for mesothelioma this was most evident for the first residence Table 2 No other residential or neighborhood source of asbestos exposure for the dog was found to be associated with mesothelioma Management factors that might have increased the likelihood of a dog being exposed to environmental sources of asbestos without the knowledge of its owner Qi 308 Qo 5 4= z fa < | cete SZz qof 0) poruedwoasy 0} SOOLALGSY 10 ajqisod auON ouON Jaumo Juaselpe pseAdiys aUON dUuON Jeaoppm4od _ QUuOoN er Jopmod suoN Japmod Japmod auoN aUON eojq eal e2]4 Mesothlioma/pjoyesnoy TABLE AUNSOdXY TABLE WIEH] ainsodxe BUOY -yeay Jo ulaysA su0oN DiagnosedDiagnosed TABLE 3ul Diagnosed jo years diagnosi thelioma" Owner at odAL Year Site diagnosis (H) Owner diagnosis thelioma" (Q) Aqoy -- Auto body dQHA 1978 P ony Auto body tT LV aATEaVvL 1978 aus -osaul d d jacent 9 pewolys}1978 siouseip HLIM 1979 Pe 861 Plumbing G3SONDVIC 1979 1979 1979 (szeah) P L 6 8 xag Pl W W IN VD QdfO pog pisydeys piaydeys pexlW uewien uelen 7 quaneg P z Sheet aUON A10198} dUuON _ aUuON and O of ) neighborhod neighbord neighborhod ydo1 0 yoays (w) shipyard shipyard d None Id heating 6L61 Cement Cement factory None 8 8 None None None qS-A = W None None Jayosulg Sap Sap 431}9 uewaqog YSU] JaIAnog SaJpurelJ 2PexlW Ja1Anog soipuel] spackling spackling Demolition Demolition Demolition aus aus UOD RN puonulwesg UONSIUOD euON swuooneyjsulUOnINySUOD SuON aUuoNF YOWOSN] ASBESTOS setsy coe Buryoeds (QO)ou0oN auoN -diys aUuONauON ye posibleNone yD01 (O) Bumyadiq None preAdiysJo04S 12 pae^' Id to Idd Idd Id 9d Id ad adjacent None None 6161 6461 0861 1861 LL61 1861 dats powder powder L LS Ol +9 od et Ww W W W W W = Len cts eh pusydeys Jota], pisydays 20dMyBopdasy ma 4239S 8uq PRU uewer UOISOg YSU] uewsenH esowag PIO powder 6 olmat Tl <l vt . , CANINE MESOTHELIOMA AND ASBESTOS EXPOSURE 309 a Sa Japmod ~~oUuON SIO pouedsy a}4 0} Japmod . Bouvier Flandres auON ouoN _ 8 JOUMO yom ealy ve-{ eaty ea]j uonENsut uOneR[Nsul auoN QUuON A vonwsg 9 German eaREING uoNs he aus dis UOD pues 2 sais SuON duON duON UO! - euoN auoN German Shepherd ee - Qeruamde aUON - aUuON VAN? 1Aite (H) Surpyoeds 12. German 4901 13 390y4S 14 German ShepherdShepherd ye Mtn Eng Shepdog 5 pesn 1981 _ (O) 10 pue 197Apog voneyisul+6 [IO olny 1981 d 1d%d Id MIJAOIUT Id Idd 8d Mixed Hair Pointer ad Id 8 d JO} Pe JOUMO JDEOS T 6261 6161 6L61 sae 6161 6161 German German Shepherd Shepherd M 186] 6 1861 0} inkdehisncdes 8 Ol 8 scudantiac ay b Female - spayed -9 8 Ul 8 9 for interview W WwWwW W W W Ww Ww W W W W Ww = = ag interview 2c MRS Sap sap s91An0d saipuel.ojPaxXtlJolanog saipueLy [OI{USed Ppsaydos Ada], psoydes Soq "UW 3opda yg pasydaysHoYg >foyulog psoydeys jesnajd = 19}2g 3uq jg UI uewsy UOISOg YSU] uvwisy esuteg PIO uewsay uRUa eH Pext uelieg Jjeauoyed PapN[oul pades[ule.j= L 8 6 OrTI wal "el vl SI Ol LI SI JON gq, g > NH YHAaA a ersmcenroe) 310 GLICKMAN ET AL TABLE 2 MATCHED PAIR ANALYSIS OF RISK FACTORS FOR CANINE MESOTHELIOMA Noncancer controls Cancer controls Risk factor Odds ratio No. D.P. Confidence limits 95 Odds ratio No. D.P.a Confidence limits 95 Domestic and owner occupational exposures Home remodeling or construction 0.3 8 Addition of home insulation 0.5 6 Home in vicinity of asbestosrelated industry 2.0 6 Occupation or hobby asbestos related 8.0 9 Urban vs rural residence of dog First residence S Longest residence Residence at diagnosis 4.0 S 2.0 6 Management of dog Source stray vs all other Time outside 5vs050 2.0 3 5.0 6 Supervision allowed to roam vs confined 2.0 9 Pesticides used on dog Flea powder Flea spray Flea dip Flea collar Any pesticide 5.0 6 3.0 4 2.5 7 1.3 7 11.0 S 0.1-1.2 0.1-2.6 0.4-10.6 1.4-10.6 _ 0.5-30.3 0.5-10.6 0.2-21.0 0.7-34.5 0.5-7.8 0.7-34.5 0.4-25.8 0.5-12.2 0.3-5.9 1.5-82.1 1 10 % 17 % 7 3 10 322 9 322 11 11 322 10 b 47 2.5 7 3.0 8 1.7 8 1.5 10 1.5 10 1.0 6 5.0 6 0.1-1.6 0.2-3.3 0.2-3.3 0.6-8.7 0.4-5.3 0.4-3.9 _ _ 0.5-12.2 0.7-13.8 0.4-6.9 0.4-5.3 0.4-5.3 _ 0.7-35.5 Number of Discordant Pairs b Not able to calculate The cases were all strays while the controls were of known origin 'Not able to calculate The cases all had an urban residence while the controls had a rural residence are listed in Table 2. For example if the dog was obtained as a stray exposure to asbestos could have occurred prior to adoption None of these management factors was significantly associated with mesothelioma when analyzing the control groups separately or combined as matched triplets The medical histories did not reveal an association between mesothelioma and other illnesses requiring hospitalization in the study dogs or in other household dogs The number of other dogs in the household was similarly unrelated to development of mesothelioma No asbestos tumors were identified among household members of the study dogs Information on the use of pesticides and insect repellents was obtained because talc may be contaminated with asbestos and other mineral fibers 14 The relative risk for all forms of pesticides was elevated and was significant when any pesticide use was considered in comparison to noncancer controls OR = 11.0 CL95 1.5-82.1 The risk associated with any pesticide use when the control groups were combined was also significant OR = 7.6 CL95 1.2-49.0 Preliminary microscopic observations of seven commercially available pet flea powders and C sprays revealed of antigonite a were not specif been associated Results of th dogs with mesc bole consisted 1 where it was co tremolite and a able source of a 12 14 and 18 As in epidem identify possibl : included a hous nine dogs hom dential proximit 5. powder for five were higher tha lung in humans squamous cell c dogs with meso of humans with 16 Patient Mesoth 218 218 218 Lung ( ABC Squa ABC Bron ABC Bron Contro DEFOI DEFOI DEFOI H I * respiratory Tei: lala OTHELIOMA tO eh Cancer controls A SA No. Confidence ae ett D.P. limits 95 Bit dbl iA 10 0.1-1.6 7 0.2-3.3 7 0.2-3.3 10 0.6-8.7 9 0.4-5.3 11 0.4-3.9 10 _ 4 _ 7 0.5-12.2 8 0.7-13.8 8 0.4-6.9 10 0.4-5.3 10 0.4-5.3 6 0.7-35.5 of known origin ols had a rural residence as a stray exposure these management 1 analyzing the con- n mesothelioma and in other household nilarly unrelated to ere identified among as obtained because ers 14 The relative I when any pesticide the control groups .0 Preliminary mit flea powders and CANINE MESOTHELIOMA AND ASBESTOS EXPOSURE 311 sprays revealed large amounts of quartz silicates and silica and small amounts of antigonite a fiber closely related to chrysotile asbestos While asbestos fibers were not specifically identified exposure of humans to other mineral fibers has been associated with pulmonary disease e.g. silicosis Results of the lung tissue fiber analysis are presented in Table 3. The three dogs with mesothelioma had the highest levels of chrysotile fibers The amiphibole consisted of tremolite and actinolite except in the case of control dog 1 where it was commercial amphibole in the form of amosite and crocidolite The tremolite and actinolite were probably contaminants of the chrysotile The probable source of asbestos exposure for the three mesothelioma patients Numbers 12 14 and 18 in whom asbestos content was determined is shown in Table 1 DISCUSSION As in epidemiological studies of humans with mesothelioma we were able to identify possible sources of asbestos exposure for 12 of 16 75 dogs These included a household member with an asbestos occupation or hobby for nine dogs home remodeling or addition of home insulation for five dogs residential proximity to an industrial source of asbestos for five dogs and use of flea powder for five dogs The asbestos levels in lung tissue of dogs with mesothelioma were higher than levels found in control dogs Squamous cell carcinoma of the lung in humans has been associated with asbestos exposure 15 The dog with squamous cell carcinoma of the lung had asbestos fiber levels similar to levels in dogs with mesothelioma and these were similar to levels reported in lung tissue of humans with mesothelioma who had had occupational exposure to asbestos 16 TABLE 3 ASBESTOS FIBER CONTENT IN LUNG TISSUE OF DOGS Patient 12 14 18 ABC ABC ABC DEFGI DEFGI DEFGI DEFGI H Category Mesothelioma Lung Cancer Squamous cell carcinoma Bronchial carcinoma Bronchial carcinoma Controls" -- respiratory disease and noncancer Age at Diagnosis Years , 10 6 6 230 230 8 nab nab 6 6 8 8 Fiber type No./g dry wt Chrysotile Amphibole 3,100,000 7,200,000 22,000,000 8,200,000 280,000 69,000 325,000 700,000 300,000 2,900,000 1,100,000 0 0 3,300,000 760,000 4,800,000 280,000 0 81,000 0 200,000 720,000 0 340,000 " " " 312 n GLICKMAN ET AL a ja EB & We cannot Mesothelioma cupational pat if the predomi different expo There appea Flandres may sothelioma Th until the findin dog breeds a c Pet animals . miological studi been used prev teosarcoma 21 histologically v niques are used and dietary fact and human mesothelioma Also when additional identified it will be possible to dogs with mesothelioma are occupational asbestos evaluate interactive effects of pesticide use and exposure An urban residence was associated with lioma Although this association an increased risk of canine mesothe- was seen with first was not statistically significant the greatest risk residence and the lowest risk with residence at suggests that early exposures may be important in the initiation of dmieasgontohseilsiTohmias 1. Wagner C. S 2. Selikoff I. J. 3. McDonald J. C. p 587 IARC 4. Selikoff I. J. Ha 5. Anderson H. A. Acad Sci 271 6. Vianna N. J. and 7. McDonald J. C. 8. Wilbur R. H. 19 February 3-5 9. McDonald A. D 10. Churg A. 1982 11. Mantel N. and H 12. Miettinen O. S. ( 13. Rothman K. J. Publication No. 14. Blejer H. A. and 15. Craighead J. E. a 16. Whitwell F. Scott 17. Cramer D. W. W 372-376 18. LeBeau A. 1953 19. Schneider R. Dorn 20. Schneider R. 1970 21. Tjalma R. A. 1966 22. Gilette E. L. 1981 Holland found with an I with pesticide y indicate preold members oping asbestoslevelopment in y many years " asbestos Demechanism for . Efforts could and to provide eened for early ervals unrecognized ioma Analysis prays revealed silicate similar s These fibers ell as humans tion of ovarian tion should be epellents since of human me- dog ownership sothelioma are sticide use and anine mesothehe greatest risk diagnosis This mesothelioma when mesothe- to cancer con- ne explanation ciated with an is also consis- amount of time ciated with in- lly significant as unaware dogs with me- ents the mean 2 to 64 years long in propor- CANINE MESOTHELIOMA AND ASBESTOS EXPOSURE 313 We cannot explain why male dogs were at such a high risk for mesothelioma Mesothelioma usually occurs in males in humans and this is consistent with occupational patterns of asbestos exposure Further studies are needed to determine if the predominance of male dogs is related to genetic or hormonal factors or to different exposure patterns than female dogs There appeared to be a breed related risk for mesothelioma The Bouvier des Flandres may be a potentially valuable model for experimental studies of mesothelioma This breed susceptibility however must be interpreted with caution until the findings are replicated elsewhere Since there are over 125 recognized dog breeds a chance association with any given breed is not unlikely Pet animals with spontaneous tumors provide a valuable resource for epidemiological studies of environmental and dietary risk factors for cancer They have been used previously to evaluate risk factors for breast cancer 19 20 and osteosarcoma 21 22 that are difficult to study in humans Provided that only histologically verified tumors are included and accepted epidemiological techniques are used pet animals may provide insight into the role of environmental and dietary factors in human cancers REFERENCES 1. Wagner J. C. Sleggs C. A. and Marchlan P. 1960 Brit J. Industr Med 17 260 2. Selikoff I. J. Churg J. and Hammond E. C. 1964 J. Amer Med Assoc 188 142 3. McDonald J. C. 1980 In Biological Effects of Mineral Fibers J. C. Wagner Ed Vol 2 p 587 IARC Scientific Publications No. 30 Lyon 4. Selikoff I. J. Hammond E. C. and Seidman H. 1980 Cancer 46 2736 5. Anderson H. A. Lilis R. Daum S. M. Fischbein A. S. and Selikoff I. J. 1976 Ann N.Y. Acad Sci 271 311 6. Vianna N. J. and Polan A. K. 1977 Lancet 1 1061 7. McDonald J. C. and McDonald A. D. 1977 Prev Med 6 426 8. Wilbur R. H. 1976 In Proceedings of the National Conference on Dog and Cat Control February 3-5 1976 Denver Colorado The American Humane Association Denver 9. McDonald A. D. and McDonald J. C. 1980 Cancer 46 1650 10. Churg A. 1982 Human Pathology 13 381 392 11. Mantel N. and Haenszel W. 1959 J. Natl Cancer Inst 22 720 12. Miettinen O. S. 1969 Biometrics 25 339 13. Rothman K. J. and Boice J. D. 1979 U.S. Dept. of Health Education and Welfare NIH Publication No. 79-1649 Washington D.C. 14. Blejer H. A. and Arlon R. 1973 J. Occup Med 15 92 15. Craighead J. E. and Mossman B. T. 1982 N. Eng J. Med 306 1446 1455 16. Whitwell F. Scott J. and Grimshaw M. 1977 Thorax 32 377 17. Cramer D. W. Welch W. R. Scully R. E. and Wojciechowski C. A. 1982 Cancer 50 372-376 18. LeBeau A. 1953 Bull Acad Vet France 26 229 19. Schneider R. Dorn C. R. and Taylor D. O. N. 1969 J. Natl Cancer Inst 43 1249 20. Schneider R. 1970 Cancer 26 419 21. Tjalma R. A. 1966 J. Natl Cancer Inst 36 1137 22. Gilette E. L. 1981 In Design of Models for Testing Cancer Therapeutic Agents Elsevier Holland