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FILE NAME: Talc (TALC) DATE: 1984 DOC#: TALC032 DOCUMENT DESCRIPTION: Journal Article - Mesothelioma in Pet Dogs Associated with Exposure of Their Owners to Asbestos ENVIRONMENTAL RESEARCH 32, 305-313 (1983) D epo. E x . Ho*i S i I S a te _________>/ l l j & y ___ b j JHL Mesothelioma in 12 Pet Dogs Associated with Owners to Asbestos Exposure of Their Lawrence T. Glickman,*'3 Linda M. Domanski,* Tobi G. Maguire,* Richard R. Dubielzig,! and Andrew Churg$ *Department o f Clinical Studies, Section o f Epidemiology, and fDepartment o f Pathobiology, University o f Pennsylvania, School o f Veterinary Medicine, Philadelphia, Pennsylvania; and fDepartment o f Pathology, University o f 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-related 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 sex-matched controls were interviewed to determine their occupation and medical history and their dog's medical history, life style, diet, and exposure to as bestos. An asbestos-related 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 well-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-related 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- 1Presented 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. I 3To whom correspondence should be addressed: University of Pennsylvania, School of Veterinary Medicine, Department of Clinical Studies. 3800 Spruce St., Philadelphia, Pa. 19104. 305 0013-9351/83 $3.00 Copynghi 1983 by Academic Press, Inc AH rights of reproduction m any form reserved -i i 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 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 bestos related pulmonary diseases. PATIENT SELECTION AND METHODS The study group consisted of 18 dogs with histologically confirmed mesothe lioma that were diagnosed between April 1977 and December 1981 at the Veter inary Hospital of the University of Pennsylvania (VHUP). The VHUP is a major veterinary referral center for the Northeast and Middle-Atlantic regions of the United States. Each year there are approximately 17,000 admissions and visits 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 ( 1 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 (manage ment factors), as well as the occupation and medical history of household mem 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 (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 diagnosis. Only residences and occupations for the time period prior to the date of diagnosis of mesothelioma were considered. Lung tissue from three meso thelioma patients was analyzed using an electron microprobe for fiber content (10). 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 dis ease. These comparison dogs were not included in the epidemiological study. Because controls had been matched on age, sex, and breed, these character 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, was determined using the Mantel-Haenszel procedure (11). Age was controlled in sex comparisons, and sex was controlled in age comparisons. Odds ratios for other risk factors were determined for matched pairs using the cancer and noncancer control groups separately. (12) The control groups were then combined and odds ratios calculated for matched triplets. Using a 95% con fidence interval, the null hypothesis of an odds ratio equal to one was tested with computer program s developed by R othm an and Boice (13). % Eighteen do diagnosis for e ii-- (R.R.D.) and Hospital Centi lioma and the The distributic pleural, five (2 The mean ag were male and hospital popul 6.4-97.3). Whc greatest risk w 97.3) and in do for purebreed i difference was individual pure Bouvier des FI CL95%1.4-9.6) The cancer ; eases and cone of 16 of the 18 for suspected i findings were t cancer or none; a stronger asst noncancer con hobby was four using noncanct I were used the relative risk for i 1.1-11.0). Two s 1 time period the with him was e shipyard. No o dog's lifetime, workers are lik mesothelioma(9 Location of n mesothelioma i; first, longest, a increase the ris. (Table 2). No oi the dog was fou Management exposed to envi CANINE MESOTHELIOMA AND ASBESTOS EXPOSURE 307 RESULTS 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 (11%) 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 ( C L ^ 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%6.4 97.3) and in dogs 10 years of age or older (OR = 16.9, C L ^ 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, C L ^ 62.6-246.7), Irish Setter (OR = 5.3, CL95%1.4-9.6), and German Shepherd (OR = 3.3, C L ^ 1.3-8.2). The cancer and noncancer control patients represented a wide variety of dis eases 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, C L ^ 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 ( C L ^ 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(9). 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 <O0>0> TABLE 1 Characteristics of 18 Canine Patients Diagnosed with M esothelioma at VHUP between 1977 and 1981, and T heir E xposure to Asbestos O Type of asbestos exposure r Age at Site of ----------------------------------------------------------------------------------------- o diagnosis Year of meso Owner occupation (0)/ Household/ Other x 2 Patient Breed Sex (years) diagnosis thelioma" hobby (H) neighborhood possible > z 1. Mixed M 12 2. German Shepherd M 7 1978 p 1978 p Auto body repair (0) Auto mechanic (H) Extensive home remodeling Change of heat None mH None >r ing system 3. German Shepherd M 9 1978 p Truck repair (0) ad None Accompanied jacent to shipyard owner to job adjacent to shipyard 4. Doberman Pinscher M 8 1978 p &pi None None None 5. Irish Setter F -S fc 8 1979 Pe Plumbing, heating, Cement factory None sheet rock spackling (H) 6. Bouvier des M 8 1979 P None None Flea powder Flandres 7. Mixedr M 10 1979 P&PI -- -- -- 8. Bouvier des M 8 1979 PI None None None Flandres 9. German Shepherd M 7 10. Boston Terrier M 7 11. Irish Setter M 5 12. German Shepherd M 10 13. Bernese Mtn. Dog M 4 14. Old Eng. Sheepdog M 6 1979 P&PI Sheet rock spackling at shipyard (O) 1979 P&PI None 1980 PI None 1981 P&PI Pipefitting at ship yard (0) 1977 PI None 1981 Pe None Demolition and construction site None Home insulation, construction site None Flea powder None Flea powder Flea powder None Demolition & con- None > None 2 Bouvier des Flandres Mixedc Bouvier des Flandres M 8 M 10 M 8 1979 P 1979 P&P1 1979 PI ... o (H) None None None None Flea powder None 9. German Shepherd M 7 10. Boston Terrier M 7 11. Irish Setter M 5 12. German Shepherd M 10 13. Bernese Mtn. Dog M 4 14. Old Eng. Sheepdog M 6 15. German Shepherd M 8 16. German Short M 11 Hair Pointer^ 17. Mixed M 8 18. German Shepherd M 6 1979 P&P1 Sheet rock spackling at shipyard (O) 1979 P&P1 None 1980 PI None 1981 P&P1 Pipefitting at ship yard (O) 1977 PI None 1981 Pe None 1981 P 1981 PI Auto mechanic (O) -- 1981 PI 1981 P Oil burner and furnace installation (O) Auto body and used parts supply (O) " P = peritoneal, PI = pleural, Pe = pericardial. b Female-spayed. r Not included in case-control analysis. Unable to contact owner for interview. Demolition and construction site None Home insulation, construction site None None Demolition & con struction sites Home insulation -- None None Flea powder None Flea powder Flea powder None None None -- Flea powder Accompanied owner to work CANINE MESOTHELIOMA AND ASBESTOS EXPOSURE 309 B B ttoaau ss 310 GL1CKMAN ET AL. C TABLE 2 M atched Pair Analysis of R isk F actors for C anine Mesothelioma Noncancer controls Cancer controls sprays revealed of antigonite, a were not specif Odds No. Confidence Odds No. Confidence been associated J Risk factor ratio D.P." limits (95%) ratio D.P." limits (95%) Results of th Domestic and owner dogs with mesc occupational exposures bole consisted Home remodeling or construction 0.3 8 0.1-1.2 0.4 10 0.1-1.6 1 where it was cc Addition of home insulation Home in vicinity of asbestos- related industry Occupation or hobby asbestos related 0.5 6 2.0 6 8.0 9 0.1-2.6 0.4-10.6 1.4-10.6 0.8 7 0.8 7 2.3 10 0.2-3.3 0.2-3.3 0.6-8.7 tremolite and ac able source o f ; | 12, 14, and 18) f Urban (vs rural) residence of dog First residence C 5 Longest residence 4.0 5 Residence at diagnosis 2.0 6 Management of dog ' Source: stray vs all other 2.0 3 Time outside: ==50% vs <50% 5.0 6 Supervision: allowed to roam vs confined 2.0 9 Pesticides used on dog Flea powder 5.0 6 Flea spray 3.0 4 Flea dip 2.5 7 Flea collar 1.3 7 Any pesticide 11.0 5 _ 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 1.5 9 1.2 11 1.0 10 b 4 2.5 7 3.0 8 1.7 8 1.5 10 1.5 10 1.0 6 5.0 6 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 As in epidem identify possibl included a hout f nine dogs, horn % dential proximii 4. powder for five were higher the < lung in humans squamous cell c dogs with meso * of humans with \ (16). " Number of Discordant Pairs. i b Not able to calculate; The cases were all strays while the controls were of known origin. c 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 con trol 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-related 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, 01=95% 1.5-82.1). The risk associated with any pesticide use when the control groups were combined was also significant (OR = 7.6 Cl=95%1.2-49.0). Preliminary mi croscopic observations of seven com m ercially available pet flea powders and Patient Mesotf 12 14 18 Lung C A Squa B Bron C Bron Contro D E F G H 1 " Non-respirator\ Sa i&ariyv i 5 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 prob able 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-related occupation or hobby for nine dogs, home remodeling or addition of home insulation for five dogs, resi dential 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 A sbestos F iber Content in L ung T issue of Dogs Patient Category Age at Diagnosis (Years) Fiber type (No./g dry wt.) Chrysotile Amphibole Mesothelioma 12 10 14 6 18 6 Lung Cancer A Squamous cell carcinoma 12 B Bronchial-alveolar carcinoma 13 C Bronchial-alveolar carcinoma 8 Controls" D 5 E 9 F 6 G 6 H 8 I 8 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 0 Non-respiratory disease and noncancer. I s 312 g lick m a n et a l . .0 use. The asbestos `i "" dogs were fou"d " V f 3 househo,d member and with pesticide vious i T S s l TM "7 . sni " d h bbies ide""fi' d TMa>' '"Xica P These individuals may be at increased risk o f xp sure for household members, related diseases. Because of the short 1 ^ 1 i dCVC^ MbeStOS- dogs, their mesothelioma would often precedehuma^HtUmor deveiPment " Therefore, dogs serve as useful tnt; ? e human disease by many years. velopment of an animal mesotheliom^ S T human exPsure to asbestos. De- identifying those * hfehrT ^ W U'd provide a "eehanism for fibers of talc, quartz, and silica and t V fl Powders and sprays revealed to asbestos that is often found in assor' f amount* ^f antigonite, a silicate similar or asbestos contaminants mav nres T ^ Tu* chrysotde ast)estos. These fibers These resuits f ** cancer and use of cosmetic talc in women (17? Fnrth 30 aSSOC,at,on of ovarian made of the human cancer risk T ,, V ? Further investigation should be they could explain"smne^/the^omnr!?^ ' T TM * t0 .flea rePe,lents * sothelioma. This could be examined h * UP3 *na y re*ated cases of human me- and human mesothelioma Also when^ddV ^ an associatlon of dog ownership identified, it will be possible to v S ? d gS with mesothelioma are occupational a s b e l s exposure imeraCt'Ve ^ f pesticide a"d fn: ncr ed risk f cani"e -- * was seen with first residence and the In/ S f !StJca. y SIgmficant, the greatest risk suggests that early exposures mav he ; es` nsk Wldl residence at diagnosis. This The association with urban residene mP ^ ln.t^e miration of mesothelioma, lioma cases were compared S COnSIStently hi^ when mesothe- trols. This " PP Sed l Cancer con' is that many chemicals in the urban e 4 factors analyzed- One explanation increased risk of Stumors l e r ,han I f .kT " 1' " " * als0 assoda,' d with " tenl with the finding that the amount of? Cl<>ma ln lhe d 8' Phls ,s a!so cnsis- spent outdoors unsupervised and orioin Spa1' ou,doors' lhc amoun' of time creased risks o f fn " ^ Were a" as>d a <i with in 77 Doga may hay?h!?deXDOurT ? o 1 s t? ? f Z T s,a,isIi" "V significant. Using a method to equate dog to huma? yeare(1 the'TM'r U"aware' sothelioma was found to be similar ,,,T ?" v h 8` f dogs Wl,h me` age of the dogs was 48 y,,r? ,?? "tesothehoma patients; the mean Thus, as in h u m a l ,he E fion to the dog's lifespan. ~ l d f 8' WaS equivalen' " 32 64 W f Canine mesothelioma is long in propor- 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 stud; been used prev teosarcoma (21 histologically vt niques are used and dietary factt 1- Wagner, J. C., S 2. Seiikoff, I. J., Ci 3. McDonald, J. C. P- 587, IARC 4. Seiikoff, I. J., H; 5. Anderson, H. A. Acad. Sci. 271 6. Vianna, N. J., an. 7. McDonald, J. C., 8. Wilbur, R. H. (IS February 3-5, 9. McDonald, A. D.. 10. Churg, A. (1982). 11. Mantel, N., and H 12. Miettinen, O. S. (1 13. Rothman, K. J., a 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., Dorr 20. Schneider, R. (1970 21. Tjalma, R. A. (1966 22. Gilette, E. L. (1981. Holland. 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 oc cupational 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 me sothelioma. 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 epide miological studies of environmental and dietary risk factors for cancer. They have been used previously to evaluate risk factors for breast cancer (19, 20) and os teosarcoma (21, 22) that are difficult to study in humans. Provided that only histologically verified tumors are included and accepted epidemiological tech niques 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). Bril. J. Industr. Med. 17, 260. 2. SelikofF, 1. 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. 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