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Public health aspects of animal tumor viruses
THERIOGENOLOGY
PUBLICI-IEALTIi ASPECTSOF fNIMALTt!NR VIRLJSES Gordon H. ‘Iheilen Department of Surgery Section of Clinical Oncology School of Veterinary Medicine University of California, Davis
Abstract Some believe animal tumor viruses are frequently involved in our public health, however, over 100 animal tumor viruses have been isolated and only one (Yaba Tuoor Virus) has minor public significance: FeLV is highly contagious in cats and some have reconunendedFeLV infected cats be euthanized because of “possible” public health importance. Nhen all evidence bearing on possible public health relationship is assembled, it is clear that most evidence indicates no likelihood of association between FeLV and any human disease. Introduction Animal disease agents transmissible to man include viruses, rickettsia, bacteria, fungi, protozoa, cestodes, nematodes and shown arthropods;1 among these, only viruses have been consistently to be etiologicafly associaled with cancer. Over 100 animal tumor and one has minor public health signifviruses 3hzjve been isolated, papilloma virus is the only known tumor virus icance. 3 The hm of hm origin2 Sooner or later other tumor viruses will probably be isolated Environmental factors such as chemicals, from human tissues. irradiation and smoking possibly accounts for 80 to 90% of all Interrlationships of diet, hormonal factors, genetic humancancer.5 make-up and immunecompetence play a significant role in cancer exMany believe, however, that under certain circumstances pression. animal tumor viruses may play a role in the etiology of human cancer. Recent news reports have incriminated cats as possible vectors of human cancer,and some veterinarians and physicians recommend that cats infected with Feline Leukemia virus .(FeLV) should be euthanized because of ‘possible” public health hazard. Such advice is based on theoretical evidence of human infectivity and not on scientific fact.6-7 This had caused considerable concern among cat owners and in the medical and veterinary professions as to the public health hazard involved in cats infected with FeLV. A resolution recommending in-
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vestigation of the status of FeLV in cats and its possible role in humandisease was passed at the 1974 meeting of the American Veterinary Medical Association in Denver. The AVMAresolution led to the appointment of a panel of feline leukemia research workers. The group met in February, 1975 and drew up guidelines for the handling of FeLV infected cats because of the infectious nature for cats. A statement about public health aspects of FeLV will also be included in the published report as follows: “relationships, if any, of FeLV to hman diseases is at present unknown”!9 This paper will present a brief review of ttmm viruses as a “possible” public health hazard with special enqhasis given to FeLV. Discovery to Tumor Viruses Tumor virology has spanned the last 70 years. A summy of tumor virus isolations that includes date, name of tuner and investigator(s) who first described some of the causal viral agents is presented in Table I.2 Avian leukemia and sarcoma viruses ‘(RNA-containing) were the first isolates, then for the next 40 years all isolatz ~5; JjNA-containing, until Gross isolated the murine leukemia Most virus isolates since 1964 have been BNA-containEZ -
DNA Tumor Viruses
DNAttnnor viruses are listed in Table II. They include 1) pox-like viruses, 2) Papova, 3) Herpes and 4) HumanAdenoviruses. The only animal virus that causes humandisease amng these is the Yaba Tmor Virus, a pox-like virus that cause2 (experimentally only) Q1 the other hand, histiocytomas, in non-hman primates and man. certain human adenoviruses (strains 12 and 18) believed to be non-tumori enic in people are tumor producing when inoculated into hamsters.1 8 The biological role of hman adenoviruses in oncogenesis needs further investigation. Marek’s Disease Virus, a Herpes virus, of poultry (lymphoid neoplasm inducing), was responsible for a high mortality that resulted in hundreds of millions of dollars annual loss to the world poultry industry until the recent development of a vaccine. The Epstein-Barr (E-B) virus of hman origin also belongs to the Herpes group of viruses and it may be the cause of Burkitt’s in children, infectious mnonuzleosis and nasal pharyngeal lymph ?l The exact role of the E-B virus in these diseases has not cancer. been completely elucidated.
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RNA TLnnorViruses
A list of RNAtumor viruses is presented in Table III. These viruses are of epidemic importance in some species. FeLV is highly contagious in cats and the putative bovine leukemia virus (BLV) is enzootic in cattle. l2 ,I3 Viruses of this group isolated from poult ‘fli, gcz;&?g humanprimates also cause leukemias and sarcomas. viruses.are for the most part species specify under natural condit. Avian and feline sarcoma viruses are tumorigenic in exi?tintally inoculated heterospecies including non-human primates.14 First concerns about FeLV as a “possible” public health hazard followed reports that it infects human cells in culture and induces lymphosarcoma in inoculated puppies. 15-17 Cncorna viruses of other species, however, also infect heterospecies cells in culture.18 when articles suggesting FeLV might be related to htrnan disease are listed, without qualification, the number is imposing. However, when all evidence of the relationship is assembled, it is likelihood of association between FeLV cl$arr;hatatrei~r~~~~~~ Reasons supporting “possible” public health importance of FeLV have usually centered around the following biological factors. 1) FeLV infection ‘may” cause individuals to become immmosuppressed, 2)FeLV and FeSV have a broad heterospecies host range of infectivity in cell culture and living animals (FeSV is a sarcoma inducing virus of cats that is antigentically identical to FeLV), 3) FeLV and FeW are classified as moderately biohazardous by the National Cancer Institute and 4) traditional epidemiological methods are not adequate to elucidate causes of chronic diseases.
1.
Inmunosuppression
Some have indicated that because of specific suspectibility to infection odeficient persons should avoid contact with leukemic cats.+lmun Hunan fetuses and young babies are included in this immunodeficient group. This recommendation may be prudent, but should include unnecessary exposures to any infectious agents. Almost any bacterial, viral or zoonotic agent could be dangerous to imnunoYoung cats are more susceptible to FeLV infection, deficient persons. but that doesn’t mean that m fetuses or young babies are more susceptible to FeLV. FeSV (a possible mutant of FeLV) experimentally induced tumors in 60-80 day old sheep fetuses which regressed --in utero; this demonstrated an in utero immunologic response to oncorna viruses, at least in one speci?Z.mo even in the unlikely event of in utero infection with FeLV, there is evidence to support the proposit?ost the fetus may be protected from heterospecies oncorna virus tumor induction.
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2.
FeLV and Fe.% had wide in vitro infectivity
and in vivo host range of
FeLV will infect humancells in vitro and it will cause l~hosar~ in experimental in lam=ies but apparently not in adolescent or adult dogs.ls-lqcu Cells in cultures do not possess the same biological control mechanisms as do those in living individuals, so that -in vitro infection does not necessarily infer that in vivo infection can occur. FeLV tumor inducing capacity in exper?i?iemly inoculated dogs needs to be studied further before one can support the argument that FeLV is an agent with a broad spectrum of heterospecies infectivity. On the other hand, FeSV tumors in heterospecies occur only experimentally.26-23 Most seroepidemiology studies have been negative for FeLV antibody and presence of FeLV antigen in human sera and tissue.12,29,23 However, it was recently reported that FeLV cytotoxic antibodies were found in human sera.Zg In an independent (but similar) study antibody was found not only in human sera from normal an leukemic patients but as well as sera from several heterospecies. 90 It is probable that this cytotoxic antibody is nonspecific heteroantibody, but even so this is not sufficient evidence to provide that FeLV is the cause of any humandisease. Sera from veterinarians have consistently been negative for the resence of FeLV (with one exception which on retest was negative). 2P In comprehensive epidemiologic studies, veterinarians were at a high risk only fo z9yhignant melanoma (often associated with exposure to sunlight). Children associated with “sick” cats had an increased incidence of leukemia but there was also a higher incidence of leukemia when children were associated with parakeets, thus making interpretation of this study difficult.25 In addition, there is no serologic 1 evidence that FeLV induces natural disease in other animals. 14 3.
FeLV and FeSV are classified National Cancer Institute
as moderately biohazardous by the
If one argues that because FeLV ‘and FeSV are included in the moderately group of hazardous agents by the National Cancer Institute (N.C.I.), they should be considered to be possible humanpathogens. This is a double argument, however, because placing of FeLV and FeSV in the moderately biohazardous group by N.C.I. was done on the basis of info~ation presented above. 4.
Standard Epidemiology methods are not adequate to study chronic disease
The low rate of leukemia in people makes it almost impossible to set up adequate epidemiologic studies to show a negative relationship of FeLV and human leukemia. Studies of double stranded DNA homology to find footprints of feline oncorna virus in human tissue would help determine if FeLV is related to human leukemia or chronic diseases,but so far no connection has been demonstrated.33
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The Yaba Tumor Virus is the only known animal tumor virus which has on rare occasion caused h= disease (but not malignanq) .4 It has little practical importance as a humanpathogen. There is no evidence that other animal tumor viruses are agents of hxsnandisease. Nevertheless, euthanasia for cats infected with FeLV has been reccsmnendedbecause they ‘may” carry human disease agents. This recoanner&tion seems to be arbitrarily directed at cats, because similar reasoning could also be applied to the poultry and cattle oncorna viruses that also infect heterospecies and, therefore, “might” cause human disease.S4,33 To be consistent we also shouldn’t have contact with these species or eat meat, eggs, or milk because such contact might present a “possible” public health hazard. Even if we became a vegetable-eating society and had no contact with animals, we still would have problems with “possible” tumor inducing pathogens of hm origin. The parallel could be drawn further to recormnendisolation of humans infected with human adenoviruses strains 12 or 18 because these are horizontally transmitted and when injected in hamsters cancers are readily produced.10 Who in our Public Health Service, however, would advocate the isolation of humans infected with adenoviruses (a ubiquitous class of viruses)? One could speculate that human adenovirus may cause disease. Suggestions for control of animal tumor viruses on the basis of hypothetical arguments do not supply sufficient evidence to institute test and euthanasia measures in our cat populations. It is only possible to make firm recommendations for control of zoonotic diseases when the pathogenesis of infectious agents are fully understood. Since there is no scientific evidence_ the FeLV causes human disease, one should not reccpmnendeuthanasia of an FeLV infected cat on the basis that it “may” cause human disease, however, it has not been proved they don’t. Investigations should continue to seek FeLV “footprints” in heterospecies tissue. To date, FeLV double stranded DNA homology studies have been negative, but this is a new approach and additional studies are needed before definitive statements are made. Most cats are infected with another oncorna virus referred to as IU~-114.~6 This virus is passed endogenously from generation to generation, but it is only expressed as a mature virus in heterospecies cells. It has been postulated that RD-114 originated from an endogenous old world monkey type-C virus and wa then horizontally transmitted to an ancester of the domestic cat .39 RD-114 grows very well on hunan cells, although its biological role is not known either in cats or been one of the viruses used in pioneer studies of ~~t~on~5S~7, 38
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Present evidence &es not support a public health role for FeLV, FeSV or for RD-114. Basic biological research of these agents and the possible relationship to human disease should be continued, but misplaced emotionalism about our public health should not lead to actions such as recmding that infected cats be killed because the “may” cause humandisease.
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TABLE I - Summaryof TumorVirus Isolations DATE
lI_WR
INVESTIGATOR
1908
Fowl leukemia
Ellermn and Bang
1911 1911 1920 1932
Fowl sarcoma Rabbitmyxomatosis Bovinepapilloma
Moses
1932 1933 1936 1938 1951 1951 1953 1953 1955 1958 1961 1962
Rous
Canineoralpapilloma Rabbitfibroma Rabbitpapilloma Mousemammarycarcinoma Frog kidneycarcinoma Equinepapilloma Mouse leukemia
Squirrelfibroma Polyoma
Magalhaes DeMonbreun and Goodpasture Shape Shope Bittner Lucke Cook and Olson Gross Kilham,Kermanand Fisher Stewardand Eddy - Gross
Deer fibroma Yaba tumorvirus SV-40 Human adenovimses (Tumorsin hamsters)
Shope,Mongold,et al. Bearcroft Sweet Trentin
1963
Marek'sdisease (Avianlymphoidtumors)
Biggsand Payne
1964 1965 1967
Felineleukemia
Jarret,et al.
Mouse sarcoma Guineapig leukemia
Moloney;Kirsten;Harvey
1968 1969 1971 1972 ?
Felinefibrosarcoma Bovineleukemia Simiansarcoma Gibbonape leukemia Hman CancerViruses
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Opler Synderand Theilen Olson,Miller,et al. Theilen,Deinhardt, et al. Kawakami,et al.
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TABLEII - EXAMPLESOFCANCERCALJSED BYJJNAVIRUSES VIRUS 1.
NEOPLASM 1. Myxomatosis of rabbits.
Pox-likeviruses
2. Fibromasof rabbitsand squirrels. of man and subhuman 3. Histiocytomas primates. 2.
of man, rabbits,dogs, 1. Papillomas cattleand horses. Experimentally inoculated bovinepapillomavirus causessolidtumorsof hamstersand braintumorsof rabbitsand calves.
Papovaviruses
2. Solidtumorsof hamsters. 3. Solidtumorsof mastomys. 4. Fibromasof deer. 3. Herpesviruses
1.
Luckefrog kidneyadenocarcinoma.
2. Marek'sdiseaseof poultry. neoplasmsin non3. Lymphoreticular humanprimates. 4. Possiblecauseof Burkitt's lymphomaof childreninfectious mononucleosis and nasalpharyngeal cancer. 4. Humanadenoviruses
338
1. Solidtumorsin hamsters.
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1.
Oncorna
1.
Leukemia of mice, fowl,, guinea pigs, cats and primates.
2.
Adenocarcinoma of kidney and osteopetrosis of poultry.
3.
Osteogenic
4.
Sarcoma of fowl and mice. a.
Solid txanors of marmosets.
b.
Brain tumors of rabbits, puppies, and subhumanprimates.
5.
Manmarytumors of mice.
6.
Sarcoma of cats. a.
7.
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sarcomas of mice.
Solid tumors of cats, dogs, rabbits, rats, sheep fetuses, sheep and nonhm primates.
Simian leukemia and sarcoma. a.
Sarcoma in woolly monkey.
b.
Leukemia in gibbon apes.
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References 1.
Schwabe,C.W. Veterinary Medicineand HumanHealth. Williams and Wilkins,2nd.,Ed. Baltimore,(1969)
2. Gross,L. Gncogenic Viruses.2nd.Ed., PergamonPress, Oxford,(1970). 3. Bearcroft, W.G.C.and Jamieson, M.F. An (xltbreak of SubCutaneousTumorsin RhesusMonkeys. Nature,London~182:195196 (1958). 4. Grace,J.T. and Mirandi,E.A. HumanSusceptibility to A Simian TumorVirus. Ann. N.Y. Acad.of Sci.108:1123-1128 (1963). p. 241 in Cancer 5. Higginson, J. and Muir,C.S. Epidemiology: Medicine,Ed. Hollandand Frei,Lea and Febiger,Phila.1973. A.J.,Phil,D., Hess,P.W.MacEwen, 6. Hardy,W.D.,Jr.,McClelland, E.G. FelineLeukemiaand PublicHealthAwareness.J. Amer.Vet. Med. Assoc.-165:1020-1021 (1974). 7. Levy, J.A. Cats and Cancer. J. Am. Med. Assoc.-229:1654-1655 (1974). A Threatto Man? New Eng. J. Med. 8. Levy,S.B. Cat Leukemia: (1974). -290:513-514 9. Ott, R.L.,Essex,M. Hardy,W.D.,Jr., Peman, V., Priester, W.A.,Rickard,C.G.,Schneider, R., and Theilen,G.H. A Report of the Am. Vet.Med. Assoc. Panelon FelineLeukemia.J. Amer. Vet. Med. Assoc. In press (1976). 10. Trentin,J.J.,Yabe,Y., and Taylor,G. TumorInductionin Hamstersby HumanAdenovirus.Proc.Am. Assoc. Can. Res. 3: 369 (1962). betweenthe Epstein-Barr 11. Henle,W., Henle,G. The Relationships virusand infectious Mononucleosis, Burkitt'sLymph-, and Canarythe PostNasalSpace. E. Afr. Med. J. -46:402-406(1969). 12. Hardy,W.D.,Jr., Old, L.J.,Hess,P.W.,Essex,M., and Cotter, S.M. Horizontal Transmission of FelineLeukemiaVirus in Cats. Nature-244:266-269 (1973). (Leukemia) A Synopsis.J. Amer. 13. Olson,C. BovineLymphosarcoma Vet. Med. Assn.165:630-632 (1974). 14. Theilen,G.H.,Hokama,Y., Manning,J.S.,and Callaway,E. Heterospecies Infectivity of FeSV:Neoplasmsin SheepFetuses and Lambsby Inoculation of FeSV Transformed SheepCells: In PossibleEpisomesin Eukaryotes.FourthLepetitColloquium North-Holland, Amsterdam, Elsevier,109-116(1973).
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15.
sarma,P.S.,Huebner,R.J. Basker,J.F.,Vernon,L., and Gilden, R.V. FelineLeukemiaand SarcomaViruses: Susceptibility of HumanCellsto Infection.Science-168:1098-1099 (1970).
16.
Jarret,0. Virologyand Host Rangeof FelineLeukemiaVirus. J.A.V.M.A. X8:1032-1039(1971). -
17.
Rickard,C.G.,Post.,J.E. Novonha,F., and Barr,L.M. InterspeciesInfectionby FelineLeukemiaVirus:SerialCell-free Transmission in Dogs of MalignantLymphms Inducedby Feline LeukemiaVirus. In clarifying conceptsof Leukemia,Bibl.haemat. No. 39 pp. 102-112. S. Karger,Base1 11973).
18.
Levy,J.A. ~dogeno~ M&V. Host Rangeof MurineEnotropic Views: Replication in Avian Cells. Nature253:140-142 (Jan.1975).
19.
Gardner,M. CurrentInformation of Felineand Canine Cancersand relationship or Lack of Relationships to HumanCancer. J. Nat. CancerInst.46:281-290(1971).
20.
Hanes,B. Gardner,M.B., loosli,C.G.,Heidbreder, G. Kogan, B., Marylander, H. and Huebner,R.J. Pet Association with Selected Human Cancers: A HouseholdQuestionaire Survey.J. Nat'l.Can. Inst.-45:1155-1162 (1970).
21.
Schneider, R. The NaturalHistoryof MalignantLymphomaand Sarcomain Cats and TheirAssociation with Cancerin Man and Dog. J. Amer.Vet. Med. Assn. 157:1753-1758 (1970).
22.
Schneider, R. HumanCancerin HouseholdsContaining Catswith Lymphoma. Int.J. Cancerg:338-344 (1972).
Malignant 23.
Schneider, R.S. and Riggs,J. L. A Serological Surveyof Veterinarians for Antibodyto FelineLeukemiaVirus. J.A.V.M.A. (1973). -162:217-219
24.
Bross,I.D.J.,Berteu,R., and Gibson,R. pets and AdultLeukemia. Am. J. Pub.Health62:1520-1531 (1972).
25.
Bross,I.D.J.and Gibson,R. Cats and ChildhoodLeukemia.J. Med. Exp, Clin.1 &180-187 (1970).
26.
Theilen,G.H. Continuing Studieswith Transmissible Feline Fibrosarccxna Virus in Fetaland NewbornSheep. J.Am.Vet.Med. Assoc.1%:1040 (1971).
27.
Theilen,G.H.,Synder,S.P.,Wolfe,L.G. and Landon,J.C. Biological Studieswith Viral InducedFibrosarcoma in Cats,Dogs. Non-~ Primates. Camp. Leuk. Res. -36:393-400(1969).
28.
Deinhardt, F., Wolfe,L.G.,Theilen,G.H. and Synder,S.P. ST-FelineFibrosarcoma Virus: Inductionof Tumorsin MarmosetMonkeys. Science-167:881(1970).
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29.
Caldwell,G.C.,Baumgartener, L., Carter,C., Cotter,S., Currier, R., Essex,M., Hardy,W.D.,Jr., Olson,C. and Olsen,R. Seroepidemiologic Testingin Man for Evidenceof Antibodiesto FelineLeukemiaVirusand BovineLeukemiaVirus. Proceedings VII Int'lleuk.Symp.Copenhagen.In press (1975).
30. Grant,C., et al. Seroepidemiologic Test in Man and Animalsfor Evidenceo-bodies to FeLV. Unpublished data (1976). 31. Fasal,E., Jackson,E.W. and Klauber,M.R. Mortalityin California Veterinarians.J. Chron.Dis.19:293-306(1966). 32. Botts,R.P.,Edlavitch, S., and Payne,G. Mortalityof Missouri Veterinarians.J.A.V.M.A. 149:293-306 (1966). 33. Benveniste, R.E.,Sherr,C.J.,and Todaro,G.J. Evolutionof C-TypeViralGenes: Originof FelineLeukemiaVirus. Science-190:886-888 (1975). 34. Hlozanek,I. Avian LeukosisVirus Inducedtumorsin Mammals. Ivth Int'lConf.on Camp.Leuk.Res. CherryHill,N.J. Bibl. Haemat.No. 36, pp. 106-112. S. Karger,Base1 (1970). of BovineC-Type 35. HOSS,H.E. and Olson,C. Infectivity (Leukemia) Virus for Sheepand Goats. Am. J. Vet. Res. -35: 633-637(1974). R.M.,Nicolson,M., Gardner,M.B. Rasheed,S., 36. McAllister, Rongey,R.W.,Hardy,W.D. and Gilden,R.V. RD-114VirusCompared with Felineand Murine'I&e-CVirusesReleasedfromRD Cells. NatureNew Biol.*75-78 (1973). R.E. and Todaro,G.J. Evolutionof C-TypeViral 37. Benveniste, of Exogenously AcquiredViralGenes. Nature Genes. Inheritence 252:456-459 (1974). R.E.,Todaro,G.J. Evolutionof Type C ViralGenes: 38. Benveniste, Evidencefor An Asian Originof Man. Nature.261:101-108(1976).
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PUBLICI-IEALTIi ASPECTSOF fNIMALTt!NR VIRLJSES Gordon H. ‘Iheilen Department of Surgery Section of Clinical Oncology School of Veterinary Medicine University of California, Davis
Abstract Some believe animal tumor viruses are frequently involved in our public health, however, over 100 animal tumor viruses have been isolated and only one (Yaba Tuoor Virus) has minor public significance: FeLV is highly contagious in cats and some have reconunendedFeLV infected cats be euthanized because of “possible” public health importance. Nhen all evidence bearing on possible public health relationship is assembled, it is clear that most evidence indicates no likelihood of association between FeLV and any human disease. Introduction Animal disease agents transmissible to man include viruses, rickettsia, bacteria, fungi, protozoa, cestodes, nematodes and shown arthropods;1 among these, only viruses have been consistently to be etiologicafly associaled with cancer. Over 100 animal tumor and one has minor public health signifviruses 3hzjve been isolated, papilloma virus is the only known tumor virus icance. 3 The hm of hm origin2 Sooner or later other tumor viruses will probably be isolated Environmental factors such as chemicals, from human tissues. irradiation and smoking possibly accounts for 80 to 90% of all Interrlationships of diet, hormonal factors, genetic humancancer.5 make-up and immunecompetence play a significant role in cancer exMany believe, however, that under certain circumstances pression. animal tumor viruses may play a role in the etiology of human cancer. Recent news reports have incriminated cats as possible vectors of human cancer,and some veterinarians and physicians recommend that cats infected with Feline Leukemia virus .(FeLV) should be euthanized because of ‘possible” public health hazard. Such advice is based on theoretical evidence of human infectivity and not on scientific fact.6-7 This had caused considerable concern among cat owners and in the medical and veterinary professions as to the public health hazard involved in cats infected with FeLV. A resolution recommending in-
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331
THERIOGENOLOGY
vestigation of the status of FeLV in cats and its possible role in humandisease was passed at the 1974 meeting of the American Veterinary Medical Association in Denver. The AVMAresolution led to the appointment of a panel of feline leukemia research workers. The group met in February, 1975 and drew up guidelines for the handling of FeLV infected cats because of the infectious nature for cats. A statement about public health aspects of FeLV will also be included in the published report as follows: “relationships, if any, of FeLV to hman diseases is at present unknown”!9 This paper will present a brief review of ttmm viruses as a “possible” public health hazard with special enqhasis given to FeLV. Discovery to Tumor Viruses Tumor virology has spanned the last 70 years. A summy of tumor virus isolations that includes date, name of tuner and investigator(s) who first described some of the causal viral agents is presented in Table I.2 Avian leukemia and sarcoma viruses ‘(RNA-containing) were the first isolates, then for the next 40 years all isolatz ~5; JjNA-containing, until Gross isolated the murine leukemia Most virus isolates since 1964 have been BNA-containEZ -
DNA Tumor Viruses
DNAttnnor viruses are listed in Table II. They include 1) pox-like viruses, 2) Papova, 3) Herpes and 4) HumanAdenoviruses. The only animal virus that causes humandisease amng these is the Yaba Tmor Virus, a pox-like virus that cause2 (experimentally only) Q1 the other hand, histiocytomas, in non-hman primates and man. certain human adenoviruses (strains 12 and 18) believed to be non-tumori enic in people are tumor producing when inoculated into hamsters.1 8 The biological role of hman adenoviruses in oncogenesis needs further investigation. Marek’s Disease Virus, a Herpes virus, of poultry (lymphoid neoplasm inducing), was responsible for a high mortality that resulted in hundreds of millions of dollars annual loss to the world poultry industry until the recent development of a vaccine. The Epstein-Barr (E-B) virus of hman origin also belongs to the Herpes group of viruses and it may be the cause of Burkitt’s in children, infectious mnonuzleosis and nasal pharyngeal lymph ?l The exact role of the E-B virus in these diseases has not cancer. been completely elucidated.
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RNA TLnnorViruses
A list of RNAtumor viruses is presented in Table III. These viruses are of epidemic importance in some species. FeLV is highly contagious in cats and the putative bovine leukemia virus (BLV) is enzootic in cattle. l2 ,I3 Viruses of this group isolated from poult ‘fli, gcz;&?g humanprimates also cause leukemias and sarcomas. viruses.are for the most part species specify under natural condit. Avian and feline sarcoma viruses are tumorigenic in exi?tintally inoculated heterospecies including non-human primates.14 First concerns about FeLV as a “possible” public health hazard followed reports that it infects human cells in culture and induces lymphosarcoma in inoculated puppies. 15-17 Cncorna viruses of other species, however, also infect heterospecies cells in culture.18 when articles suggesting FeLV might be related to htrnan disease are listed, without qualification, the number is imposing. However, when all evidence of the relationship is assembled, it is likelihood of association between FeLV cl$arr;hatatrei~r~~~~~~ Reasons supporting “possible” public health importance of FeLV have usually centered around the following biological factors. 1) FeLV infection ‘may” cause individuals to become immmosuppressed, 2)FeLV and FeSV have a broad heterospecies host range of infectivity in cell culture and living animals (FeSV is a sarcoma inducing virus of cats that is antigentically identical to FeLV), 3) FeLV and FeW are classified as moderately biohazardous by the National Cancer Institute and 4) traditional epidemiological methods are not adequate to elucidate causes of chronic diseases.
1.
Inmunosuppression
Some have indicated that because of specific suspectibility to infection odeficient persons should avoid contact with leukemic cats.+lmun Hunan fetuses and young babies are included in this immunodeficient group. This recommendation may be prudent, but should include unnecessary exposures to any infectious agents. Almost any bacterial, viral or zoonotic agent could be dangerous to imnunoYoung cats are more susceptible to FeLV infection, deficient persons. but that doesn’t mean that m fetuses or young babies are more susceptible to FeLV. FeSV (a possible mutant of FeLV) experimentally induced tumors in 60-80 day old sheep fetuses which regressed --in utero; this demonstrated an in utero immunologic response to oncorna viruses, at least in one speci?Z.mo even in the unlikely event of in utero infection with FeLV, there is evidence to support the proposit?ost the fetus may be protected from heterospecies oncorna virus tumor induction.
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2.
FeLV and Fe.% had wide in vitro infectivity
and in vivo host range of
FeLV will infect humancells in vitro and it will cause l~hosar~ in experimental in lam=ies but apparently not in adolescent or adult dogs.ls-lqcu Cells in cultures do not possess the same biological control mechanisms as do those in living individuals, so that -in vitro infection does not necessarily infer that in vivo infection can occur. FeLV tumor inducing capacity in exper?i?iemly inoculated dogs needs to be studied further before one can support the argument that FeLV is an agent with a broad spectrum of heterospecies infectivity. On the other hand, FeSV tumors in heterospecies occur only experimentally.26-23 Most seroepidemiology studies have been negative for FeLV antibody and presence of FeLV antigen in human sera and tissue.12,29,23 However, it was recently reported that FeLV cytotoxic antibodies were found in human sera.Zg In an independent (but similar) study antibody was found not only in human sera from normal an leukemic patients but as well as sera from several heterospecies. 90 It is probable that this cytotoxic antibody is nonspecific heteroantibody, but even so this is not sufficient evidence to provide that FeLV is the cause of any humandisease. Sera from veterinarians have consistently been negative for the resence of FeLV (with one exception which on retest was negative). 2P In comprehensive epidemiologic studies, veterinarians were at a high risk only fo z9yhignant melanoma (often associated with exposure to sunlight). Children associated with “sick” cats had an increased incidence of leukemia but there was also a higher incidence of leukemia when children were associated with parakeets, thus making interpretation of this study difficult.25 In addition, there is no serologic 1 evidence that FeLV induces natural disease in other animals. 14 3.
FeLV and FeSV are classified National Cancer Institute
as moderately biohazardous by the
If one argues that because FeLV ‘and FeSV are included in the moderately group of hazardous agents by the National Cancer Institute (N.C.I.), they should be considered to be possible humanpathogens. This is a double argument, however, because placing of FeLV and FeSV in the moderately biohazardous group by N.C.I. was done on the basis of info~ation presented above. 4.
Standard Epidemiology methods are not adequate to study chronic disease
The low rate of leukemia in people makes it almost impossible to set up adequate epidemiologic studies to show a negative relationship of FeLV and human leukemia. Studies of double stranded DNA homology to find footprints of feline oncorna virus in human tissue would help determine if FeLV is related to human leukemia or chronic diseases,but so far no connection has been demonstrated.33
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The Yaba Tumor Virus is the only known animal tumor virus which has on rare occasion caused h= disease (but not malignanq) .4 It has little practical importance as a humanpathogen. There is no evidence that other animal tumor viruses are agents of hxsnandisease. Nevertheless, euthanasia for cats infected with FeLV has been reccsmnendedbecause they ‘may” carry human disease agents. This recoanner&tion seems to be arbitrarily directed at cats, because similar reasoning could also be applied to the poultry and cattle oncorna viruses that also infect heterospecies and, therefore, “might” cause human disease.S4,33 To be consistent we also shouldn’t have contact with these species or eat meat, eggs, or milk because such contact might present a “possible” public health hazard. Even if we became a vegetable-eating society and had no contact with animals, we still would have problems with “possible” tumor inducing pathogens of hm origin. The parallel could be drawn further to recormnendisolation of humans infected with human adenoviruses strains 12 or 18 because these are horizontally transmitted and when injected in hamsters cancers are readily produced.10 Who in our Public Health Service, however, would advocate the isolation of humans infected with adenoviruses (a ubiquitous class of viruses)? One could speculate that human adenovirus may cause disease. Suggestions for control of animal tumor viruses on the basis of hypothetical arguments do not supply sufficient evidence to institute test and euthanasia measures in our cat populations. It is only possible to make firm recommendations for control of zoonotic diseases when the pathogenesis of infectious agents are fully understood. Since there is no scientific evidence_ the FeLV causes human disease, one should not reccpmnendeuthanasia of an FeLV infected cat on the basis that it “may” cause human disease, however, it has not been proved they don’t. Investigations should continue to seek FeLV “footprints” in heterospecies tissue. To date, FeLV double stranded DNA homology studies have been negative, but this is a new approach and additional studies are needed before definitive statements are made. Most cats are infected with another oncorna virus referred to as IU~-114.~6 This virus is passed endogenously from generation to generation, but it is only expressed as a mature virus in heterospecies cells. It has been postulated that RD-114 originated from an endogenous old world monkey type-C virus and wa then horizontally transmitted to an ancester of the domestic cat .39 RD-114 grows very well on hunan cells, although its biological role is not known either in cats or been one of the viruses used in pioneer studies of ~~t~on~5S~7, 38
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Present evidence &es not support a public health role for FeLV, FeSV or for RD-114. Basic biological research of these agents and the possible relationship to human disease should be continued, but misplaced emotionalism about our public health should not lead to actions such as recmding that infected cats be killed because the “may” cause humandisease.
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THERIOGENOLOGY
TABLE I - Summaryof TumorVirus Isolations DATE
lI_WR
INVESTIGATOR
1908
Fowl leukemia
Ellermn and Bang
1911 1911 1920 1932
Fowl sarcoma Rabbitmyxomatosis Bovinepapilloma
Moses
1932 1933 1936 1938 1951 1951 1953 1953 1955 1958 1961 1962
Rous
Canineoralpapilloma Rabbitfibroma Rabbitpapilloma Mousemammarycarcinoma Frog kidneycarcinoma Equinepapilloma Mouse leukemia
Squirrelfibroma Polyoma
Magalhaes DeMonbreun and Goodpasture Shape Shope Bittner Lucke Cook and Olson Gross Kilham,Kermanand Fisher Stewardand Eddy - Gross
Deer fibroma Yaba tumorvirus SV-40 Human adenovimses (Tumorsin hamsters)
Shope,Mongold,et al. Bearcroft Sweet Trentin
1963
Marek'sdisease (Avianlymphoidtumors)
Biggsand Payne
1964 1965 1967
Felineleukemia
Jarret,et al.
Mouse sarcoma Guineapig leukemia
Moloney;Kirsten;Harvey
1968 1969 1971 1972 ?
Felinefibrosarcoma Bovineleukemia Simiansarcoma Gibbonape leukemia Hman CancerViruses
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1976
Opler Synderand Theilen Olson,Miller,et al. Theilen,Deinhardt, et al. Kawakami,et al.
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THERIOGENOLOGY
TABLEII - EXAMPLESOFCANCERCALJSED BYJJNAVIRUSES VIRUS 1.
NEOPLASM 1. Myxomatosis of rabbits.
Pox-likeviruses
2. Fibromasof rabbitsand squirrels. of man and subhuman 3. Histiocytomas primates. 2.
of man, rabbits,dogs, 1. Papillomas cattleand horses. Experimentally inoculated bovinepapillomavirus causessolidtumorsof hamstersand braintumorsof rabbitsand calves.
Papovaviruses
2. Solidtumorsof hamsters. 3. Solidtumorsof mastomys. 4. Fibromasof deer. 3. Herpesviruses
1.
Luckefrog kidneyadenocarcinoma.
2. Marek'sdiseaseof poultry. neoplasmsin non3. Lymphoreticular humanprimates. 4. Possiblecauseof Burkitt's lymphomaof childreninfectious mononucleosis and nasalpharyngeal cancer. 4. Humanadenoviruses
338
1. Solidtumorsin hamsters.
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1976 VOL. 6 NO. 2-3
1.
Oncorna
1.
Leukemia of mice, fowl,, guinea pigs, cats and primates.
2.
Adenocarcinoma of kidney and osteopetrosis of poultry.
3.
Osteogenic
4.
Sarcoma of fowl and mice. a.
Solid txanors of marmosets.
b.
Brain tumors of rabbits, puppies, and subhumanprimates.
5.
Manmarytumors of mice.
6.
Sarcoma of cats. a.
7.
AUGIJST-SEPTEMBER
1976
sarcomas of mice.
Solid tumors of cats, dogs, rabbits, rats, sheep fetuses, sheep and nonhm primates.
Simian leukemia and sarcoma. a.
Sarcoma in woolly monkey.
b.
Leukemia in gibbon apes.
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THERIOGENOLOGY
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Gardner,M. CurrentInformation of Felineand Canine Cancersand relationship or Lack of Relationships to HumanCancer. J. Nat. CancerInst.46:281-290(1971).
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