Veterinary Research Communications, 5 (1981) 117--126 117

Elsevier Scientific Publishing Company, Amsterdam -- Printed in The Netherlands

THE ZOONOTIC POTENTIAL OF BOVINE LEUKEMIA VIRUS

M. J. BURRIDGE
Department of Preventive Medicine, College of Veterinary Medicine,
U n i v e r s i t y of F l o r i d a , G a i n e s v i l l e , Florida 32610 (U.S.A.)
(Accepted i0 September 1981)

ABSTRACT
Burridge, M. J . , 1981. The zoonotic potential of bovine leukemia v i r u s .
Vet. Res. Commun., 5: 117-126.
Many workers have investigated the p o s s i b i l i t y that bovine leukemia
v i r u s (BLV) might be transmissible to man. The epidemiological studies
were designed to examine for associations between human leukemia and a
rural environment, c a t t l e farming, v e t e r i n a r y a c t i v i t i e s , or bovine leu-
kosis. The serological studies were used to test serum samples from human
cancer patients and from persons with potential occupational exposure to
BLV, among others, f o r evidence of BLV antibodies. A l l these studies are
c r i t i c a l l y reviewed. I t is concluded that there is no epidemiological or
serological evidence from human studies to indicate that BLV can i n f e c t
man.

INTRODUCTION
Bovine leukemia v i r u s (BLV) is causally associated with enzootic bovine
leukosis (Mussgay and Kaaden, 1978) and thus with adult bovine lymphosar-
coma, one of the more common neoplastic diseases of c a t t l e . The p o s s i b i l i t y
that the v i r u s might be associated with human disease had been raised be-
cause: ( i ) man has close occupational contact with c a t t l e ; (ii) BLV is
r e a d i l y transmitted h o r i z o n t a l l y between c a t t l e (Piper et a l . , 1979);
(iii) BLV r e p l i c a t e s in human c e l l s in c u l t u r e ( D i g l i o and Ferrer, 1976);
( i v ) v i r u s - l i k e p a r t i c l e s have been found in milk of cows from a herd with
a high incidence of bovine leukosis (Dutcher et a l . , 1964); (v) 2 of 6
chimpanzees fed from b i r t h on unpasteurized milk from cows infected with
BLV died with erythroleukemia (McClure et a l . , 1974); and ( v i ) 8 chimpan-
zees inoculated with cultured BLV developed antibodies to the v i r u s 6-15
weeks l a t e r that persisted for more than 18 months even though BLV i t s e l f
was never recovered from any of the chimpanzees (Van Der Maaten and M i l l e r ,
1976, 1977).
Results of two recent studies ( B l a i r and Hayes, 1980; Donham et a l . ,
1980) have created a renewed i n t e r e s t in the zoonotic potential of BLVo
Firstly, B l a i r and Hayes conducted a survey of m o r t a l i t y among v e t e r i n a r i a n s

0165-7380/81/0000--0000/$02.50 9 1981 Elsevier Scientific Publishing Company

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and compared the causes of death from 1966 to 1977 among 1,551 white male
v e t e r i n a r i a n s to an expected d i s t r i b u t i o n based upon the general U.S. popu-
l a t i o n ( B l a i r and Hayes, 1980). They found a s i g n i f i c a n t l y higher (P <
0.01) m o r t a l i t y from leukemia and Hodgkin's disease among v e t e r i n a r i a n s .
They suggested that t h i s increased m o r t a l i t y from lymphoid cancer might be
related to the e f f e c t s of i o n i z i n g r a d i a t i o n f o l l o w i n g inadequate use of
X-ray protective equipment and excessive use of hand-held fluoroscopes.
However, since the increased m o r t a l i t y was p r i m a r i l y among v e t e r i n a r i a n s
in c l i n i c a l practice, the authors cautioned that the zoonotic potential
of animal viruses should be considered. Secendly, the r e s u l t s from an epi-
demiological study of human leukemia in lowa indicated a p o s i t i v e corre-
l a t i o n (P < 0.025) between acute lymphoid leukemia in male persons and
c a t t l e density, and an additional p o s i t i v e r e l a t i o n s h i p between counties
with a high incidence of acute lymphoid leukemia in man and the presence
of d a i r y herds affected with bovine lymphosarcoma (Donham et a l . , 1980).
The r e s u l t s of these two studies and the theory proposed by Donham et al.
(1980) that c a t t l e and perhaps bovine lymphosarcoma are major a g r i c u l t u r a l
variables associated with human lymphoid leukemia, have renewed speculation
that BLV might be associated in some way with leukemia or other diseases of
man. This review w i l l c r i t i c a l l y evaluate the many epidemiological and
serological studies that have been used to i n v e s t i g a t e the zoonotic poten-
tial of BLV. Previous reviews of some of the public health aspects of BLV
i n f e c t i o n have been w r i t t e n by Burridge (1979), Caldwell (1979), and Ferrer
(1980).
Studies designed to i n v e s t i g a t e a possible zoonotic r e l a t i o n s h i p between
bovine leukosis and human disease started before the discovery of the BLV
in 1969 ( M i l l e r et a l . , 1969) and the subsequent development of serological
tests. Consequently, the e a r l i e r workers r e l i e d upon epidemiological
methods. Since some of them were the f i r s t to suggest a possible l i n k
between enzootic bovine leukosis (and, by inference, BLV) and human leukem-
i a , i t is p e r t i n e n t to discuss f i r s t the r e s u l t s of these studies.

HUMAN LEUKEMIA AND A RURAL ENVIRONMENT

Some of the e a r l i e r epidemiological studies on human leukemia were de-
signed to examine f o r r e l a t i o n s h i p s between the disease and general environ-
mental factors. Analysis of data from Denmark (Clemmesen et a l . , 1952),
the United States (Mancuso et a l . , 1955; Meadors, 1956; Levin et a l . , 1960;
Githens et a l . , 1965; Stark and O l e i n i c k , 1966), and Great B r i t a i n (Stewart
et a l . , 1958; Knox, 1964) a l l showed that human leukemia was not more common
in rural i n h a b i t a n t s . In f a c t , the r e s u l t s of three of the studies
 119

(Stewart et a l . , 1958; Knox, 1964; Githens et a l . , 1965) showed a s i g n i f i -

cantly higher (P < 0.02) frequency of cases in urban areas than in rural
areas. These reports indicated that human leukemia was, in general, more
common in an urban environment, giving no evidence f or an association be-
tween the disease and enzootic bovine leukosis~

HUMAN LEUKEMIA AND CATTLE FARMING

A 1964 review paper stated that the leukemia m o r t a l i t y rate f o r 40-60
year-old men employed in farming in Nebraska was more than twice the
expected age-specific rate f o r that occupational group (Lemon, 1964). At
the same time, reports from Africa had mentioned a possible l i n k between
c a t t l e and human cancer; i t had been suggested that the high incidence and
l i m i t e d geographical d i s t r i b u t i o n of B u r k i t t ' s lymphoma might be due to a
r e l a t i o n s h i p with a v i r a l disease of c a t t l e (O'Conor, 1961). (However,
there is now strong evidence to implicate Epstein-Barr virus in the cause
of B u r k i t t ' s lymphoma (de-The et a l . , 1978)). Also, three cases of leu-
kemia/lymphoma had an East African slaughterhouse as a common l i n k , with
two of the cases and the father of the t h i r d employed at that slaughter-
house ( H e l l e r and Roubenoff, 1961). These reports led to speculation that
c a t t l e might be involved in the cause of human cancers.
Some i n v e s t i g a t o r s examined clusters of cases of human leukemia in a
given v i c i n i t y because such clusters represented a s i g n i f i c a n t increase
over the expected incidence of the disease. A German study revealed a p a i r
of leukemia cases in a f a t h e r and son, both of whom were employed in dairy
farming (Wisniewski and Weinreich, 1966). Another study was of an adult
c l u s t e r of leukemia cases around a v i l l a g e in Wisconsin over a four-year
period (Bartsch et a l . , 1975). That c l u s t e r represented a greater than
20-fold increase in the expected frequency of the disease f o r that popula-
tion. The authors speculated that the cases might have been related to
enzootic bovine leukosis because the v i l l a g e was located in dairy-farming
country and some of the patients had e i t h e r worked in or l i v e d near the
local creamery. Consequently, they had sera from two surviving p a t i e n t s ,
23 r e l a t i v e s , and the 20 creamery employees tested f o r antibodies to BLV;
a l l serum samples were negative. These unusual clusters of leukemia cases
in rural populations are uncommon, and none has been shown to be associated
with BLV.
A number of s t a t i s t i c a l studies have been designed to inv e s t igat e the
possible association of c a t t l e farming to human leukemia. A California
study examined the m o r t a l i t y risk from various diseases in farm residents,
and the authors found no s i g n i f i c a n t l y increased risk of death from leu-
120

kemia (Fasal et a l . , 1968). Analysis of a more recent study from Sweden

showed no association between human leukemia and exposure to c a t t l e in a
farming community (Kvarnfors et a l . , 1975). These negative r e s u l t s are in
contrast to those of other i n v e s t i g a t o r s . A case-control study in Oregon
and Washington State demonstrated a s i g n i f i c a n t (P < 0.05) association be-
tween farming and death from leukemia, with p o u l t r y farmers showing a par-
ticularly high frequency of the disease (Milham, 1971). The f i n d i n g s from
a Polish study of data on male patients at one c l i n i c , showed leukemia
s i g n i f i c a n t l y more co~lon (P < 0 . 0 0 1 ) in those having occupational contact
with c a t t l e , such as farmers, butchers and tanners ~leksandrowicz, 1968);
evaluation of t h i s r e s u l t is impossible because the author did not give
d e t a i l s of his i n v e s t i g a t i v e methods. An i n v e s t i g a t i o n of human leukemia
in a Minnesota county resulted in the demonstration of a higher than ex-
pected number of patients to be farmers (Linos et a l . , 1978); the v a l i d i t y
of t h i s f i n d i n g is in doubt since c a l c u l a t i o n of the expected number did
not include adjustment for the age d i s t r i b u t i o n of the study population.
Furthermore, the f i n d i n g s of a follow-up study by the same authors (Linos
et a l . , 1980) f a i l e d to demonstrate excess r i s k of leukemia f o r farmers or
persons l i v i n g on farms in the same Minnesota county. A study of leukemia
among Nebraska farmers showed increased r i s k (P < 0.05) of lymphatic
leukemia in those from counties with large numbers of c a t t l e ( B l a i r and
Thomas, 1979). F i n a l l y , a d e s c r i p t i v e epidemiological study of leukemia in
Iowa demonstrated a p o s i t i v e c o r r e l a t i o n (P < 0.025) between acute
lymphoid leukemia in male persons and c a t t l e density, with the r e l a t i o n s h i p
greater for dairy c a t t l e than f o r beef c a t t l e (Donham et a l . , 1980). The
relevance of these c o n f l i c t i n g f i n d i n g s to the cause of human leukemia is
impossible to evaluate. The weakness of some of the published reports have
been mentioned. In others, serious biases were present, e s p e c i a l l y in those
studies considering occupation on death c e r t i f i c a t e s (Fasal et a l . , 1968;
Milham, 1971; Linos et a l . , 1978; B l a i r and Thomas, 1979); information from
such v i t a l s t a t i s t i c s may be misleading since i t often r e f l e c t s the occupa-
t i o n at death rather than the occupation of the person at the time of ac-
q u i s i t i o n of the disease.

HUMAN LEUKEMIA AMONGVETERINARIANS

A number of i n v e s t i g a t o r s have examined the causes of death among U.S.
veterinarians. Three studies were of m o r t a l i t y in v e t e r i n a r i a n s in C a l i -
f o r n i a (Fasal et a l . , 1966), Missouri (Botts et a l . , 1966), and I l l i n o i s
(Schnurrenberger et a l . , 1977). None of the r e s u l t s from these studies
showed a s i g n i f i c a n t increase in r i s k of death from leukemia w i t h i n members
 121

of the v e t e r i n a r y profession. I n contrast, those from a l a r g e r national

study demonstrated a s i g n i f i c a n t l y higher (P < 0 . 0 1 ) m o r t a l i t y from leukem-
ia among v e t e r i n a r i a n s than among the general U.S. population, with the
excessive m o r t a l i t y p r i m a r i l y among v e te r i n a r i ans in c l i n i c a l practice
( B l a i r and Hayes, 1980). I n t e r p r e t a t i o n of these c o n f l i c t i n g findings w i l l
have to await more d e t a i l e d i n v e s t i g a t i o n s .

HUMAN LEUKEMIA AND BOVINE LEUKOSIS

A number of reports have indicated geographical clustering of cases of
human leukemia and bovine leukosis. Two farms in the Latvian and Estonian
Republics of the USSR had cases of both human and bovine leukosis within a
f i v e - y e a r period (Khokhlova and Rakhmanin, 1970). Another report discussed
a c l u s t e r of human cases around a d a i r y farm in the United States that was
infected with bovine leukosis (Heath, 1970). This i n v e s t i g a t o r found that
over a lO-year period two farm employees and two farm neighbors a l l devel-
oped leukemia of the same type. While these geographical clusters of cases
found in man and c a t t l e are i n t e r e s t i n g , they have not been s u f f i c i e n t l y
common to conclude that t h e i r occurrence was due to anything more than
chance.
Two Polish studies reported an association between human leukemia and
bovine leukosis. In one study, the blood of c a t t l e raised by patients at
one c l i n i c was examined (Aleksandrowicz, 1968). I t was found that a " s i g -
n i f i c a n t l y " higher lymphocytosis occurred in c a t t l e raised by patients with
two of four types of leukemia than in those raised by a group of " h e a l t h y " ,
but undefined, controls. The author of another study reported a c o r r e l a t i o n
(P < 0.02) between geographical frequency of bovine leukosis and human leu-
kemia (Wolska, 1968). I t is impossible to evaluate the Polish findings be-
cause n e i t h e r paper gave adequate d e t a i l s of i t s i n v e s t i g a t i v e methods and
ne ith e r author confirmed t h e i r diagnosis of bovine leukosis h i s t o l o g i c a l l y .
A recent i n v e s t i g a t i o n in lowa demonstrated a p o s i t i v e r e l a t i o n s h i p
between counties with a high incidence of acute lymphoid leukemia and the
presence of dairy herds affected with bovine lymphosarcoma (Donham et a l . ,
1980). Affected herds were i d e n t i f i e d through a search of the records of
the lowa Veterinary Diagnostic Laboratory and of the lowa State University
College of Veterinary Medicine and through a mail survey of p r a c t i c i n g
veterinarians, However, no apparent e f f o r t was made to ascertain i f un-
affected herds were t r u l y unaffected or j u s t had not been reported or recog-
nized as having cases of bovine lymphosarcoma. Consequently, t h i s " p o s i t i v e
r e l a t i o n s h i p " cannot be considered to have any s c i e n t i f i c v a l i d i t y .
The results of other studies f a i l e d to indicate a r e l a t i o n s h i p between
human cancer and bovine leukosis. Scandinavian workers have compared the
122

geographical d i s t r i b u t i o n of human leukemia and bovine leukosis on a nation-

al level in Denmark (Jensen, 1968) and Sweden (Henricson and Ringertz,
1968), and both groups found no association between t h e i r d i s t r i b u t i o n s . A
retrospective study conducted during 1960-70 in a rural county of Sweden
was carried out in order to compare households containing cases of human
leukemia with a l l other households located 5• km d i s t a n t (Kvarnfors et
al., 1975). The prevalence of bovine leukosis, as determined from d e t a i l e d
slaughterhouse records and from the Central Bovine Leukosis Registry, was
not s i g n i f i c a n t l y d i f f e r e n t between the case and control households. A
prospective study was designed to i n v e s t i g a t e cancer among persons l i v i n g
in Michigan on d a i r y farms where bovine leukosis had been confirmed h i s t o -
l o g i c a l l y ( P r i e s t e r et a l . , 1970). The human m o r t a l i t y from 1961-69 in
farm households in the bovine-leukosis group was compared with that of
households in the same county matched f o r herd size but with no reported
cases of bovine leukosis. There was no s i g n i f i c a n t association between
exposure to c a t t l e with bovine leukosis and the subsequent development in
man of f a t a l cancer, including leukemia.

BOVINE LEUKEMIA VIRUS AND HUMAN INFECTION

Recent serological studies have been conducted in order to examine
human serum samples f o r evidence of BLV antibodies (Olson, 1974; Bartsch
et a l . , 1975; Gilden et a l . , 1975; Olson and Baumgartener, 1975; Caldwell
et a l . , 1976; Donham et a l . , 1977; Van Der Maaten and M i l l e r , 1977; Res-
sang, 1977; Olson and D r i s c o l l , 1978; Caldwell, ~979). In these ten
studies, a t o t a l of 386 human cancer p a t i e n t s , 1082 persons free of cancer,
and 593 persons with p o t e n t i a l occupational exposure to BLV or BLV-infected
c a t t l e were tested. The cancer patients included 200 i n d i v i d u a l s with
lymphoid neoplasia. The persons free of cancer included 416 r e l a t i v e s of
cancer p a t i e n t s , 410 healthy i n d i v i d u a l s , 197 non-cancer p a t i e n t s , 33 of -
f i c e workers, 20 creamery employees, and 6 animal caretakers. The f i n a l
group contained 271 residents of farms with BLV-infected c a t t l e (including
26 who r o u t i n e l y drank unpasteurized milk from t h e i r cows), 256 v e t e r i n a r -
ians, 63 employees from BLV research l a b o r a t o r i e s , and 3 meat inspectors.
Not one of these studies found a single i n d i v i d u a l with antibodies to BLV,
even though most examined people n a t u r a l l y exposed to the virus. A variety
of serological tests were employed, including the agar gel immunodiffusion
t e s t with e i t h e r an i n t e r n a l p23/p24 or a glycoprotein antigen, the com-
plement f i x a t i o n t e s t , the i n d i r e c t fluorescent antibody t e s t , and the
radioimmunoassay.
I f i t were possible f o r BLV to be transmitted to human beings, i t would
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appear that adequate opportunity would have occurred through d i r e c t contact

with infected c a t t l e , through contact with bovine carcasses, or through
ingestion of raw milk. However, people occupationally exposed to infected
c a t t l e and carcasses and persons drinking raw milk from infected animals
have been u n i v e r s a l l y negative f o r antibodies to BLV. The same is true f o r
research workers with p o t e n t i a l exposure to BLV. Therefore, there is strong
serological evidence to indicate that BLV is not transmissible to man.
In two reports i t has been suggested that there is the p o s s i b i l i t y of
a transmissible f a c t o r from c a t t l e with lymphosarcoma to man. Romanian i n -
vestigators found antibodies to a virus "associated with bovine lymphosar-
coma" in 34 out of 60 dairy-farm workers compared with two out of 56 con-
t r o l s (Nastac et a l . , 1974). The results of an I s r a e l i study showed that
antibody that attached to the surface of bovine lymphoid tumor c e l l s in the
sera of 13 of 18 people with lymphomalignancies and f i v e of six i n d i v i d u a l s
working in a BLV research l a b o r a t o r y , but not in the sera of i i persons with
no d i r e c t contact with c a t t l e (Trainin et a l . , 1976). The relevance of
these two studies to the zoonotic p o t e n t i a l of BLV is impossible to deter-
mine. The Romanian report did not define the virus studied, and the I s r a e l i
report gave scant mention to i t s materials and methods, including a complete
lack of d e t a i l s of the immunological reagents used. In the absence of f o l -
low-up studies, the v a l i d i t y of these two reports must be considered doubt-
ful.

BOVINE LEUKEMIA VIRUS AND CHIMPANZEES

The s u s c e p t i b i l i t y of subhuman primates to BLV i n f e c t i o n has been ex-
amined experimentally in two studies in the hope that the results would
throw some l i g h t on the zoonotic p o t e n t i a l of BLV. The f i r s t study in-
volved 12 chimpanzees that were removed from t h e i r mothers at b i r t h (McClure
et a l . , 1974). Six were fed unpasteurized milk from cows infected with BLV,
whereas the other six were fed on a commercially-prepared i n f a n t formula.
Two of the milk-fed chimpanzees developed Pneumocystis c a r i n i i pneumonia
and erythroleukemia, and died at 34 and 45 weeks of age a f t e r a f i v e to s i x -
week i l l n e s s . A recent i n q u i r y revealed that the remaining ten animals
continue healthy, and none have contracted leukemia (Caldwell, 1979). Anti-
bodies to BLV were not detectable by immunofluorescence in any of the 12
chimpanzees. Electron microscopic studies f o r the presence of BLV com-
menced a f t e r the two deaths, and a l l I0 surviving animals were negative f o r
BLV.
The second study involved the i n o c u l a t i o n of eight chimpanzees with
cultured BLV (Van Der Maaten and M i l l e r , 1976, 1977). All eight chimpanzees
124

developed s p e c i f i c antibody responses to both the i n t e r n a l polypeptide and

glycoprotein antigens of BLV in the agar gel immunodiffusion test 6-15 weeks
after inoculation. The serological responses persisted f o r more than 18
months, but BLV was never isolated from any of the animals. Serological
responses of t h i s duration indicate continued synthesis of v i r a l antigens,
suggesting that v i r a l information persisted in the chimpanzees. This study
provides proof of the immunological responsiveness to BLV of a primate
species c l o s e l y related to man. In contrast, the t o t a l l y negative r e s u l t s
obtained from the human serological studies already reviewed suggest that
man is not s i m i l a r l y responsive to BLV.
The r e s u l t s of the l a t t e r study raise questions about the former study.
I f the erythroleukemia found in two chimpanzees developed as the d i r e c t
r e s u l t of BLV i n g e s t i o n , why did none of the six milk-fed chimpanzees devel-
op antibodies to BLV, f o r i t has been shown by Van Der Maaten and M i l l e r
(1976, 1977) that chimpanzees are immunologically responsive to BLV a n t i -
gens? Because of t h i s anomaly and the lack of i s o l a t i o n of BLV from any
animal, the v a l i d i t y of the association of erythroleukemia in chimpanzees
with BLV must be considered very questionable.

CONCLUSIONS
There is no epidemiological or serological evidence from human studies
to indicate that BLV can i n f e c t man. Consequently, there is no reason to
take any s p e c i f i c action with BLV-infected c a t t l e from the public health
standpoint.

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