ArticlePDF Available

Herbicide exposure and the risk of transitional cell carcinoma in Scottish Terriers

Authors:

Abstract and Figures

To determine whether exposure to lawn or garden chemicals was associated with an increased risk of transitional cell carcinoma (TCC) of the urinary bladder in Scottish Terriers. Case-control study. 83 Scottish Terriers with TCC (cases) and 83 Scottish Terriers with other health-related conditions (controls). Owners of study dogs completed a written questionnaire pertaining to exposure to lawn or garden chemicals during the year prior to diagnosis of TCC for case dogs and during a comparable period for control dogs. The risk of TCC was significantly increased among dogs exposed to lawns or gardens treated with both herbicides and insecticides (odds ratio [OR], 7.19) or with herbicides alone (OR, 3.62), but not among dogs exposed to lawns or gardens treated with insecticides alone (OR, 1.62), compared with dogs exposed to untreated lawns. Exposure to lawns or gardens treated with phenoxy herbicides (OR, 4.42) was associated with an increased risk of TCC, compared with exposure to untreated lawns or gardens, but exposure to lawns or gardens treated with nonphenoxy herbicides (OR, 3.49) was not significantly associated with risk of TCC. Results suggest that exposure to lawns or gardens treated with herbicides was associated with an increased risk of TCC in Scottish Terriers. Until additional studies are performed to prove or disprove a cause-and-effect relationship, owners of Scottish Terriers should minimize their dogs' access to lawns or gardens treated with phenoxy herbicides.
Content may be subject to copyright.
1290 Scientific Reports: Original Study JAVMA, Vol 224, No. 8, April 15, 2004
SMALL ANIMALS/
EXOTIC
T
ransitional cell carcinoma (TCC) of the urinary
bladder is the most common cancer of the urinary
tract in dogs, with 1.2% to 2% of all cancers in dogs being
TCCs of the urinary bladder.
1
While the incidence of
TCC in the pet dog population is unknown, the preva-
lence of TCC in dogs examined at veterinary teaching
hospitals in North America increased by > 600% between
1975 and 1995.
2
In that study,
2
the risk that Scottish
Terriers would develop TCC was approximately 18 times
the risk of mixed-breed dogs. Other breeds with a signif-
icantly increased risk of TCC, compared with mixed-
breed dogs, were the Shetland Sheepdog (4.5 times),
Wirehaired Fox Terrier (3.2 times), and West Highland
White Terrier (3.0 times). This pattern of increased risk
in terriers suggested a genetic predisposition.
The pathogenesis of TCC in dogs is probably multi-
factorial, involving both genetic and environmental
determinants. A previous case-control study
3
of pet dogs
of a wide variety of breeds found that TCC risk was
unrelated to side-stream cigarette smoke and household
chemical exposures, but was significantly increased in a
dose-response manner in dogs exposed to topical insec-
ticides, particularly flea and tick dips. This increased
risk of TCC was further enhanced in overweight or
obese dogs and in dogs living in close proximity to
another potential source of insecticides, namely a marsh
that had been sprayed for control of mosquitoes.
In 1991, an association was reported between an
increased risk of malignant lymphoma in pet dogs and
the owner’s use of 2,4-dichlorophenoxyacetic acid
(2,4-D) herbicides in and about the home.
4
In this
study, dogs belonging to owners that applied 2,4-D to
their lawn or employed commercial lawn care compa-
nies to treat their yards 4 times/y had twice the risk
of developing lymphoma, compared with dogs exposed
to nontreated lawns. These findings were later chal-
lenged by a Chemical Industry Task Force,
5
and
reanalysis of the original data, funded by an industry
task force, failed to find a significant association
between 2,4-D use and malignant lymphoma or a dose-
response relationship.
6
A subsequent study,
7
however,
demonstrated that dogs living in and around a resi-
dence recently treated with 2,4-D absorbed measurable
amounts of the herbicide for several days after applica-
tion. For example, dogs exposed to treated lawns dur-
ing the preceding 7 days were 50 times as likely to have
urine 2,4-D concentrations > 50 µg/L as were dogs that
had been exposed to treated lawns > 7 days previously.
Phenoxy herbicides in general, and 2,4-D specifical-
ly, are among the most widely used chemicals in con-
temporary agriculture, and 2,4-D has been commercial-
ly available throughout the world for approximately 55
years.
8
The most convincing evidence suggesting that
phenoxy herbicides are human carcinogens arises from
epidemiologic studies of patients with non-Hodgkin’s
lymphoma.
9,10
However, lifetime cancer bioassays of rats,
mice, and dogs have generally concluded that there was
a lack of evidence of carcinogenicity, at least under
experimental conditions.
11
The recent finding that
Herbicide exposure and the risk
of transitional cell carcinoma
of the urinary bladder in Scottish Terriers
Lawrence T. Glickman, VMD, DrPH; Malathi Raghavan, DVM, PhD;
Deborah W. Knapp,
DVM, MS, DACVIM; Patty L. Bonney; Marcia H. Dawson, DVM
Objective—To determine whether exposure to lawn
or garden chemicals was associated with an increased
risk of transitional cell carcinoma (TCC) of the urinary
bladder in Scottish Terriers.
Design—Case-control study.
Animals—83 Scottish Terriers with TCC (cases) and
83 Scottish Terriers with other health-related condi-
tions (controls).
Procedure—Owners of study dogs completed a writ-
ten questionnaire pertaining to exposure to lawn or
garden chemicals during the year prior to diagnosis of
TCC for case dogs and during a comparable period for
control dogs.
Results—The risk of TCC was significantly increased
among dogs exposed to lawns or gardens treated
with both herbicides and insecticides (odds ratio [OR],
7.19) or with herbicides alone (OR, 3.62), but not
among dogs exposed to lawns or gardens treated
with insecticides alone (OR, 1.62), compared with
dogs exposed to untreated lawns. Exposure to lawns
or gardens treated with phenoxy herbicides (OR,
4.42) was associated with an increased risk of TCC,
compared with exposure to untreated lawns or gar-
dens, but exposure to lawns or gardens treated with
nonphenoxy herbicides (OR, 3.49) was not signifi-
cantly associated with risk of TCC.
Conclusions and Clinical Relevance—Results sug-
gest that exposure to lawns or gardens treated with
herbicides was associated with an increased risk of
TCC in Scottish Terriers. Until additional studies are
performed to prove or disprove a cause-and-effect
relationship, owners of Scottish Terriers should mini-
mize their dogs’ access to lawns or gardens treated
with phenoxy herbicides. (
J Am Vet Med Assoc
2004;
24:1290–1297)
From the Departments of Veterinary Pathobiology (Glickman,
Raghavan) and Veterinary Clinical Sciences (Knapp, Bonney), School
of Veterinary Medicine, Purdue University, West Lafayette, IN 47907-
2027; and 3220 N County Rd 575 E, Danville, IN 46122-8689
(Dawson).
Supported in part by matching grants from the Scottish Terrier Club of
America and the American Kennel Club Canine Health Foundation.
Address correspondence to Dr. Glickman.
03-05-0231.qxd 3/25/2004 10:59 AM Page 1290
JAVMA, Vol 224, No. 8, April 15, 2004 Scientific Reports: Original Study 1291
SMALL ANIMALS/
EXOTIC
Scottish Terriers had a significantly increased risk of
TCC, compared with dogs of other breeds, afforded us
an opportunity to use a spontaneously occurring cancer
in an apparently genetically susceptible breed to test the
hypothesis that natural exposure to phenoxy herbicides
in general, and 2,4-D in particular, increases the risk of
TCC. Specifically, the purpose of the study reported here
was to determine whether exposure to lawn or garden
chemicals was associated with an increased risk of TCC
of the urinary bladder in Scottish Terriers.
Materials and Methods
Starting in June 2001, owners of Scottish Terriers with
TCC (cases) and Scottish Terriers with other health prob-
lems, including other cancers (controls), were recruited
through the Web site of the Scottish Terrier Club of America
and through the Purdue Comparative Oncology Program.
One of the authors (MHD) also contacted, by telephone or e-
mail, individual Scottish Terrier owners and veterinarians
known to be interested in Scottish Terriers. All potential par-
ticipants were told the study was designed to collect infor-
mation on potential risk factors for cancer, such as diet,
water, medical history, medications, chemical exposures, and
side-stream cigarette smoke. The specific study hypothesis
was not revealed to the participants or recruiters, and ques-
tions were asked about a variety of environmental exposures.
Case dogs were Scottish Terriers in which TCC was
diagnosed anytime after January 1, 1995. Dogs were includ-
ed in the study as case dogs only if the owner submitted writ-
ten proof of the diagnosis of TCC (ie, a histology report,
cytology report, or both). Only 1 dog from a household could
participate, even if TCC was diagnosed in > 1 dog in the
household.
Control dogs were Scottish Terriers that were > 6 years
old as of July 1, 1995, in which TCC had never been diag-
nosed (control dogs had to be > 6 years old because we
expected that few case dogs would be < 6 years old). In addi-
tion, dogs were included as control dogs only if they did not
have any history of urinary tract disease during the 2 years
prior to entry into the study or death. Only 1 dog per house-
hold could serve as a control dog, and control dogs could not
come from the same households as case dogs.
All case and control dogs enrolled in the study by
January 31, 2003, were included in the analyses. The Purdue
University Committee on Human Subjects approved all pro-
cedures used in this study by expedited review.
Owners of case and control dogs agreed to complete a writ-
ten questionnaire pertaining to the dog’s medical history and
exposure to household lawn or garden chemicals during the
year prior to diagnosis of TCC for case dogs and during a com-
parable period for control dogs (ie, during the year before death
or the year before entry into the study). A list of commonly used
household, lawn, and garden chemicals, including brand names
and active ingredients, was provided to the owners with the
mailed questionnaire. Owners were instructed to consult the list
to identify specific products they had used. Space was also pro-
vided for owners to write in the names of any commercial prod-
ucts they had used that were not included on the list. Owners
were asked how often (never, sporadic, seasonal, or year-round)
and the average number of times a year they used each product,
as well as who treated the lawn or garden. In addition to their
completed questionnaire, they were instructed to mail back the
labels for lawn products they applied or to contact the commer-
cial applicator for specific product information.
Types of lawn and garden pesticides used, determined on
the basis of owner responses and product labels, were charac-
terized as herbicides, insecticides, fungicides, algicides, acari-
cides, and molluscicides. A dog could possibly have been
exposed to > 1 pesticide type or to > 1 brand-name product
within each pesticide type. The active ingredient for each prod-
uct was determined from owner-provided information or on the
basis of trade name of the product, using the pesticide database
of the Office of Indiana State Chemist.
12
Because a single brand
could potentially contain > 1 active ingredient, exposure to > 1
herbicide was recorded, and each chemical was treated indepen-
dently. Herbicide exposure was further grouped by chemical
class as phenoxy acid, amino acid type, benzoic acid, dini-
troaniline, picolinic acid, benzonitrile, or chloracetamide.
13
Each
dog could potentially have been exposed to > 1 chemical class
of herbicides. If owners were uncertain as to what specific prod-
uct was used or if they provided incomplete label information,
the exposure was considered as being of unknown type.
Data were analyzed with standard epidemiologic soft-
ware.
14,a
Descriptive data were compared between case and con-
trol groups by use of χ
2
tests (categorical variables), indepen-
dent-samples t tests (normally distributed continuous vari-
ables), or Mann-Whitney tests (non-normally distributed con-
tinuous variables). Each potential risk factor was examined for
an association with TCC by means of univariate logistic regres-
sion
b
and the maximum likelihood method.
15,16
The association
between potential risk factors and TCC was expressed as an
odds ratio (OR) with 95% confidence intervals (CIs). A test for
a linear trend in the ORs was performed when appropriate.
14,c
Multivariate logistic regression was used to model the risk of
TCC for potential risk factors with a P value < 0.05 in univari-
ate analyses. The fit of multivariate models was determined by
use of the Pearson χ
2
and Hosmer and Lemeshow statistics.
17
Results
Eighty-three case and 83 control dogs were
enrolled in the study. Fifty-two (63%) of the case dogs
were dead at the time of enrollment in the study versus
10 (12%) control dogs. In 62 (74%) case dogs, the diag-
nosis of TCC was confirmed by means of histologic
evaluation of tissue samples. In the remaining 21 (26%)
dogs, the diagnosis was presumptive in that histologic
examination of tissue samples had not been performed.
In these dogs, the diagnosis was made on the basis of
results of microscopic examination of a needle aspirate
(12 dogs), cytologic examination of a urine sample (11
dogs), or cytologic examination of a bladder wash sam-
ple (1 dog). For 7 of these 21 dogs, diagnostic imaging
(6 dogs) and tumor antigen testing (1 dog) were per-
formed in addition to cytologic evaluation.
The most common health-related conditions affect-
ing control dogs at the time of the study were cancer (20
dogs; 24%), skin disease (18; 22%), parasitic infections
(16; 19%), idiopathic increases in hepatic enzyme activ-
ities (12; 14%), and scottie cramp (6; 7%).
Four (5%) control dogs had a history of urinary
tract disease that had been treated successfully at least
2 years prior to enrollment in the study. In contrast, 27
(33%) case dogs were reported to have had signs com-
patible with chronic urinary tract disease within 2
years prior to the diagnosis of TCC.
Mean ± SD ages at the time of enrollment in the
study for case and control dogs were 9.9 ± 2.0 years
and 9.1 ± 2.3 years, respectively; case dogs were sig-
nificantly (P = 0.01) older than control dogs. Thirty-
four (41%) case dogs were male, as were 34 (41%) con-
trol dogs. All but 4 (5%) case and 15 (18%) control
dogs had been neutered; a significantly (P = 0.04) high-
er proportion of control than of case dogs was sexual-
03-05-0231.qxd 3/25/2004 10:59 AM Page 1291
1292 Scientific Reports: Original Study JAVMA, Vol 224, No. 8, April 15, 2004
SMALL ANIMALS/
EXOTIC
ly intact. One hundred forty-eight dogs (89%) were
registered with the American Kennel Club.
Twenty (24%) case dog owners and 42 (51%) control
dog owners indicated that their dogs had not been
exposed to commonly used lawn or garden chemicals at
their homes (P < 0.001; Table 1). Forty-two (51%) case
and 15 (18%) control dogs had been exposed to herbi-
cides, and 33 case (40%) and 20 (24%) control dogs had
been exposed to insecticides. The 3 most common chem-
ical classes of herbicides that dogs in the study were
exposed to were phenoxy acids (34 [41%] case and 11
[13%] control dogs), represented by 2,4-D, 2-(4-chloro-2-
methyl) phenoxy propionic acid (MCPP), and 4-chloro-
2-methyl phenoxy acetic acid (MCPA); benzoic acids (20
[24%] case and 5 [6%] control dogs), represented by
dicamba; and amino acids (18 [22%] case and 9 [11%]
control dogs), represented by glyphosate. Many case and
control dogs were exposed to herbicides belonging to
more than 1 chemical class (Table 2). The owner of 1 con-
trol dog exposed to herbicides was not aware of the spe-
cific trade name or the common name of the herbicide
used on his lawn by a commercial lawn care company.
Host factors found in univariate logistic regression
analyses to be significantly associated with risk of TCC
included age, neutering status, coat color, body weight,
weight-to-height ratio, and having a first-degree rela-
tive with a history of TCC (Table 3). Univariate analy-
sis also revealed that risk of TCC was higher for dogs
with seasonal or year-round exposure to any lawn or
garden (whether treated or not), compared with dogs
with no or only sporadic exposure; for dogs with sea-
sonal or year-round exposure to a lawn or garden treat-
ed with a herbicide; and for dogs with seasonal or year-
round exposure to a lawn or garden treated with an
insecticide (Table 4). In addition, the risk of TCC for
dogs exposed to a lawn or garden treated with both a
herbicide and an insecticide was higher than the risk
for dogs exposed to a lawn or garden treated only with
a herbicide or only with an insecticide.
Risk of TCC was significantly higher for dogs
owned by individuals who used herbicides, regardless
of whether the herbicides were applied by the owner or
a commercial company (Table 5). The risk of TCC was
also higher when the herbicide was applied seasonally
or year round versus sporadically or never and when
the herbicide was applied more often. In addition, risk
of TCC was higher among dogs exposed to phenoxy
acid herbicides (compared with dogs not exposed) or
benzoic acid herbicides, but not among dogs exposed
to amino acid type herbicides or to other types of her-
bicides. In general, risk of TCC was higher among dogs
exposed to phenoxy acid herbicides or nonphenoxy
acid herbicides, compared with dogs exposed to lawns
or gardens to which no herbicides had been applied.
Two separate multivariate models were construct-
ed. One model used information for all dogs regardless
of whether the owners had reported access to a lawn or
garden, while the second model used information only
for those dogs reported to have had access to a lawn or
garden. Since the pattern of risk was similar for the 2
models, only results for dogs with access to lawns or
gardens were reported. Also, a separate multivariate
model was developed including information only for
confirmed cases of TCC. Since there was no apprecia-
ble difference between the models that included or
excluded presumptive cases, only the model including
all cases was reported. For all multivariate models,
information regarding history of TCC in a first-degree
relative was not included because this information was
missing for 59 (71%) case dogs and 39 (47%) control
dogs. Also, body weight was included in multivariate
models rather than weight-to-height ratio because
information on weight was missing for fewer dogs than
was information on height.
Table 1—Exposure to common lawn and garden chemicals
among 83 Scottish Terriers with transitional cell carcinoma (TCC)
of the urinary bladder (case dogs) and 83 Scottish Terriers with
other health problems (control dogs)
No. of case No. of control
Pesticide dogs (%) dogs (%)
None 20 (24) 42 (51)
Herbicide 42 (51) 15 (18)
Insecticide 33 (40) 20 (24)
Fungicide 4 (5) 1 (1)
Algicide 1 (1) 1 (1)
Molluscicide 1 (1) 0 (0)
Acaricide 1 (1) 0 (0)
Unknown or uncertain 7 (8) 12 (14)
Owners were asked to indicate exposure to household lawn or
garden chemicals during the year prior to diagnosis of TCC for case
dogs and during a comparable period for control dogs. Values in
each column do not add to 83 because some dogs were exposed to
1 type of pesticide.
Table 2—Exposure to various herbicide active ingredients
among 83 Scottish Terriers with TCC (case dogs) and 83 Scottish
Terriers with other health problems (control dogs)
No. of case No. of control
Active ingredient dogs (%) dogs (%)
None (not exposed to any
herbicides) 34 (41) 56 (67)
2,4-D* only 2 (2) 1 (1)
MCPA* only 3 (4) 0 (0)
Glyphosate only 5 (6) 1 (1)
Pendimethalin only 0 (0) 1 (1)
Halosulfuran methyl only 1 (1) 0 (0)
Alachlor only 0 (0) 1 (1)
2,4-D and MCPP* 3 (4) 0 (0)
2,4-D and MCPA 1 (1) 0 (0)
2,4-D and glyphosate 1 (1) 0 (0)
2,4-D and dicamba 0 (0) 1 (1)
2,4-D and triclopyr 1 (1) 0 (0)
MCPA and triclopyr 1 (1) 0 (0)
2,4-D, MCPP, and glyphosate 1 (1) 2 (2)
2,4-D, MCPP, and dicamba 7 (8) 1 (1)
2,4-D, MCPA, and glyphosate 2 (2) 2 (2)
MCPA, dicamba, and
pendimethalin 1 (1) 0 (0)
4 active ingredients 13 (16) 4 (5)
Unknown or uncertain 7 (8) 13† (16)
Owners were provided a list of commonly used lawn and garden
chemicals and asked to indicate what chemicals their dogs had
been exposed to during the year prior to diagnosis of TCC for case
dogs and during a comparable period for control dogs.
*Phenoxy acid herbicide class.
2,4-D = 2,4-Dichlorophenoxyacetic acid. MCPA = 4-Chloro-2-
methyl phenoxy acetic acid. MCPP = 2-(4-Chloro-2-methyl) phe-
noxy propionic acid.
†Active ingredient and trade name were unknown for type of her-
bicide used on 1 control dog.
03-05-0231.qxd 3/25/2004 10:59 AM Page 1292
JAVMA, Vol 224, No. 8, April 15, 2004 Scientific Reports: Original Study 1293
SMALL ANIMALS/
EXOTIC
Table 3—Results of univariate logistic regression analysis of host factors potentially associated with
risk of TCC in Scottish Terriers
No. of case No. of control OR
P
value
Factor dogs (%) dogs (%) (95% CI)
P
value for trend
Age (y) 0.003
4 to 8 13 (16) 35 (42) NA NA
8 to 11 41 (49) 27 (33) 4.09 (1.84–9.11) 0.001
11 29 (35) 21 (25) 3.72 (1.59–8.69) 0.002
Sex NA
Male 34 (41) 34 (41) NA NA
Female 49 (59) 49 (59) 1.00 (0.54–1.86) 1.00
Neutering status NA
Sexually intact 4 (5) 15 (18) NA NA
Neutered 79 (95) 68 (82) 4.36 (1.38–13.75) 0.01
Coat color NA
All or partly black 59 (71) 47 (57) NA NA
Not black* 23 (28) 36 (43) 0.51 (0.27–0.97) 0.04
Body condition NA
Optimum 56 (67) 58 (70) NA NA
Overweight 27 (33) 23 (28) 1.22 (0.62–2.37) 0.57
Height (tertiles†) 0.30
First 9 (11) 17 (21) NA NA
Second 21 (25) 31 (37) 1.28 (0.48–3.41) 0.62
Third 18 (22) 20 (24) 1.70 (0.61–4.76) 0.31
Weight (tertiles†) 0.04
First 23 (28) 35 (42) NA NA
Second 22 (27) 24 (29) 1.40 (0.64–3.05) 0.40
Third 33 (40) 23 (28) 2.18 (1.03–4.62) 0.04
Weight-to-height ratio (tertiles†) 0.02
First 11 (13) 28 (34) NA NA
Second 15 (18) 23 (28) 1.66 (0.64–4.31) 0.30
Third 21 (25) 17 (21) 3.14 (1.22–8.10) 0.02
Mating NA
Outcross or nonselective 10 (12) 24 (29) NA NA
Inbred or line bred 24 (29) 41 (49) 1.41 (0.58–3.43) 0.46
First-degree relative with TCC NA
No 8 (10) 30 (36) NA NA
Yes 16 (20) 14 (17) 4.29 (1.49–12.37) 0.007
Values in some categories may not add to 83 because of missing data.
*Includes brindle and wheaten coat colors. †Tertiles were sex specific.
OR = Odds ratio. CI = Confidence interval. NA = Not applicable.
Table 4—Results of univariate logistic regression analysis of potential associations between exposure
to lawn or garden chemicals and risk of TCC in Scottish Terriers
No. of case No. of control OR
Factor dogs (%) dogs (%) (95% CI)
P
value
Residence
Urban 13 (16) 16 (19) NA NA
Suburban 51 (61) 49 (59) 1.28 (0.56–2.94) 0.56
Rural or farm 19 (23) 18 (22) 1.30 (0.49–3.45) 0.60
Access to lawn or garden
(treated or nontreated)
None or sporadic 9 (11) 19 (23) NA NA
Seasonal or year-round 74 (89) 64 (77) 2.44 (1.03–5.77) 0.04
Access to herbicide-treated
lawn or garden
None or sporadic 37 (45) 57 (69) NA NA
Seasonal or year-round 39 (47) 14 (17) 4.29 (2.05–8.97) 0.001
Access to insecticide-treated
lawn or garden
None or sporadic 47 (57) 56 (68) NA NA
Seasonal or year-round 29 (35) 15 (18) 2.30 (1.11–4.80) 0.03
Treatment of lawn or garden
to which dog had access
None 20 (24) 42 (51) NA NA
Insecticide only 13 (16) 14 (17) 1.95 (0.77–4.91) 0.16
Herbicide only 22 (27) 9 (11) 5.13 (2.00–13.15) 0.001
Both insecticide and herbicide 20 (24) 6 (7) 7.00 (2.43–20.13) 0.001
Exposure to insecticides indoors
No 39 (47) 49 (59) NA NA
Yes 42 (51) 33 (40) 1.60 (0.86–2.97) 0.14
Owners were provided a list of commonly used lawn and garden chemicals and asked to indicate what
chemicals their dogs had been exposed to during the year prior to diagnosis of TCC for case dogs and dur-
ing a comparable period for control dogs.
See
Table 3 for key.
03-05-0231.qxd 3/25/2004 10:59 AM Page 1293
1294 Scientific Reports: Original Study JAVMA, Vol 224, No. 8, April 15, 2004
SMALL ANIMALS/
EXOTIC
When potential risk factors associated with risk of
TCC in univariate analyses (ie, P < 0.05) were included in
a multivariate model, the only host factor that remained
significantly associated with risk of TCC was age
(Table 6), with risk of TCC increasing as age increased.
The risk of TCC was higher for dogs exposed to lawns or
Table 5—Results of univariate logistic regression analysis of potential associations between exposure
to herbicides and risk of TCC in Scottish Terriers
No. of case No. of control OR
Factor dogs (%) dogs (%) (95% CI)
P
value
Individual applying herbicide
None (no herbicides used) 34 (41) 56 (68) NA NA
Owner 25 (30) 9 (11) 4.58 (1.91–10.95) 0.001
Commercial company 14 (17) 4 (5) 5.77 (1.75–18.95) 0.004
Pattern of herbicide application
None or sporadic 40 (48) 62 (75) NA NA
Seasonal or year-round 31 (37) 7 (8) 6.86 (2.76–17.08) 0.001
No. of applications/y*
0 34 (41) 56 (68) NA NA
1–4 28 (34) 8 (10) 5.77 (2.36–14.09) 0.001
5 6 (7) 1 (1) 9.88 (1.14–85.56) 0.04
Phenoxy acid
No 42 (51) 59 (71) NA NA
Yes 34 (41) 11 (13) 4.34 (1.98–9.54) 0.001
Benzoic acid
No 56 (68) 65 (78) NA NA
Yes 20 (24) 5 (6) 4.64 (1.64–13.18) 0.004
Amino acid type
No 58 (70) 61 (74) NA NA
Yes 18 (22) 9 (11) 2.10 (0.88–5.06) 0.10
Other herbicide†
No 68 (82) 66 (80) NA NA
Yes 8 (10) 4 (5) 1.94 (0.56–6.76) 0.30
Class of herbicide
None used 34 (41) 56 (68) NA NA
Not phenoxy acid‡ 8 (10) 3 (4) 4.39 (1.09–17.70) 0.04
Phenoxy acid‡ 34 (41) 11 (13) 5.09 (2.28–11.36) 0.001
*
P
value for trend, 0.001. †Includes dinitroaniline, picolinic acid, benzonitrile, and chloracetamide. ‡Could
include dogs exposed to another class of herbicides. Owners were provided a list of commonly used lawn and
garden chemicals and asked to indicate what chemicals their dogs had been exposed to during the year prior
to diagnosis of TCC for case dogs and during a comparable period for control dogs.
See
Table 3 for key.
Table 6—Results of multivariate logistic regression analysis of potential associations between expo-
sure to lawn or garden chemicals and risk of TCC in Scottish Terriers
No. of case No. of control OR
Factor dogs (%) dogs (%) (95% CI)
P
value
Age (y)*
4 to 8 11 (13) 32 (39) NA NA
8 to 11 33 (40) 18 (22) 5.43 (1.99–14.86) 0.001
11 23 (28) 14 (17) 4.01 (1.38–11.63) 0.01
Neutering status
Sexually intact 4 (5) 10 (12) NA NA
Neutered 63 (76) 54 (65) 2.07 (0.49–8.79) 0.32
Coat color
All or partly black 50 (60) 39 (47) NA NA
Not black† 17 (21) 25 (30) 0.72 (0.29–1.79) 0.48
Weight (tertiles‡)§
First 18 (22) 27 (33) NA NA
Second 19 (23) 16 (19) 1.40 (0.47–4.12) 0.55
Third 30 (36) 21 (25) 1.85 (0.72–4.79) 0.20
Access to lawns or gardens
None or sporadic 5 (6) 8 (10) NA NA
Seasonal or year-round 62 (75) 56 (68) 1.69 (0.42–6.76) 0.46
Treatment of lawn or garden to
which dog had access
None 16 (19) 36 (43) NA NA
Insecticide only 13 (16) 13 (16) 1.62 (0.56–4.74) 0.38
Herbicide only 20 (24) 9 (11) 3.62 (1.17–11.19) 0.03
Both insecticide and herbicide 18 (22) 6 (7) 7.19 (2.15–24.07) 0.001
Owners were provided a list of commonly used lawn and garden chemicals and asked to indicate what
chemicals their dogs had been exposed to during the year prior to diagnosis of TCC for case dogs and dur-
ing a comparable period for control dogs.
See
Table 3 for key. Values in some categories may not add to 80
cases and 77 controls because of missing data.
*
P
value for trend, 0.01. †Includes brindle and wheaten coat colors. ‡Tertiles were sex specific. §
P
value
for trend, 0.23.
03-05-0231.qxd 3/25/2004 10:59 AM Page 1294
JAVMA, Vol 224, No. 8, April 15, 2004 Scientific Reports: Original Study 1295
SMALL ANIMALS/
EXOTIC
gardens treated with both herbicides and insecticides than
for dogs exposed to lawns or gardens treated with herbi-
cides or insecticides alone. The fit of this model was
found to be acceptable (P = 0.70; R
2
= 0.25). In a second
multivariate model, exposure to lawns or gardens treated
with phenoxy herbicides remained significantly associat-
ed with risk of TCC (Table 7), whereas exposure to lawns
or gardens treated with nonphenoxy herbicides did not.
For the host factors, only age remained significantly asso-
ciated with risk of TCC. The fit of this model was also
found to be acceptable (P = 0.30; R
2
= 0.25). Risk of TCC
associated with exposure to individual pesticide types or
individual chemical classes of herbicides could not be
included in a single multivariate model because of exces-
sive colinearity between these exposures. That is, many
dogs exposed to 1 type of herbicide were also exposed to
another type of herbicide.
Discussion
Results of the present case-control study provide
evidence that the risk of TCC in Scottish Terriers
exposed to phenoxy herbicides is 4.4 times the risk in
Scottish Terriers without such exposure. Contact with
nonphenoxy herbicides was also associated with an
increased risk of TCC, but this increase was not signif-
icant. These findings suggest a gene-environment
interaction for susceptibility to TCC and are consistent
with findings of a recent meta-analysis
18
in which
humans with a GSTM1 null genotype had 1.4 times the
risk of bladder cancer. In humans, the product of the
GSTM1 gene, glutathione S-transferase M1, is involved
in detoxification of aromatic polycyclic hydrocarbons
found in tobacco smoke, chemicals known to be asso-
ciated with bladder cancer.
19
Scottish Terriers might
have a similar gene that is responsible for an enzyme
that detoxifies pesticide ingredients.
The median lethal dose (LD
50
) of 2,4-D in dogs is
approximately 100 mg/kg (45 mg/lb) and is lower than
the LD
50
in rats, mice, guinea pigs, and rabbits.
20
In dogs,
phenoxy herbicides are absorbed mainly from the stom-
ach and intestines following ingestion or grooming, with
dermal absorption being slower and less complete.
21
Once absorbed, phenoxy herbicides are protein bound
and rapidly distributed to the liver, kidney, and brain.
21
They are excreted through the renal tubules by an organ-
ic anion transport system, with most of the dose excret-
ed unchanged in the urine.
21
The half-life of 2,4-D is
approximately 18 hours.
21
Thus, dogs with daily or week-
ly exposure to lawns treated with 2,4-D might be expect-
ed to chronically excrete 2,4-D in their urine where it
would come in constant contact with bladder epithelium.
Phenoxy herbicides have been shown to depress ribonu-
clease synthesis, uncouple oxidative phosphorylation,
and increase the number of hepatic peroxisomes.
21
However, whether any of these effects might initiate or
promote development of TCC of the urinary bladder in
Scottish Terriers is unclear, and further study is needed.
In particular, research on the health effects of herbicides
in dogs should shift from studies of acute toxicity to
studies of chronic effects associated with long-term expo-
sure, especially in genetically predisposed individuals.
Two phenoxy herbicides other than 2,4-D to
which dogs in this study were exposed included MCPP
and MCPA. The reported no observable-effect concen-
trations for these chemicals are 4 mg/kg (1.8 mg/lb)
and 0.2 mg/kg (0.09 mg/lb), respectively, compared
with a no observable-effect concentration for 2,4-D of
1 mg/kg (0.45 mg/lb) in dogs.
22,23
Carcinogenic activity
Table 7—Results of multivariate logistic regression analysis of potential associations between expo-
sure to herbicides and risk of TCC in Scottish Terriers
No. of case No. of control OR
Factor dogs (%) dogs (%) (95% CI)
P
value
Age (y)*
4 to 8 11 (13) 32 (39) NA NA
8 to 11 34 (41) 18 (22) 5.72 (2.10–15.54) 0.001
11 23 (28) 13 (16) 4.29 (1.48–12.48) 0.008
Neutering status
Sexually intact 4 (5) 10 (12) NA NA
Neutered 64 (77) 53 (64) 2.11 (0.51–8.84) 0.31
Coat color
All or partly black 51 (61) 38 (46) NA NA
Not black† 17 (21) 25 (30) 0.70 (0.29–1.69) 0.42
Weight (tertiles‡)§
First 18 (22) 26 (31) NA NA
Second 20 (24) 16 (19) 1.42 (0.48–4.19) 0.52
Third 30 (36) 21 (25) 1.73 (0.67–4.50) 0.26
Access to lawns or gardens
treated with insecticides
None or sporadic 41 (49) 48 (58) NA NA
Seasonal or year-round 27 (33) 15 (18) 1.64 (0.69–3.86) 0.26
Class of herbicide
None used 30 (36) 49 (59) NA NA
Not phenoxy acid¶ 7 (8) 3 (4) 3.49 (0.67–18.12 0.14
Phenoxy acid¶ 31 (37) 11 (13) 4.42 (1.74–11.19) 0.002
Owners were provided a list of commonly used lawn and garden chemicals and asked to indicate what
chemicals their dogs had been exposed to during the year prior to diagnosis of TCC for case dogs and dur-
ing a comparable period for control dogs.
See
Table 3 for key. Values in some categories may not add to 80
cases and 77 controls because of missing data.
*
P
value for trend, 0.007. †Includes brindle and wheaten coat colors. ‡Tertiles were sex specific. §
P
value
for trend, 0.30. ¶Could include dogs exposed to another class of herbicides.
03-05-0231.qxd 3/25/2004 10:59 AM Page 1295
1296 Scientific Reports: Original Study JAVMA, Vol 224, No. 8, April 15, 2004
SMALL ANIMALS/
EXOTIC
of these compounds in dogs has not been reported, and
there is minimal published evidence implicating them
as human carcinogens.
24
There is convincing evidence that phenoxy herbi-
cides are human carcinogens
9,10
; however, lifetime can-
cer bioassays of rats, mice, and dogs have not found
any evidence of carcinogenicity.
11
In 1989, the Harvard
School of Public Health convened an expert panel of
scientists to examine the weight of evidence on the
potential carcinogenicity of 2,4-D.
25
The predominant
opinion among the panel members was that exposure
to 2,4-D could possibly cause cancer in humans,
although not all of the panelists believed the possibili-
ty was equally high.
A previous case-control study of TCC in dogs
3
found that the risk of TCC was associated with being
overweight or obese and with the use of flea and tick
dips. The authors suggested that the latter association
could be attributable to inert ingredients, such as
petroleum distillates, aromatic petroleum solvents,
polyethers, and xylene, that often comprise 96% or
more of flea and tick dips. Such substances are likely to
be stored in body fat because of their lipophilic nature,
and this may help explain the association between obe-
sity and TCC. In the present study in which only
Scottish Terriers were included, the risk of TCC also
increased as body weight increased. This raises the
possibility that inert ingredients, including solvents,
emulsifiers, and spreaders, in lawn and garden pesti-
cide products might be responsible. Many of these
inert ingredients have adverse health effects and may
themselves be used as pesticides. At least 382 chemi-
cals on the US Environmental Protection Agency list of
pesticide inert ingredients are or were once registered
as pesticide active ingredients.
26
Eight inert ingredients
are considered to be of toxicologic concern, and many
others are potentially toxic.
26
While the identity of spe-
cific inert ingredients in a particular pesticide product
is not available to the public, it has been estimated by
the US Environmental Protection Agency that 1.2 bil-
lion pounds of conventional pesticides and 725 million
pounds of wood preservatives are used each year in the
United States.
27
If active ingredients represent 32% of
the average pesticide product, about 4 billion pounds
of inert ingredients are used each year. In comparison,
in 1997, about 29 to 33 million pounds of 2,4-D were
applied in the United States, and 2,4-D was ranked
eighth on a list of commonly used active ingredients in
pesticides.
28
As with any retrospective study, there was a poten-
tial for recall bias among owners of case and control
dogs included in the present study. However, because
owners enrolled in this study were not aware of the
specific hypotheses being tested when they completed
the questionnaire, any recall bias would likely have
been nondifferential with respect to case or control sta-
tus. Also, as in a previous study of 2,4-D exposure and
lymphoma risk in dogs,
4
owners may not have had
accurate information regarding lawn products they
used in the past. Recall error was minimized in the pre-
sent study by providing owners with a reference list of
commonly used lawn and garden products and by
requesting that they either submit the actual package
label from products they applied or contact the com-
mercial applicator for this information. It is likely that
any inaccurate recall of products used between owners
of case and control dogs that did occur would have
biased the OR toward 1 (ie, no association). Evidence
against inaccurate recall in the present study is the
finding that risk of TCC associated with exposure to
herbicides used on lawns or gardens was high and was
higher among dogs with seasonal or year-round expo-
sure, compared with dogs with no or sporadic expo-
sure. Also, the risk of TCC was higher for dogs
exposed to phenoxy herbicides than for those not
exposed to herbicides and for those exposed to non-
phenoxy herbicides.
On the basis of the findings in this study, we rec-
ommend that owners of Scottish Terriers decrease their
dogs’ access to lawns or gardens that have been treated
with pesticides, particularly phenoxy herbicides and
possibly nonphenoxy herbicides as well, until addi-
tional risk studies have been conducted. In addition,
we suggest that veterinarians discuss with owners rou-
tine (ie, every 6 months) cytologic examination of
urine in Scottish Terriers > 6 years old and in other ter-
riers. Genetic studies are needed to determine whether
Scottish Terriers might have a gene that specifically
predisposes them to TCC. Epidemiologic studies with
genetically susceptible breeds of pet dogs could pro-
vide a humane alternative to experimental studies dur-
ing the process of evaluating chemicals for human can-
cer risk.
a
SAS, version 8.2, SAS Institute Inc, Cary, NC.
b
Proc Logistic, SAS Institute Inc, Cary, NC.
c
Proc GLM, SAS Institute Inc, Cary, NC.
References
1. Withrow SJ. Tumors of the urinary system. In: Withrow SJ,
MacEwan EG, eds. Small animal clinical oncology. 2nd ed. Philadelphia:
WB Saunders Co, 1996;380–392.
2. Knapp DW, Glickman NW, DeNicola DB, et al. Naturally-
occurring canine transitional cell carcinoma of the urinary bladder:
a relevant model of human invasive bladder cancer. Urol Oncol 2000;
5:47–59.
3. Glickman LT, Schofer FS, McKee LJ, et al. Epidemiologic
study of insecticide exposures, obesity, and risk of bladder cancer in
household dogs. J Toxicol Environ Health 1989;28:407–414.
4. Hayes HM, Tarone RE, Cantor KP, et al. Case-control study
of canine malignant lymphoma: positive association with dog owner’s
use of 2,4-dichlorophenoxyacetic acid herbicides. J Natl Cancer Inst
1991;83:1226–1231.
5. Carlo GL, Cole P, Miller AB, et al. Review of a study report-
ing an association between 2,4-dichlorophenoxyacetic acid and
canine malignant lymphoma: report of an expert panel. Regul Toxicol
Pharmacol 1992;16:245–252.
6. Kaneene JB, Miller R. Re-analysis of 2,4-D use and the
occurrence of canine malignant lymphoma. Vet Hum Toxicol 1999;41:
164–170.
7. Reynolds PM, Reif JS, Ramsdell HS, et al. Canine exposure
to herbicide-treated lawns and urinary excretion of 2,4-dichlorophe-
noxyacetic acid. Cancer Epidemiol Biomarkers Prev 1994;3:233–237.
8. Ritter L. Report of a panel on the relationship between pub-
lic exposure to pesticides and cancer. Cancer 1997;80:2019–2033.
9. Persson B, Dahlander AM, Fredriksson M, et al. Malignant
lymphomas and occupational exposure. Br J Ind Med 1989;46:
516–520.
10. Hoar SK, Blair A, Holmes FF, et al. Agricultural herbicide
use and risk of lymphoma and soft-tissue sarcoma. JAMA 1986;256:
1141–1147.
03-05-0231.qxd 3/25/2004 10:59 AM Page 1296
JAVMA, Vol 224, No. 8, April 15, 2004 Scientific Reports: Original Study 1297
SMALL ANIMALS/
EXOTIC
11. Industry Task Force on 2,4-D Research Data. Combined tox-
icity and oncogenicity study in rats: 2,4-dichlorophenoxyacetic acid:
final report. Vol 1. Vienna, Va: Hazelton Laboratories America Inc,
1986.
12. Pesticide Database Searches. Office of Indiana State Chemist
Web site. Available at: www.kellysolutions.com/in/. Accessed May 15,
2003.
13. Monaco TJ, Weller SC, Ashton FM. Weed science: principles
and practices. 4th ed. New York: John Wiley & Sons, 2002;183–197.
14. Dean AG, Dean AJ, Coulombier D, et al. Epi Info, version 6:
a word-processing, database, statistics program for public health on
IBM-compatible microcomputers. Atlanta, Ga: Centers for Disease
Control and Prevention, 1995.
15. Allison PD. Logistic regression using the SAS system: theory
and application. Cary, NC: SAS Institute Inc, 1999;5–84.
16. SAS/STAT user’s guide: version 8. Vol 2. Cary, NC: SAS Institute
Inc, 1999;1903–2042.
17. Hosmer DW, Taber S, Lemeshow S. The importance of assess-
ing the fit of logistic regression models: a case study. Am J Public Health
1991;81:1630–1635.
18. Engel LS, Taioli E, Pfeiffer R, et al. Pooled analysis and
meta-analysis of glutathione S-transferase M1 and bladder cancer: a
HuGE review. Am J Epidemiol 2002;156:95–109.
19. Matanoski GM, Elliott EA. Bladder cancer epidemiology.
Epidemiol Rev 1981;3:203–229.
20. Stevens JT, Sumner DD. Herbicides. In: Hayes WJ Jr, Laws ER
Jr, eds. Handbook of pesticide toxicology. Vol 3. New York: Academic
Press Inc, 1991;1317–1408.
21. Osweiler GD. Toxicology. Philadelphia: The Williams &
Wilkins Co, 1996;257–265.
22. Yeary RA. Lawn care products. In: Bonagura JD, ed. Kirk’s
current veterinary therapy XIII. Philadelphia: WB Saunders Co, 2000;
221–222.
23. Guidelines for drinking water quality. Health criteria and
other supporting information. 2nd ed. Vol 2. Geneva: World Health
Organization, 1996;763–787.
24. Bond GG, Rossbacher R. A review of potential human car-
cinogenicity of the chlorophenoxy herbicides MCPA, MCPP, and 2,4-
DP. Br J Ind Med 1993;50:340–348.
25. Ibrahim MA, Bond GG, Burke TA, et al. Weight of the evi-
dence on the human carcinogenicity of 2,4-D. Environ Health Perspect
1991;96:213–222.
26. Knight H. Hidden toxic “inerts”: a tragicomedy of errors.
J Pesticide Reform 1997;10:10–11.
27. Pesticide industry sales and usage: 1994 and 1995 market esti-
mates. Circular 733-R-97002. Washington, DC: Environmental
Protection Agency, 1997.
28. Acquavella J, Doe J, Tomenson J, et al. Epidemiologic stud-
ies of occupational pesticide exposure and cancer: regulatory risk
assessments and biologic plausibility. Ann Epidemiol 2003;13:1–7.
03-05-0231.qxd 3/25/2004 10:59 AM Page 1297
... 11,12 Pesticide exposure has been linked to several diseases in pet dogs including lymphoma, 13−16 mammary, 17 and bladder cancers. 18,19 Pesticides used in lawn care, particularly the herbicide 2,4-D, have been reported to be associated with lymphoma in dogs. 13−16 Dogs in India with mammary cancer had higher levels of total pesticides (which include fipronil and permethrin) measured in mammary tissues (β = 4.99). ...
... 13−16 Dogs in India with mammary cancer had higher levels of total pesticides (which include fipronil and permethrin) measured in mammary tissues (β = 4.99). 17 Also, two studies have reported that dogs diagnosed with bladder cancer (transitional cell carcinoma) were significantly more likely to experience greater exposure to household insecticides 18,19 and lawn herbicides, particularly phenoxy herbicides. 19 The value of investigating chronic diseases in dogs, particularly cancer, is increasingly being recognized by researchers to aid in both drug development and therapeutics and also to further our understanding of genomic (e.g., single-nucleotide polymorphisms) and environmental (e.g., exposures) risk factors. ...
... 17 Also, two studies have reported that dogs diagnosed with bladder cancer (transitional cell carcinoma) were significantly more likely to experience greater exposure to household insecticides 18,19 and lawn herbicides, particularly phenoxy herbicides. 19 The value of investigating chronic diseases in dogs, particularly cancer, is increasingly being recognized by researchers to aid in both drug development and therapeutics and also to further our understanding of genomic (e.g., single-nucleotide polymorphisms) and environmental (e.g., exposures) risk factors. ...
Article
Full-text available
Pesticides are used extensively in residential settings for lawn maintenance and in homes to control household pests including application directly on pets to deter fleas and ticks. Pesticides are commonly detected in the home environment where people and pets can be subject to chronic exposure. Due to increased interest in using companion animals as sentinels for human environmental health studies, we conducted a comparative pesticide exposure assessment in 30 people and their pet dogs to determine how well silicone wristbands and silicone dog tags can predict urinary pesticide biomarkers of exposure. Using targeted gas chromatography–mass spectrometry analyses, we quantified eight pesticides in silicone samplers and used a suspect screening approach for additional pesticides. Urine samples were analyzed for 15 pesticide metabolite biomarkers. Several pesticides were detected in >70% of silicone samplers including permethrin, N,N-diethyl-meta-toluamide (DEET), and chlorpyrifos. Significant and positive correlations were observed between silicone sampler levels of permethrin and DEET with their corresponding urinary metabolites (rs = 0.50–0.96, p < 0.05) in both species. Significantly higher levels of fipronil were observed in silicone samplers from participants who reported using flea and tick products containing fipronil on their dog. This study suggests that people and their dogs have similar pesticide exposures in a home environment.
... Dogs and cats develop chronic diseases similar to those of humans but with a shorter latency period (Knapp et al., 2013). Pesticide exposure in dogs and cats has been linked to mammary cancer (Gautam et al., 2020), lymphoma (Takashima-Uebelhoer et al., 2012), bladder cancer (Glickman et al., 2004), and oral squamous cell carcinoma (Bertone et al., 2003), reflecting effects similar to those reported in human studies (Calaf, 2021;Fritschi et al., 2005;Koutros et al., 2016). Nevertheless, studies reporting the occurrence of pesticides in dog urine are limited (Forster et al., 2014;Karthikraj and Kannan, 2019;Knapp et al., 2013;Reynolds et al., 1994;Wise et al., 2022), and no previous studies have determined the exposure of cats to OPs, neonics, PYRs, or PAs. ...
Article
Full-text available
Exposure of pet dogs and cats to pesticides used in and around homes (e.g., lawns and gardens) is a significant health concern. Furthermore, some pesticides are directly used on dogs and cats for flea, lice, and tick control. Despite this, little is known regarding the extent of pesticide exposure in pets. In this study, we determined the concentrations of 30 biomarkers of pesticide exposure in urine collected from dogs and cats in New York State, USA: 6 dialkylphosphate (DAP) metabolites of organophosphates (OPs); 14 neonicotinoids (neonics); 3 specific metabolites of OPs; 5 pyrethroids (PYRs); and 2 phenoxy acids (PAs). The sum median concentrations of these 30 pesticide biomarkers (ΣPesticides) in dog and cat urine were 35.2 and 38.1 ng/mL, respectively. Neonics were most prevalent in dogs (accounting for 43% of the total concentrations), followed by DAPs (17%), PYRs (16%), OPs (13%), and PAs (∼10%). In cat urine, neonics alone accounted for 83% of the total concentrations. Elevated concentrations of imidacloprid were found in the urine of certain dogs (max: 115 ng/mL) and cats (max: 1090 ng/mL). Some pesticides showed gender- and sampling location- related differences in urinary concentration. We calculated daily exposure doses of pesticides from the measured urinary concentrations through a reverse dosimetry approach. The estimated daily intakes (DIs) of chlorpyrifos, diazinon, and cypermethrin were above the chronic reference doses (cRfDs) in 22, 76, and 5%, respectively, of dogs. The DIs of chlorpyrifos, parathion, diazinon, and imidacloprid were above the cRfDs in 33, 14, 100, and 29%, respectively, of cats. This study thus provides evidence that pet dogs and cats are exposed to certain pesticides at levels that warrant immediate attention.
... Dogs represent valid animal models for several naturally occurring neoplasia including, but not limited to, urinary bladder tumours [2], osteosarcomas [3], and lymphomas [4,5], as they bear notable similarities to their human counterparts in terms of biological behavior, morphology, molecular features [6] and genetics [7,8]. Furthermore, as they share the same environment with their owners, dogs can be sentinels of environmental exposures to carcinogens, as reported in mesothelioma due to the exposure to asbestos [9] and testicular and bladder tumours due to exposure to herbicides [10,11] and insecticides [12]. ...
Article
Full-text available
Advances in tumour research are crucial, and comparative oncology can improve the knowledge in several ways. Dogs are not only models of specific naturally occurring tumours but can also be sentinels of environmental exposures to carcinogens, as they share the same environment with their owners. The purpose of this work was to describe the data collected by The Italian Network of Laboratories for Veterinary Oncology in the first 9 years of activity (2013-2021) and to evaluate their potential epidemiological significance. Frequencies of tumour topographies and main morphologies in dogs were described, analysed and compared, calculating age-adjusted proportional morbidity ratios and considering several risk factors (breed, sex, period and region of residence). These observations allowed us to highlight differences not only in morphology and topography of some tumours but also to formulate hypotheses on the potential role of some risk factors, e.g., neutering/spaying or geographical location. In our opinion, the results of this case series confirm the importance of initiating and consolidating animal cancer registration initiatives that would facilitate the possibility of conducting multicentric collaborative studies to deepen the knowledge of the epidemiology of tumours in dogs from a comparative perspective.
... Based on their size, biological features, and ease of behavioral evaluation and handling, dogs can be good animal models. Since humans and dogs share a common environment, food, and carcinogenic load, it is not surprising that the dog has emerged as a viable model for human disease [2]. Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are the most common X-linked recessive muscular dystrophies caused by mutations in the dystrophin gene leading to a defective dystrophin-glycoprotein complex [3]. ...
Article
Full-text available
Dystrophinopathy is caused by mutations in the dystrophin gene, which lead to progressive muscle degeneration, necrosis, and finally, death. Recently, golden retrievers have been suggested as a useful animal model for studying human dystrophinopathy, but the model has limitations due to difficulty in maintaining the genetic background using conventional breeding. In this study, we successfully generated a dystrophin mutant dog using the CRISPR/Cas9 system and somatic cell nuclear transfer. The dystrophin mutant dog displayed phenotypes such as elevated serum creatine kinase, dystrophin deficiency, skeletal muscle defects, an abnormal electrocardiogram, and avoidance of ambulation. These results indicate that donor cells with CRISPR/Cas9 for a specific gene combined with the somatic cell nuclear transfer technique can efficiently produce a dystrophin mutant dog, which will help in the successful development of gene therapy drugs for dogs and humans.
... The aetiology of the canine disease is thought to be multifactorial. Several risk factors have been proposed to play a role, such as exposure to older topical insecticides for flea and tick control, obesity, female sex, herbicides and breed predisposition (e.g., Scottish Terrier, West Highland White Terrier, Shetland Sheepdog, Beagle and others) [7][8][9]. ...
Article
Full-text available
Cancer of the urinary bladder is a neoplasm with considerable importance in veterinary medicine, given its high incidence in several domestic animal species and its life-threatening character. Bladder cancer in companion animals shows a complex and still poorly understood biopathology, and this lack of knowledge has limited therapeutic progress over the years. Even so, important advances concerning the identification of tumour markers with clinical applications at the diagnosis, prognosis and therapeutic levels have recently been made, for example, the identification of pathological BRAF mutations. Those advances are now facilitating the introduction of targeted therapies. The present review will address such advances, focusing on small animal oncology and providing the reader with an update on this field. When appropriate, comparisons will be drawn with bladder cancer in human patients, as well as with experimental models of the disease.
... Due to pesticide poisoning, there is more than 1 million deaths and chronic diseases worldwide. A study on association between lawn chemical's exposure and its adverse impacts in dogs (Scottish Terriers) that were exposed to gardens or lawns treated with phenoxy herbicides has been shown to have more risk of transitional cell carcinoma of the urinary bladder as compared with exposure to untreated lawns or gardens (Glickman et, al., 2004). ...
Article
Full-text available
Pesticides are group of synthetic chemicals used for the extermination of insects, rodents and unwanted plants. Most of the pesticides have the ability to disrupt of a wide variety of pests by disturbing the physiological activities of the target organism resulting in dysfunction and reduced vitality. The unstrained use of pesticide use in agriculture, houses and lawns has affected the environment and biodiversity Agriculture workers are exposed to many pesticides and suffer from respiratory and other symptoms. Pesticide residues have been linked with the health of agricultural workers. The Available scientific data indicate that pesticide exposure induces lung inflammation in farmers and workers engaged in agricultural sectors. Hence, we need the new programme to educate farmers against the ill usage and harmful effects of pesticides.
... Nature (see for instance whales with bladder cancer in [51] and even our companion animals were revealing a truth that we have long ignored. Continuous studies, from 1938 up to now, suggested the evidence that exposure to herbicides, insecticide, and waste pollutants poses a risk of cancer, particularly of the bladder, to dogs [52][53][54][55][56][57]. Yet, the coincident rise of synthetic dyes and bladder cancer among textile workers [58] and the growing evidence of higher bladder cancer risk for workers in rubber and metal industries [59][60][61] did not do much to address socio-economic and political actions. ...
Article
Full-text available
Besides our current health concerns due to COVID-19, cancer is a longer-lasting and even more dramatic pandemic that affects almost a third of the human population worldwide. Most of the emphasis on its causes have been posed on genetic predisposition, chance, and wrong lifestyles (mainly, obesity and smoking). Moreover, our medical weapons against cancers have not improved too much during the last century, although research is in progress. Once diagnosed with a malignant tumour, we still rely on surgery, radiotherapy, and chemotherapy. The main problem is that we have focused on fighting a difficult battle instead of preventing it by controlling its triggers. Quite the opposite, our knowledge of the links between environmental pollution and cancer has surged from the 1980s. Carcinogens in water, air, and soil have continued to accumulate disproportionally and grow in number and dose, bringing us to today’s carnage. Here, a synthesis and critical review of the state of the knowledge of the links between cancer and environmental pollution in the three environmental compartments is provided, research gaps are briefly discussed, and some future directions are indicated. New evidence suggests that it is relevant to take into account not only the dose but also the time when we are exposed to carcinogens. The review ends by stressing that more dedication should be put into studying the environmental causes of cancers to prevent and avoid curing them, that the precautionary approach towards environmental pollutants must be much more reactionary, and that there is an urgent need to leave behind the outdated petrochemical-based industry and goods production.
Article
Human urothelial carcinoma (UCC) and non-Hodgkin lymphoma are considered environmental cancers in people, but less is known about environment risk for UCC and lymphoma in dogs. The objective of this study was to determine whether dogs with these cancers, compared to unaffected control dogs, live in counties with higher tap water contaminants or higher levels of air pollution as measured by the Environmental Protection Agency (EPA) and by National Air Toxics Assessment chemical exposure risk estimates. Dogs with available home addresses from two previously published case-control populations were included: 66 dogs with UCC and 70 unaffected controls; and 56 boxer dogs with lymphoma and 84 unaffected boxer controls. Tap water total trihalomethanes, which are water disinfection by-products, were more than 3-fold higher in UCC case counties of residence compared to controls (P < 0.0001), and a higher proportion of dogs with UCC lived in counties exceeding EPA ozone limits (41.8%) compared to controls (13.6% P = 0.0008). More boxers with lymphoma lived in counties exceeding EPA ozone limits (52.1%) compared to controls (29.0%; P = 0.018), with higher exposure risk estimates for airborne 1,3 butadiene and formaldehyde (P = 0.004-0.005). These data support the hypothesis that tap water contaminants and airborne environmental pollutants contribute to the risk of both urothelial carcinoma and lymphoma in dogs. If these findings reflect causal relationships, then it is possible that tap water filtration units and more effective air pollution controls could decrease the overall incidence of these cancers in dogs. This article is protected by copyright. All rights reserved.
Article
Soybean is an important oilseed crop, but weed can have a significant effect on soybean yield. Clomazone, fomesafen, and haloxyfop-methyl are high-efficacy herbicides, and the combination of these herbicides shows an ideal effect on weed control. However, the residues of these herbicides and their impacts on human health are still largely unknown. In the current study, a rapid, sensitive, and selective method using modified QuECHERS procedure combined with HPLC-MS/MS was established to detect these herbicides in soybean matrices. The limits of quantification were 0.01, 0.01 and 0.025 mg/kg for haloxyfop-methyl, haloxyfop and fomesafen, and 0.005, 0.005 and 0.0125 mg/kg for clomazone in green soybean, soybean grain, and straw, with the average recoveries ranging from 80% to 107%. The terminal residues of the target compounds were all below the corresponding limits of quantification. The dietary risk assessment showed that the risk quotient values were far below the acceptable human consumption levels.
Preprint
Full-text available
Dystrophinopathy is caused by mutations in the dystrophin gene, which lead to progressive muscle degeneration, necrosis, and finally death. Recently, golden retrievers have been suggested as a useful animal model for studying human dystrophinopathy, but the model has limitations due to difficulty in maintaining the genetic background using conventional breeding. In this study, we successfully generated a dystrophin mutant dog using the CRISPR/Cas9 system and somatic cell nuclear transfer. The dystrophin mutant dog displayed typical phenotypes, such as elevated serum creatine kinase, dystrophin deficiency, skeletal muscle defects, an abnormal ECG, and avoidance of ambulation, all of which are consistent with human dystrophinopathy. These results indicate that dystrophin mutant dogs can be a reliable and effective animal model for preclinical studies into new therapies for human dystrophinopathy.
Article
BACKGROUND Pesticides, which by their nature are biologically active compounds, continue to raise public concern regarding their possible role as important etiologic agents in the development of human cancer.METHODS To examine this potential role, the National Cancer Institute of Canada convened an Ad Hoc Panel on Pesticides and Cancer to examine the possible contribution of pesticide exposure, particularly in the general population, to the development of human cancer.RESULTSThe Panel focused primarily on exposure in the general population and reviewed a range of studies that addressed issues related to dietary exposure as well as incidental home and garden uses. In addition, the Panel examined the regulatory framework that exists to safeguard the public from potentially carcinogenic pesticides and also reviewed some potential benefits of pesticide use, including the availability of an abundant and low cost supply of fresh fruits and vegetables as an important strategy in the overall mitigation of cancer risk.CONCLUSIONS The Panel concluded that it was not aware of any definitive evidence to suggest that synthetic pesticides contribute significantly to overall cancer mortality. The Panel also concluded that it did not believe that any increased intake of pesticide residues associated with increased intake of fruits and vegetables poses any increased risk of cancer. The Panel further concluded, among other things, that tobacco use continues to be the most important preventable cause of cancer and premature mortality and thus is an appropriate focus for cancer control strategy. [See editorial on pages 1887-8, this issue.] Cancer 1997; 80:2019-33. © 1997 American Cancer Society.
Article
Invasive bladder cancer results in over 10,000 deaths yearly in the United States alone. More effective therapy for invasive bladder cancer is clearly needed. As new cellular and molecular targets for therapy are identified, relevant animal models are needed to test new therapeutic strategies aimed at these targets prior to human clinical trials. The purpose of this review is to characterize spontaneous invasive transitional cell carcinoma of the urinary bladder (TCC) in dogs, to summarize the similarities and differences between canine and human invasive TCC, and to describe how canine TCC could serve as a relevant model of human invasive bladder cancer. Information was summarized from 102 dogs with TCC evaluated and treated at the Purdue University Veterinary Teaching Hospital, from a review of the Veterinary Medical Data Base, and from reports in the literature. Canine TCC was found to be very similar to human invasive bladder cancer in histopathologic characteristics, molecular features, biological behavior including metastasis, response to medical therapy, and prognosis. Differences between canine and human TCC were few, but included gender predilection with a male:female ratio of 2.8:1 in humans versus a male:female ratio of 0.5:1 in dogs. The location of the TCC within the bladder also differed: Most canine TCC was trigonal in location, whereas more than 50% of human TCC was in the lateral and posterior walls of the bladder. Considering the great similarity between invasive bladder cancer in humans and dogs, spontaneous canine TCC can be considered a relevant animal model of human invasive bladder cancer.
Article
The logistic regression model is being used with increasing frequency in all areas of public health research. In the calendar year 1989, over 30% of the articles published in the American Journal of Public Health employed some form of logistic regression modeling. In spite of this increase, there has been no commensurate increase in the use of commonly available methods for assessing model adequacy. We review the current status of the use of logistic regression modeling in the American Journal of Public Health. We present a brief overview of currently available and easily used methods for assessing the adequacy of a fitted logistic regression model. An example is used to demonstrate the methods as well as a few of the adverse consequences of failing to assess the fit of the model. One important adverse consequence illustrated in the example is the inclusion of variables in the model as a result of the influence of one subject. Failure to address model adequacy may lead to misleading or incorrect inferences. Recommendations are made for the use of methods for assessing model adequacy and for future editorial policy in regard to the review of articles using logistic regression.
Article
The phenoxy herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) is widely used to control the growth of weeds and broadleaf plants. We convened a panel of 13 scientists to weigh the evidence on the human carcinogenicity of 2,4-D. The panel based its findings on a review of the toxicological and epidemiological literature on 2,4-D and related phenoxy herbicides. The toxicological data do not provide a strong basis for predicting that 2,4-D is a human carcinogen. Although a cause-effect relationship is far from being established, the epidemiological evidence for an association between exposure to 2,4-D and non-Hodgkin's lymphoma is suggestive and requires further investigation. There is little evidence of an association between use of 2,4-D and soft-tissue sarcoma or Hodgkin's disease, and no evidence of an association between 2,4-D use and any other form of cancer. Scientists on the panel were asked to categorize 2,4-D as a "known," "probable," "possible," or "unlikely" carcinogen or as a noncarcinogen in humans. The predominant opinion among the panel members was that the weight of the evidence indicates that it is possible that exposure to 2,4-D can cause cancer in humans, although not all of the panelists believed the possibility was equally likely: one thought the possibility was strong, leaning toward probable, and five thought the possibility was remote, leaning toward unlikely. Two panelists believed it unlikely that 2,4-D can cause cancer in humans.
Article
A hospital-based case-control study of companion dogs examined the risk of developing canine malignant lymphoma associated with the use of chemicals in and about the home. Information from a self-administered owner questionnaire and/or a telephone interview of about 491 cases, 466 nontumor controls, and 479 tumor controls indicated that owners in households with dogs that developed malignant lymphoma applied 2, 4-dichlorophenoxyacetic acid (2, 4-D) herbicides to their lawn and/or employed commercial lawn care companies to treat their yard significantly more frequently than control owners (odds ratio = 1.3). In addition, the risk of canine malignant lymphoma rose to a twofold excess with four or more yearly owner applications of 2, 4-D. The findings in this study are consistent with occupational studies in humans, which have reported modest associations between agricultural exposure to 2, 4-D and increased risk of non-Hodgkin's lymphoma, the histology and epidemiology of which are similar to those of canine malignant lymphoma. The present study suggests that human health implications of 2, 4-D exposure in the home environment should receive further investigation. [J Natl Cancer Inst 83:1226–1231, 1991]
Article
A case-control study of household dogs was conducted to determine if exposure to sidestream cigarette smoke and chemicals in the home, use of topical insecticides, and obesity are associated with the occurrence of bladder cancer. Information was obtained by interview from owners of 59 dogs with transitional-cell carcinoma of the bladder and 71 age- and breed size-matched control dogs with other chronic diseases or neoplasms. Bladder cancer risk was unrelated to sidestream cigarette smoke and household chemical exposures. Risk was significantly increased by topical insecticide use (OR = 1.6 for 1-2 applications per year and OR = 3.5 for greater than 2 applications per year; chi 2 trend; p = .008). This risk was enhanced in overweight or obese dogs. Further studies of this canine model may facilitate identification of specific carcinogens present in insecticides commonly used on pet animals and in the environment.