Page 36 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 1 The Etiology of Cancer 15

Pesticides, Herbicides, and Insecticides Canine transitional cell carcinoma (TCC) of the urinary blad-
der is another malignancy that has been linked to environmen-
tal carcinogens, including insecticides and herbicides. To further
In 1991, investigators at the National Cancer Institute (NCI) com-
VetBooks.ir pleted a case-control study to examine the relationship between elucidate a mechanism for the carcinogenesis of canine urothe-
the exposure of dogs to the herbicide 2,4-dichlorophenoxyacetic
lium exposed to lawn chemicals, 2,4-D and other herbicides were
acid (2,4-D), and the development of lymphoma. 165 Dogs with a measured in the urine of dogs within a 50 mile radius of West
histologically confirmed diagnosis of lymphoma during a 4-year Lafayette, Indiana. 172 Interestingly, chemicals were found in the
period were identified through the computerized medical record urine of dogs from both treated and untreated yards. However,
information from three veterinary teaching hospitals. Each case dogs in this study were not followed for the development of
animal was age matched with two control animals. The first con- TCC. 172 In a case-control study of 59 dogs with TCC and 71
trol group consisted of dogs diagnosed with tumors other than age-matched and breed size–matched control dogs with other
lymphoma during the same time period, and the second control neoplasms or chronic disease, investigators compared the two
group was a nontumor group, selected from all other dogs pre- populations to assess the effect of obesity, exposure to sidestream
senting for conditions deemed unrelated to chemical exposure. cigarette smoke and chemicals, and the use of topical insecticides,
Owners were questioned about household use of and potential on the risk of TCC. 173 They reported an increased risk of TCC in
pet exposure to commercial lawn care and owner-applied her- dogs treated with topical insecticides, with an enhancement of this
bicides. A positive association was found between exposure to risk in overweight or obese dogs. Scottish terriers, already at an
owner-applied 2,4-D or the use of commercial lawn care services increased risk of developing urothelial cancer because of a breed
and the development of lymphoma. The risk of lymphoma dou- predisposition, 174 have been more extensively studied in regard to
bled when owners applied 2,4-D liquid or granules to the lawn chemical exposure. Scottish terriers exposed to lawn and garden
four or more times a year. After these findings were reported, an care products containing phenoxy herbicides, including 2,4-D,
independent review panel was convened to assess the validity of 4-chloro-2-methylphenoxy acetic acid (MCPA), and 2-(4-chloro-
the NCI study. 166 The panel voiced concerns about the original 2-methylphenoxyl) propionic acid (MCPP), have an increased
study design, data analysis, and interpretation, concluding that risk of developing TCC. 175 Newer topical spot-on flea and tick
a relationship between 2,4-D exposure and the development of products have been evaluated in Scottish terrier populations and
canine lymphoma could not be established based on the reported were not associated with an increased risk of TCC. 176
data. In response, the original investigators reanalyzed their data, In the aforementioned study of risk factors for oral SCC in
addressing many of the concerns raised by the scientific review cats, a significantly increased risk of oral SCC was seen in cats
panel. 167 A more stringent definition of exposure to 2,4-D was that wore flea collars. 160 Although links between phenoxy herbi-
used, including only cases in which the owner applied 2,4-D as cides and the development of cancers such as SCC, lymphoma
the sole herbicide and did not use other lawn chemicals or lawn and TCC have been inconsistent, attempts to limit exposure of
care services. The second report did not show a statistically sig- pets to these products is advised.
nificant association between exposure to 2,4-D and the develop-
ment of lymphoma 167 ; however, it did indicate a dose-response Cyclophosphamide
relationship between disease incidence and the number of yearly
2,4-D applications by dog owners. In a subsequent study con- The cytotoxic alkylating agent cyclophosphamide (CYC) has been
ducted by researchers at Michigan State University, the original implicated in the development of urinary bladder cancer in people
1991 data again were reanalyzed, using the more stringent defi- and dogs. 177–179 A known potential side effect of CYC therapy is
nition of exposure, and a dose-response analysis was completed. sterile hemorrhagic cystitis, which develops from the generation
The study, which was funded by a chemical industry task force, of its metabolite, acrolein. 180 Acrolein causes a pyroptotic reac-
showed no dose-response relationship between the number of tion in the urothelium, leading to ulceration; it also upregulates
2,4-D applications and the occurrence of canine lymphoma. 168 reactive oxygen species and nitric oxide production. 181 A recent
Although increased urinary excretion of 2,4-D has been demon- review of CYC use for human rheumatic diseases listed several
strated in dogs exposed to herbicide-treated lawns, a direct link key conclusions. Daily oral CYC was associated with an increased
between such exposure and development of lymphoma has not risk of both hemorrhagic cystitis and bladder cancer, and patients
been shown. 169 who developed hemorrhagic cystitis had an increased risk of blad-
A 2011 case-control study conducted in Italy was designed to der cancer years later. 182 In dogs treated with metronomic chemo-
assess the effect of residential exposure to environmental pollut- therapy, 183,184 the occurrence of hemorrhagic cystitis appears to be
ants on the risk of developing lymphoma. 170 The investigators higher than in dogs receiving maximally tolerated dose CYC. 185,186
were unable to demonstrate an association between exposure to Although rare, bladder cancer development after CYC therapy has
pesticides (which by their definition included herbicides) and the been reported in dogs. 187 Diligent monitoring of the urogenital
development of lymphoma. However, they did find that living tract seems warranted in patients receiving metronomic CYC.
in industrial areas and owner use of chemicals such as paints and
solvents were significantly and independently associated with lym- Rural Versus Urban Environment
phoma. A larger case-control study with more 260 cases of canine
lymphoma and 240 and 230 cases of benign tumors and chronic Several reports have identified differences in the cancer incidence
diseases, respectively, was performed at a single veterinary teach- between companion animals living in urban settings and those liv-
ing hospital. 171 In this questionnaire-based study, cases of canine ing in rural settings. The underlying cause for these differences is
lymphoma were more likely to come from a household with pro- unclear. An increased incidence of some canine cancers, including
fessionally applied pesticides (OR = 1.7) or self-applied insect lymphoma, tonsillar SCC, and nasal carcinoma, 154,170,173,188 has
growth regulators (OR = 2.7). Flea and tick control products were been reported in urban/industrial settings compared with rural
not associated with the risk of lymphoma. 171 settings. However, the coexistence of multiple environmental