Page 113 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

92 PART I The Biology and Pathogenesis of Cancer

Environmental Exposures Exposure misclassification is a primary limitation of using geo-
The identification of environmental exposures that are related to graphic proximity as a marker of exposure to an industrial or waste
site because it may or may not be a good proxy for individual-
canine cancer risk have a broad public health interest, given the
VetBooks.ir shared environments of companion animals and their owners, level exposure. For example, a validation study would need to be
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conducted that provides information on whether dogs that live
and they have similar etiology of some cancers. In a compre-
hensive review, a historic perspective is provided on how stud- close to an industrial site are necessarily exposed at higher levels to
ies in pet populations have informed human health with respect environmental hazards compared with dogs that live further from
to the specific exposures of air pollution, environmental tobacco the site. Misclassification of exposure that does not differ by dis-
smoke (ETS), and pesticides. The shared etiologic characteristics ease status (e.g., nondifferential misclassification) typically results
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of cancers such as lymphoma, OSA, and mammary cancer also in an underestimate of the exposure–cancer association, although
support the utility of looking to both pet and human populations there are situations when the observed association results in an
to investigate environmental–cancer associations. 51 overestimate of the true association. 70,71
There is experimental evidence for an underlying biologic
mechanism for the compounds of cigarette smoke to have a Hormones and Neuter Status
causal relationship with canine carcinogenesis. 52,53 There are few Hormones may act as either growth factors or inhibitors, depend-
observational studies that were designed to specifically evaluate ing on the sex of the dog and the tissue type. 72–74 For some
associations between ETS exposure and canine cancer risk. 54,55 cancers, such as breast cancer, less exposure to sex hormones is
There is support for a positive association (3.4-fold increased risk) protective; whereas for others, such as OSA, lymphoma, and pros-
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between ETS and lymphoma and sinonasal cancers, but not tate cancer, less exposure has been reported to increase risk. 72,75–82
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for lung cancer. In a clinic-based case-control study, household Neuter/spay status and age at neuter/spay are the most commonly
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ETS exposure was strongly associated with feline lymphoma. used measures of endogenous hormone exposure. In spite of some
The OR for any exposure, compared with no exposure, was 2.4, newer studies, there is limited evidence that the age of the dog at
and statistically significant trends were reported for more years of the time of neuter/spay can have an effect on the risk of develop-
ETS exposure, more smokers in the household, and number of ing cancer in certain breeds of dogs. 79,81 Given the widespread rec-
cigarettes smoked per day in the household. In contrast, there is ommendation for early spay/neuter, especially in North America,
only weak observational evidence for ETS as a risk factor for oral this is a topic in need of further study.
squamous cell carcinoma in cats. In summary, avoiding ETS In a mammary cancer case-control study, there was clear evi-
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exposure may reduce the risk of lymphoma in cats and dogs and dence that spayed dogs were at lower risk of mammary cancer.
the risk of sinonasal cancers in dogs. In particular, the earlier age at which dogs were spayed the lower
Pesticides are a heterogeneous group of chemicals, some of their mammary cancer risk compared with dogs that were not
which are known human and canine carcinogens. 58–60 Dogs may spayed. This finding has been supported by other observational
be exposed to pesticides in the home, in the yard/garden, and studies of spay status and mammary cancer risk. 83
on application of flea and tick treatments. The most consistent Contrary to human epidemiologic and experimental evi-
observational evidence for pesticide exposure as a cancer risk fac- dence, 84,85 exposure to sex hormones such as androgens may be
tor is for phenoxy acid–containing herbicides and lymphoma risk, protective for canine prostate cancer. From two case-control
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both in humans and dogs. These data, however, have not been studies using large veterinary teaching hospital databases, neu-
deemed strong enough to establish causality. In a large case- tered dogs had a 2.8- and 3.4-fold increased risk of prostate cancer
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control study (n = 491 cases and n = 945 controls), any use of compared with intact dogs. 77,78 The apparent opposite associa-
pesticides that contained dichlorophenoxyacetic acid (2,4-D) was tions between hormone exposure and prostate cancer risk in men
associated with a 30% increased risk of lymphoma compared with and dogs are likely a result of the higher rate of androgen-indepen-
no use. 63,64 Although modest, the positive association also dem- dent tumors in dogs than in men. 86,87
onstrated a dose-dependent effect in which more frequent use of Neuter status is also a risk factor for OSA and transitional cell
2,4-D pesticides resulted in a stronger positive association with carcinoma of the urinary bladder, 44,72,76,78 regardless of sex. 72,76
lymphoma risk (p for trend <0.02). Additional support for 2,4-D Cooley et al conducted a retrospective cohort study in 1999
and canine bladder cancer risk is from the result of a small case- among 683 Rottweilers and used a self-administered question-
control study in Scottish terriers. 42 naire to test the hypothesis that neuter/spay status was related to
Residential proximity to environmental hazard–containing the development of OSA. The owners were identified through
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sites has been used to estimate chemical exposure and canine can- eight national Rottweiler breed specialty clubs and had a purebred
cer risk in several observational studies. 43,65,66 A 2.4-fold increase Rottweiler that was alive on January 1, 1995. The participation
in risk of lymphoma was observed among dogs living in the cit- rate ([number of participants] ÷ [total number of invited owners]
ies containing illegal waste sites compared with dogs living in × 100) was 49%. This low participation rate suggests that selection
other cities. No association was observed with mast cell tumors bias may have influenced the results of this study. In other words,
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(MCTs) or breast cancer. Mortality caused by cancer is also higher the participants of the study are likely to have systematic differ-
among human populations living near the same waste sites com- ences compared with those who did not participate. However, a
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pared with the general population. Chemical mixtures that have strength of this study is the ability to calculate incidence because
been identified at hazard waste landfills include organic solvents, the total number of dog-months of observation were estimated
polychlorinated biphenyls, and heavy metals. These can reach retrospectively among dogs that were neutered/spayed and those
human and pet populations through contaminated air, water, that were not. During a total of 71,004 dog-months of obser-
and/or soil, and have been causally related to adverse human vation, there were 86 cases of OSA. Collectively, the findings of
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health effects, including childhood lymphoma. The biologic a positive association between neuter/spay status and OSA from
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plausibility and the observational findings from Marconato et al both case-control and cohort studies, and the biologic plausibility
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both help strengthen the evidence that living near the waste sites of the association, provide strong evidence that neutering/spaying
increases risk of canine lymphoma. dogs, regardless of sex, increases risk of OSA.