Investigations of pesticides and cancer have, quite appropriately, focused on potential effects of individuals chemicals whenever possible for ease of analysis and policy and regulation purposes. Multiple exposures, however, complicate assessment of relationships between pesticides and cancer and more accurately reflect how pesticides are used in practice. McDuffie [5
] previously reported that the risk of NHL in the Cross-Canada Study of Pesticides and Health tended to increase with the number of pesticides used. In a study from the United States, DeRoos [4
] reported similar results in some cases, noting that risk increases when only pesticides with some evidence of carcinogenicity were included in the analysis and that risk were also increased for several specific combinations. Our results extend these findings.
The risk of NHL rose with increasing numbers of pesticides used and tests for trend were almost always statistically significant. Two additional findings stand out. First, the rising trend did not appear to be associated with any particular pesticide class and was observed for herbicides, insecticides, and fungicides. These analyses, however, are not on mutually exclusive exposure groups because many individuals used pesticides from all three classes. Second, odds ratios increased further when only pesticides with some evidence of carcinogenicity were considered in the summation. Risk rose to nearly two-fold among those reporting use of five or more potentially carcinogenic pesticides.
Our findings and those from earlier studies [4
] might be explained in a several ways. It could be that several pesticides each contribute a small risk that sums to a larger relative risk when they are considered in combination. Another explanation might be that as the number of pesticides used increases, the chances of including one or more that has considerable carcinogenic properties may also increase. Finally, use of multiple pesticides may be acting as a proxy measure for a more complex farming operation that may present some unique exposures that could be related to NHL.
] had found that specific combinations of pesticides led to higher risks than would have been predicted from additive models, particularly those combinations that included atrazine. We were unable to evaluate findings for atrazine because its use was only reported by five individuals in the Cross-Canada Study of Pesticides and Health. Our analyses of specific combinations of pesticides did find some evidence of increased risk related to use of malathion in combination with 2,4-D, mecoprop, carbaryl, glyphosate, and DDT, where odds ratios increased beyond that from use of either pesticide alone. Interaction odds ratios should be interpreted cautiously because odds ratios for most combinations are not much larger than for malathion alone and were not statistically significant, and only the combination of malathion and carbaryl appeared to have a super-additive effect.
Findings indicating increased risk with reported use of pesticide combinations including malathion, a common organophosphate insecticide used on a wide range of crops and gardens and for public health-related mosquito control, are somewhat unexpected given that there is limited evidence of its carcinogenicity in human and animal studies. IARC categorized malathion as a group 3 substance (not classifiable as to its carcinogenicity to humans), and the US EPA classified it as having “suggestive evidence of carcinogenicity” [10
]. There are several hypothesized mechanisms of carcinogenicity for malathion but they are not well-established, particularly for NHL [12
A major limitation of our analysis is that our proxy measures for pesticide exposure were based on self-reported lifetime use. It is not clear whether use of combinations of pesticides were from actual tank mixtures, combinations used during the same growing season, or use in different years over a lifetime. These are quite different exposure scenarios and, even if the pesticides were carcinogenic, we might expect quite different biologic effects from these different exposure patterns. Moreover, we have no direct information on pesticide exposure or absorbed dose because analyses were based on self-reported pesticide use, which was measured in a binary fashion. This may result in exposure measurement error and depending on the underlying distribution of true exposure, and the presence of confounding and other factors, risk estimates can be biased in unpredictable ways.
Furthermore, recall bias for exposures is a concern in case-control studies because cases may have spent more time thinking about past exposures than controls. This could lead to differential misclassification and bias relative risks away from null. We lack direct information to address this issue, however, results from a methodological analysis of this issue in a similar case-control study in the United States did not uncover any evidence of case-response bias [13
This study has several strengths. Information was obtained on pesticide use for a relatively large number of cases and controls. About 45% of cases and controls had lived or worked on a farm and occupational pesticide use was largely confined to this group. Accuracy of past events from questionnaires is always a concern, but farmer’s recall of pesticide has been found to be as good as for many other factors traditionally obtained by interview for epidemiologic studies [14
]. Finally, information on many potential confounders for NHL was obtained and used in the models where appropriate but did not have a significant impact on risk.