We found that a few pesticides, in particular chlorpyrifos and aldicarb, were associated with significant excess risks of rectal or colon cancer among pesticide applicators in the Agricultural Health Study cohort. Since we evaluated 50 pesticides and did not have strong a priori hypotheses linking specific pesticides with human colorectal cancer risk, these maybe chance findings from small numbers and multiple comparisons. However, these excesses did show consistency of the findings by state and some evidence of an exposure-response relation.
-(3,5,6-trichloro-2-pyridyl)-phosphorothioate] is one of the most widely used organophosphate insecticides in the United States.39
Although the literature provided little evidence of mutagenic or carcinogenic effects of chlorpyrifos in humans,40
some experimental studies found that chlorpyrifos induced mutagenicity,41,42
and chromosomal loss.45
Chlorpyrifos has been found to modify endogenous antioxidants in rats, possibly leading to the development of oxidative stress.46
A case–control study reported increased risk of non-Hodgkin's lymphoma 47
among male farmers exposed to chlorpyrifos in the United States. In a previous analysis of cancer among chlorpyrifos users in the Agricultural Health Study cohort, we reported an increased risk of rectal cancer consistent with our current findings, as well as excesses for cancers of the lung and brain.49,50
However, the biologic mechanisms for carcinogenicity of chlorpyrifos is not clear and should be further studied.
Aldicarb [2-methyl-2-(methylthio) propionaldehyde-O-methylcarbamoyloxime] is a carbamate insecticide. Since aldicarb has not been tested extensively for carcinogenicity in experimental animals and there are no adequate human studies of the relationship between exposure to aldicarb and human cancer reported to date,51
our positive association with colon cancer is new and unexpected. The only human study, which had an ecologic design, found that aldicarb application was associated with breast cancer incidence in England.53
However, our results were based on a small number of exposed cases (n=29), so we will need to continue to follow-up before a firm conclusion about colon cancer and aldicarb exposure can be made. Another insecticide showed a positive association with colon cancer (fonofos) and two were positively associated with rectal cancer (carbaryl and toxaphene) by ever/never exposure history; however, they did not have significant exposure-response relationships, which weakens a causal inference.
We did not find significant associations with alachlor, aldrin, and dieldrin, which are all pesticides previously associated with colorectal cancer in production workers.22,23,25-27
However, these previous studies from pesticide manufacturing workers were based on few colorectal cancer cases. Our previous study from the Agricultural Health Study cohort53
also did not support any significant association between alachlor exposure and colorectal cancer risk.
Unexpectedly we found a lower risk of colon cancer among applicators ever exposed to 2,4-D. Previous epidemiologic studies of 2,4-D have focused on risks for soft tissue sarcoma, non-Hodgkin's lymphoma, and Hodgkin's disease, but on few other cancers.54
A slight excess of colon cancer among farmers in Kansas reporting use of 2,4-D was based on small numbers.29
The lack of a monotonic exposure-response pattern with lifetime exposure-days weakens somewhat the argument for a true protective relationship, but further evaluation of this inverse association is planned for the Agricultural Health Study cohort.
No significant exposure-response relation between pendimethalin and rectal cancer was observed here, whereas a previous report on pendimethalin from the Agricultural Health Study found a significantly increased risk of rectal cancer among applicators with the highest lifetime pendimethalin exposure days.55
The difference in results is due to use of different exposure cut-points. In the chemical specific analysis, the tertiles were based on total number of cancer cases, but here the tertiles were based on specific pesticide use by colorectal cancer cases. The instability in the risk estimate for rectal cancer and pendimethalin exposure using different cut points suggests that the results should be interpreted cautiously.
We attempted to evaluate the relationship between pesticide exposure and risk of colorectal cancer by anatomic sub-sites because previous studies have suggested etiologic distinctions by anatomic sub-site.56,57
Occupational factors also have been reported to influence the risk of colon and rectal cancer in different ways.58,59
However, the pesticides we analyzed did not show significantly different risks by anatomic sub-sites, although the number of cases in the sub-groups was small.
Other factors that may be related to colorectal cancer risk (i.e., physical activity, body mass index, and smoking) showed results consistent with previous literature,2
while others (i.e., family history of colorectal cancer among first-degree relatives, dietary factors and use of aspirin) were not associated with colorectal cancer risk within the Agricultural Health Study cohort. Since these factors were not a focus of the Agricultural Health Study research, our data on dietary factors, non-steroidal anti-inflammatory drug use and family cancer history were limited and it is possible that misclassification of these exposures may have masked expected associations. The number of regular users of aspirin and other non-steroidal anti-inflammatory drugs was small, possibly reflecting the fact that applicators were relatively healthy at enrollment. Adjusting for lifestyle factors known to be related to colorectal cancer risk did not alter our results.
One possible limitation of this study is the potential recall bias associated with subjects recalling pesticide use from many years ago. We have carried out several efforts to assess the reliability of our pesticide data. A previous evaluation of this issue has shown that recall of pesticide use by the Agricultural Health Study cohort is as reliable as that for other factors routinely evaluated by questionnaire in epidemiology studies, such as smoking and alcohol use, and to be better than others, such as consumption of fruits and vegetables and physical activity.60
In addition, we have found that participants in our cohort have provided plausible information regarding the duration of use of specific pesticides.61
A recent report showed that our pesticide exposure scores provide a reasonably valid measure of exposure intensity for pesticide applicators by comparing pesticide exposure algorithm and urine metabolites monitoring results.62
Although these findings are encouraging, undoubtedly exposure misclassification occurs. This misclassification would be expected to be nondifferential for cases and non-cases and the observed effect estimates would likely be biased toward the null.
Since we examined risks for 50 pesticides, it is possible that as a result of multiple comparisons, some significant findings might have occurred by chance alone. The appropriate method for adjusting for multiple comparisons in epidemiologic studies, and even the need to do so, has been a matter of some controversy.63-65
However, consistency of the findings across states, replication of similar results among participants who completed the take-home questionnaire, and some evidence of an exposure-response relation in our study provide some protection against purely chance results.
Despite these limitations, the Agricultural Health Study has several important strengths over previous studies of pesticide use and cancer risk. This study is the largest epidemiologic study of applicators exposed to pesticides that has been conducted to date. All exposure information was collected prior to the diagnosis of cancer, which reduces concerns regarding bias due to differential reporting among cases and non-cases. This study included comprehensive questionnaire data that were used to quantitatively estimate pesticide exposure levels and to control for potential confounding from lifestyle factors. In addition, cancer incidence was obtained from population-based tumor registries, which eliminates issues related to survival when mortality data are the outcome. The follow-up of cohort members is also very high in this cohort (>99%).
In conclusion, this explorative study suggests an association between the incidence of colorectal cancer and use of certain pesticides, in particularly chlorpyrifos and aldicarb, although some findings could be due to chance. Given the limited epidemiologic and laboratory research on these pesticides and on environmental causes of colorectal cancer, further research is warranted.