We found no increase in overall cancer incidence with increasing lifetime pendimethalin use, and no clear evidence of increased risks for any specific cancer sites. The increased risks for lung cancer did not display a monotonic exposure–response pattern and are inconsistent for different exposure metrics. The rising risk for rectal cancer was more interesting, although based on small numbers.
Only a few studies of the mutagenicity and carcinogenicity of pendimethalin have been carried out. Generally, these studies showed no clear evidence for mutagenic or carcinogenic effects of pendimethalin either in vivo or in vitro.13
However, most recently, the U.S. EPA found that pendimethalin caused thyroid follicular cell adenomas in rats5
and concluded that pendimethalin is a possible human carcinogen. In our study, the association between the incidence of rectal cancer and pendimethalin use among pesticide applicators occurred with both lifetime exposure-days and intensity-weighted lifetime exposure-days. Although, to date, no other studies could specifically focus on pendimethalin exposure and rectal cancer, some studies have investigated the effect of overall pesticides on rectal and colon cancer.14–20
Observations for rectal cancer risk have been inconsistent,14–20
with three of these studies reporting an increased risk with increasing overall pesticide use14–16
and four showing no association.17–20
The studies showing an association between rectal cancer and possible pesticide exposure reported no elevated risk for colon cancer. The observed differences in risks between colon and rectal cancers in our 306
study and other studies14–16
suggest different etiologies for these two cancer sites, as has been suggested previously.21,22
Because of small number of rectal cancer cases (21 nonexposed and 19 exposed cases) and the absence of experimental evidence, this may be a chance finding.
The evidence for an increase in lung cancer risk among subjects with increasing pendimethalin exposure is inconclusive and based on elevated RRs only among subjects in the upper half of the top tertile using the lifetime-days exposure metric. The findings for lung cancer risk in the present study were weaker than those reported in the previous Agricultural Health Study analysis.7
These differences are largely due to different exposure cut points (tertiles were based on all cancer cases in the current study,7
whereas tertiles were based only on lung cancer cases in the previous one). In addition, adjusting for different confounders in these two analyses created small differences in the results.
Several limitations of this study are noteworthy. The intensity algorithms in this study were based on a literature review and not on direct measurements of exposure made within the study cohort. These weighting factors heavily emphasize dermal absorption over inhalation and other exposure routes. Furthermore, some subjects may have had inaccurate recall of pesticide use, thereby introducing exposure misclassification. For instance, in the present study, a few subjects (n = 19) who reported no overall pesticide use did report some pendimethalin exposure. Our sensitivity analyses showed no meaningful changes in the results when we either excluded these subjects or reclassified them as nonexposed, suggesting that classification of those subjects in the pendimethalin-exposed group did not affect our conclusions. A previous study showed that recall of pesticide use by the Agricultural Health Study cohort is comparable to the recall of other variables such as diet and alcohol consumption, which have been successfully used by epidemiologists in other studies.23
Also, applicators in our study provided plausible information on dates of use of specific pesticides when compared with external data on pesticide registrations.24
A possible error in exposure assessment introduced into this prospective study would most likely lead to nondifferential misclassification that would reduce any true excesses, thereby diminishing real exposure–response relationships. Most applicators used numerous pesticides, and some of these pesticides were highly correlated with pendimethalin exposure. We identified the five most correlated pesticides (correlation coefficients from 0.70 to 0.97) and adjusted for them in the final model. Results from the analyses by excluding either all five highly pendimethalin-correlated pesticides or only two most highly correlated ones (ie, ziram and dieldrin) from the final model did not show meaningful differences. Adjusting for all pesticide applications also did not significantly change the risk estimates. The relatively small number of cancer cases limited our ability to perform stratified analyses by smoking status, histologic type, and other conditions and exposures. Better insight into the associations between pendimethalin use and the histologic specificity for both lung cancer and rectal cancer from continued follow-up of this cohort would be valuable. Finally, we are unable to evaluate time-dependent exposures and risk because follow-up of this cohort is relatively short (7.5 years).
This is the first study of the associations between pendimethalin exposure and cancer incidence among pesticide applicators. The association with rectal cancer was not an a priori hypothesis and results must therefore be interpreted cautiously. Nonetheless, the Agricultural Health Study is the largest study of pesticide exposure in the world with detailed information on exposure for each pesticide. Data collection was conducted before diagnosis of cancer, precluding response bias. The detailed and comprehensive information on other pesticide exposures and other risk factors such as smoking history, diet, and alcohol consumption allowed us to adjust for potential confounding factors. Finally, the ongoing follow-up of the cohort affords the opportunity to replicate the analyses on new incident cancer cases arising in the cohort.