An association between carbofuran and lung cancer has not been previously reported. Several studies, however, have found pesticides (Brownson et al. 1993
; Wesseling et al. 1999
) and more specifically carbamate pesticides (Pesatori et al. 1994
) to be associated with lung cancer, although not all studies have reported this association (McDuffie et al. 1990
). In our study, lung cancer was associated with lifetime exposure-days where risk increased across exposure categories to more than a 3-fold increase in the RR in the highest category when compared with those who had applied < 9 lifetime exposure-days. The risk estimates were also elevated when the components of the lifetime exposure-days exposure metric were considered separately. Lung cancer risk, however, was not associated with carbofuran exposure when the intensity-weighted exposure-days metric was used or when non-carbofuran–exposed pesticide applicators were used as the referent.
This inconsistency between the lung cancer risk estimates when nonexposed subjects were used as the referent may be caused partly by differences between nonexposed and low-exposed groups with regard to unknown factors. Initial descriptive analyses indicated that the nonexposed and the low-exposed groups had substantial differences with regard to corn production and the total number of pesticides used. The observed differences between those with carbofuran exposure and those without carbofuran exposure raise the possibility of confounding due to other unmeasured differences between the groups. Given these differences, the low-exposed subjects may be a more appropriate reference group, although the low-exposed group may be biased as well. In addition, the inconsistency observed between the lifetime exposure-days and intensity-weighted lifetime exposure-days metrics may have occurred because the AHS intensity-weighted algorithm greatly weights dermal exposure, and this route may be less appropriate for sites where the respiratory tract is the predominant exposure route, such as the lung. Further, the intensity-weighted algorithm, as constructed, also reflects more recent use of personal protective equipment and application methods. Malignant neoplasms generally have a long latency period. To the extent that recent exposure intensity does not accurately reflect past activities, the algorithm may increase exposure misclassification rather than reduce it.
The association between lung cancer and carbofuran exposure that we observed when the low-exposed group was used as the referent is unlikely to be confounded by smoking because pack-years of smoking was not correlated with lifetime exposure-days (r = 0.03) or intensity-weighted lifetime exposure-days (r = 0.02). Furthermore, we adjusted for smoking (never, < 14 pack-years, and ≥ 14 pack-years) in the models. Even when we used pack-years as a continuous variable or a combination of smoking status (never, former, current), number of cigarettes smoked per day and number of years smoked, the risk estimates were similar with each respective model. We also stratified by smoking status and found that the association was relatively consistent between former and current smokers. There were too few lung cancer cases to determine whether carbofuran was associated with lung cancer independent of smoking. Therefore, we cannot rule out the possibility that the association between carbofuran and the risk of lung cancer is limited to smokers and former smokers.
Agricultural exposure to endotoxin from rearing livestock has been hypothesized to reduce the risk of lung cancer (Lange et al. 2003a
; Mastrangelo et al. 1996
). Although we did not formally assess exposure to endotoxin, we conducted an analysis stratifying the cohort into those who were engaged in animal husbandry and those who were not. There was no indication that animal husbandry modified the effect of carbofuran use on lung cancer risk. In addition, engaging in animal husbandry did not confound the association between carbofuran use and lung cancer because the RRs were not altered when we included a binary animal husbandry variable in the model.
Several previous investigations of NHL have observed increases in risk associated with carbofuran exposure (McDuffie et al 2001
; Zheng et al. 2001
). In addition, results from several animal models support the hypothesis that exposure to carbofuran could be a risk factor for NHL (Borzsonyi and Pinter 1977
; Borzsonyi et al. 1976
). We found little evidence to support an association between NHL and carbofuran exposure, although relatively few cases of NHL had accrued at the time of this analysis.
There is evidence that carcinogenic N-nitrosocarbofuran is formed from carbofuran and nitrites in the stomach. A priori, we expected carbofuran exposure to be associated with increased risk for stomach cancer; however, at the time these analyses were conducted, too few cases of stomach cancer had occurred in the carbofuran exposed cohorts for meaningful analysis.
There are some important limitations of this study. Although the incidence of cancers will increase as the cohort ages, currently we remain constrained by small numbers of cases for many tumor sites. For instance, only five cases of stomach cancer with exposure to carbofuran were available for analysis. The resulting statistical imprecision makes interpretation of risk estimates difficult in some instances. Another potential concern in prospective studies is loss to follow-up. However, losses to follow-up (< 2%) were few and were unlikely to substantially bias the risk estimates. In addition, pesticides are commonly used as formulations where only a percentage of the total product applied is the active ingredient. Given that pesticides are applied as complex mixtures or solutions, we cannot rule out the possibility that the combination or the “inert” ingredients are the actual carcinogenic compound(s).
The strengths of this study include the prospective design, where exposure to pesticides was determined before the onset of disease, thereby eliminating the potential for recall bias. In addition, the exposure metrics used in this study represent a major improvement in the classification of pesticide exposure over previous studies, although, undoubtedly, some exposure misclassification is present in our estimates as well.
Multicolinearity between pesticides used may be another potential limitation of this study. We assessed exposure to 50 pesticides in registered pesticide applicators who, on average, used numerous pesticides. Because it is possible that carbofuran use is related to several other pesticides, we identified the five most correlated pesticides and adjusted for them in the model. Overall, exposure to other individual pesticides was highly correlated with carbofuran exposure. The correlation coefficients ranged between 0.69 (permethrin) and 0.85 (trichlorfon). However, these pesticides did not confound the association between carbofuran and lung cancer because the risk estimates were not altered when they were removed from the model. In addition, we also adjusted for cumulative lifetime application days of all pesticides, which did not appreciably alter the risk estimates.
Overall, we examined the risk of several cancer sites in relation to the carbofuran exposure. Carbofuran is a carbamate insecticide with questionable carcinogenic properties in animals. The parent compound does not seem to be genotoxic. However, the metabolites of carbofuran may be mutagenic, and there is good evidence that nitrosated carbofuran is mutagenic. This study suggests that carbofuran may be associated with an increase in the incidence of lung cancer. Conversely, carbofuran exposure was not associated with other tumor sites investigated. The results for lung cancer are provocative but should be interpreted cautiously in light of the paucity of other studies to corroborate these findings, and a reevaluation of carbofuran in the AHS cohort once more cancer cases have accrued is warranted.