Our analysis of associations between methyl bromide use and risk of all cancers combined and 12 specific cancer sites among pesticide applicators in the AHS with follow-up from 1993 through 2007 found no significant monotonic associations, except for stomach cancer, which was based on 15 exposed cases. We did not observe an association between methyl bromide and prostate cancer over the full follow-up period. However, we observed an increased risk of prostate cancer associated with high methyl bromide use in an early period of follow-up (1993–1998), consistent with a previous report in the AHS, that diminished over time. Our findings provided some evidence of an increase in prostate cancer risk with methyl bromide use among participants with a family history of prostate cancer in contrast to no association among those without a family history, but the interaction did not achieve statistical significance and there was no exposure-response relationship among those with a family history. We did not observe evidence of an interaction between methyl bromide and a family history of lung, colon, or lymphohematopoietic cancers.
Although our finding of an association between methyl bromide and stomach cancer may be due to chance, our finding is consistent with a California case-control study of stomach cancer, which observed a more than two-fold increase in risk associated with the highest compared with the lowest tertile of exposure [13
]. In addition, there is some biological plausibility for an association with stomach cancer. DNA adducts have been isolated from the stomach and forestomach of rats with oral or inhalation exposure to methyl bromide [8
], and other studies in rats have observed increased formation of hyperplastic and neoplastic lesions in the forestomach with oral exposure to methyl bromide by gavage [19
]. However, regression of the lesions following cessation of exposure raised uncertainty about the malignant nature of the lesions [20
], and the relevance of rodent forestomach carcinogenesis to human cancer risk has also been questioned [21
]. In addition, other studies in rats, using different routes of exposure, observed no evidence of methyl bromide carcinogenicity [22
Similar to a previous analysis of prostate cancer in the AHS with follow-up through 1999, which used different cutpoints for categorizing methyl bromide [10
], our findings suggested an increase in prostate cancer risk associated with methyl bromide for an early period of follow-up (1993–1998). Our results are consistent with findings from a nested case-control study among Hispanic farmworkers in California [11
], which followed participants through 1999. However, a population-based case-control study of prostate cancer in California [12
], which estimated exposure based on residential proximity to crop application of methyl bromide, observed increased prostate cancer risk for more recently diagnosed cases (2005–2006). Based on 1997 estimates, the highest methyl bromide use (pounds of active ingredient) in the United States occurred in California [24
]. More recent methyl bromide use in California compared with the AHS study region could potentially explain why the California case-control study based on diagnoses from 2005–2006 observed an association with prostate cancer, whereas we did not for recent years. In the AHS, most participants had already stopped using methyl bromide by the time of study enrollment (1993–1997), although information on specific time of cessation was not available. It is possible that the early association between methyl bromide and prostate cancer in our study was real and became diluted with continued follow-up because of the increasing time since the occurrence of exposure. We also found that the AHS prostate cancer cases diagnosed later in follow-up (1999–2007) had lower cumulative methyl bromide use compared with those diagnosed earlier (1993–1998). Thus, adding the later diagnosed cases would tend to weaken any methyl bromide association. However, it is equally possible that the early association in our study was due to chance.
A previous study among methyl bromide fumigation workers observed increased hypoxanthine-guanine phosphoribosyl transferase gene (hprt) mutations in lymphocytes and increased micronuclei formation in oropharyngeal cells [9
], which suggested a carcinogenic potential of methyl bromide with respect to hematopoietic and oropharyngeal cells. In the present study, we were unable to examine oropharyngeal cancers alone because of small numbers; however, we found little evidence of increased risk for a group of cancers in the oral cavity region, which included oropharyngeal cancers. Our findings also provided little evidence of an association between methyl bromide and lymphohematopoietic cancers. Although we observed a significant elevation in the risk of lymphohematopoietic cancers combined, as well as NHL specifically, associated with exposure in the lowest tertile (compared with the non-exposed group), the risk did not continue to increase with increasing exposure. In addition, the elevated risk did not persist when we evaluated any compared with no methyl bromide use (data not shown).
Despite the large overall sample size, infrequent use of methyl bromide resulted in relatively small numbers of exposed cases for most of the cancers, and therefore limited power to detect associations (particularly for rarer cancers). Additionally, small numbers precluded our ability to evaluate some cancers, including testicular cancer, which was of interest based on findings from a cohort of potentially exposed workers [14
]. We also expect some exposure misclassification in our study [25
], as with any study using self-reported information; however, the prospective design reduced the potential for recall or reporting bias to influence our results, and self-reported pesticide information in the AHS has been demonstrated to be reliable and consistent with the dates of introduction to the market [26
Our study had several strengths. The participation rate was high, with about 82% of the target applicator population enrolled, and there has been minimal loss to cancer follow-up (2.2% as of January 2012) in the cohort. As a cohort study, we were able to assess pesticide use prior to disease occurrence, as well as to assess exposures over time, although use of methyl bromide tended to decline over time. We focused our analyses on the intensity-weighted exposure metric, which incorporates an intensity score that has shown moderate correlation with biomarkers of pesticide exposure in post-application urine samples; however, methyl bromide has not been specifically evaluated [28
In summary, in this population of primarily white male private applicators in the AHS with follow-up from 1993 through 2007, we observed little evidence of associations between methyl bromide and most cancers examined; however, there were small numbers of exposed cases for many sites. Our finding of a significant monotonic increase in stomach cancer risk with increasing methyl bromide use is supported by a previous report of increased stomach cancer risk associated with methyl bromide in a California case-control study, as well as some experimental animal findings. This association warrants re-evaluation in the AHS with longer follow-up, as well as examination in other epidemiologic studies. Although we previously observed an association with prostate cancer in the AHS (follow-up through 1999), the association did not persist with longer follow-up. We observed a non-significant elevated risk of prostate cancer with methyl bromide use among those with a family history of prostate cancer, but the interaction with a family history did not achieve statistical significance. It is unclear whether the early finding with prostate cancer in the AHS was due to chance or whether the finding was real and potentially attenuated with continued follow-up due to diminishing methyl bromide use over time. With the declining use of methyl bromide worldwide, there are limited opportunities for further study; however, there is some potential for future work in developing countries because of the delayed phaseout in these countries, as well as areas in developed countries (e.g. California) where methyl bromide is still in use.