In this study, we prospectively evaluated associations between the reported personal use of individual OCs and incident cancers in a population of female farm spouses. Although the numbers of exposed cases were small, we observed statistically significant increased risks for use of individual OCs insecticides and several cancers, including any OC use and glioma, lindane use and glioma and pancreatic cancer, chlordane use and MM, and dieldrin use and ER−/PR- breast cancer.
In addition to chlordane, MM was non-significantly associated with any OC use and with DDT specifically. These associations are consistent with previous findings [11,12,13,14, 17, 18]. The definition of NHL used in our study is based on the most recent lymphoma classification system, which includes MM as a subtype of NHL , whereas most previous studies relied on earlier classifications which considered MM separately. A previous population-based case–control study found non-significant positive associations of ever handling (mixing or applying) aldrin, DDT, or lindane with MM . A pooled analysis of U.S. and Canadian case-controls studies found that DDT use was significantly associated with MM ; cumulative exposure to DDT, as measured by lifetime-days of use, was also significantly associated with an increasing risk trend for MM. Although not significant, in the current study, chlordane use was also positively associated with NHL and myeloid leukemia, DDT use was positively associated with NHL and myeloid leukemia, and lindane use was positively associated with NHL. There is evidence that some OCs, including lindane and DDT, cause oxidative stress and immunosuppressive effects, and that these mechanisms possibly play a role in the development of lymphohematopoietic cancers [7, 52,53,54,55].
We observed no significant association with Any OC use and breast cancer overall. Although some studies have reported an increased risk of breast cancer among women exposed to OCs during critical developmental windows in early life [41,42,43], our findings are consistent with most other studies that also did not evaluate timing of exposure [7, 29, 30, 32,33,34,35,36,37,38,39]. Although we did not have information on timing of exposure, we conducted sensitivity analyses using year of birth as a surrogate for the potential for exposure during critical developmental periods. OCs were first registered in 1948, therefore we assumed women born before 1936 would not have any OC exposures prior to menarche. When we restricted analyses to women born after 1936, the RR for breast cancer and any OC use was 1.22 (0.94–1.59) (n = 61 exposed cases) compared to 0.84 (0.60–1.18) (n = 38 exposed cases) among women who were born prior to 1936. Although there was some evidence to indicate potential differences between the two groups, the test for interaction was not statistically significant (p = 0.11. An early study by Wolff et al. found a two- to four-fold increased risk of breast cancer among women with the highest serum DDE levels, with a positive trend with increasing serum DDE . However, a follow-up study with a larger sample size found no evidence for an association of breast cancer risk with serum DDE levels . Additional studies of breast cancer and OC exposures have examined associations with mirex, HCB, and chlordane; most of these studies also reflected null or inconclusive findings [33, 36, 57,58,59].
We did, however, see an association between dieldrin use and ER−/PR- breast cancer based on only 3 exposed cases. Two previous studies reported positive associations with dieldrin use and breast cancer overall. The first, a Danish case–control study found a significant dose-related increased risk of breast cancer among women and increasing serum concentrations of dieldrin . Additionally, a previous study of AHS farm spouses found evidence for a significant increased risk of breast cancer overall among women who never personally used dieldrin, but whose husbands’ did personally apply the pesticide . This study was unable to assess associations between the wives’ personal use of dieldrin and breast cancer due to the low number of dieldrin exposed breast cancer cases. Our current analysis includes 60 more OC exposed cases and thirteen additional years of follow-up than this previous analysis , and was sufficiently powered to examine breast cancer subtypes. Few epidemiologic studies have examined associations between OC exposures and breast cancer subtypes [42, 60,61,62], and most have not found positive associations with ER-negative breast cancers. In vitro and animal studies have suggested that dieldrin, DDT, endosulfan, HCH, and toxaphene have the potential to elicit tumor promoting effects mediated through the induction of ER, androgen receptor and aromatase activities [46,47,48, 63, 64]. Given this body of literature and the small number of dieldrin exposed ER-PR- breast cancer cases, our positive finding warrants further investigation. Overall we do not see strong evidence of an association between use of an individual OC and breast cancer, consistent with the existing epidemiologic literature.
Aldrin use was associated with a non-statistically significant elevated risk for uterine cancer based on four exposed cases. Only one case–control study has examined OC exposures and endometrial cancer; no statistically significant associations were observed with several OC derivatives including DDE, oxychlordane, HCH, and HCB . Very few occupational studies have examined the relationship between endometrial cancer and exposure to other OC compounds, including polychlorinated biphenyls (PCBs) [65,66,67] and the majority of these studies’ findings were null. To our knowledge, this is the first prospective study to examine the relationship between personal use of specific OC insecticides and uterine cancer.
Any OC use and lindane specifically were associated with risk of glioma. While we lacked sufficient power for further subtype analyses, the OC-exposed glioma cases consisted of glioblastomas (n = 7), an astrocytoma (n = 1), an oligodendroma (n = 1), and mixed gliomas (n = 2). Previous studies of male farming populations have found some evidence for an increased risk of glioma with associated pesticide use [68,69,70,71,72]. However, studies examining associations between glioma and pesticide exposures among women, in agricultural populations, have provided inconsistent results. In an earlier case–control study of central nervous system cancers among women across twenty-four U.S. states, increased risks were found for women generally exposed to herbicides, insecticides, or fungicides . An analysis of occupational risk factors for glioma found significantly increased risks among women involved in occupations in agricultural services and farming, though this analysis did not examine exposures to specific pesticides . However, a case–control analysis of women in Nebraska found no association between individually evaluated OCs (i.e. aldrin, chlordane, DDT, dieldrin, heptachlor and lindane) and brain cancer . Similarly, in a case–control analysis of women in the Midwest, no association was found for gliomas and the personal application of pesticides including OCs . Mechanisms of action for OC-induced gliomas have not been proposed; however, in vitro studies have found that neurotoxic effects induced by the interaction of OCs with ER-mediated signaling pathways may play a role .
The increased risk of pancreatic cancer associated with lindane use in our study was based on only three exposed cases. Some studies have shown significant increased risks for pancreatic cancer with occupational DDT exposure [26, 27] and significantly higher levels of DDT exposure among pancreatic cancer cases versus controls . However, a previous AHS study found no evidence for an increased risk of pancreatic cancer with the OCs aldrin, DDT, heptachlor or toxaphene . The aforementioned study did not evaluate risk estimates among the spouses only, but examined combined risk estimates among the applicators and their spouses. Furthermore, a lack of exposed cases prohibited the insecticide-specific evaluation of chlordane, dieldrin and lindane. To our knowledge, no other studies have evaluated OC use and pancreatic cancers among women.
Strengths of our study include the prospective longitudinal design with little loss-to-follow-up, questionnaire information on the use of specific OCs, and regular assessment of cancer incidence and mortality via linkage with state registries. The AHS also has detailed information on many possible confounders. Most previous studies of OC exposures and cancer, except for studies of DDT and breast cancer [7, 29,30,31,32, 36, 38, 78] have primarily focused on occupationally-exposed men . Our study examined the personal use of DDT, and other specific OCs, in a population of farm women. Few studies have evaluated personal use of specific OCs. While breast cancer has been the most widely studied cancer with respect to OCs, in particular DDT, no studies thus far have prospectively studied OCs and other hormone-mediated cancers.
Limitations of this analysis include the small number of cases exposed to specific OCs and lack of information on duration, time period, and intensity of OC use. While we had a low response rate of the female and family health questionnaire, our reported results and final models were based solely on information collected from the spousal enrollment questionnaire. Questionnaire information was collected at study enrollment (1993–1997), thus changes in individual characteristics (i.e. menopausal status, smoking) since enrollment were not captured in this analysis. In addition, most OCs examined in this analysis have been banned for use in the United States since the 1970s. Because OCs have long half-lives, and are known to persist in the environment and human body for long periods of time [1,2,3], exposure to OCs through environmental exposure pathways may also contribute to lifetime cumulative exposure. This could be particularly important in farm situations where OCs may have been used in the past.