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Supplemental Digital Content is available in the text., Background: Evidence from epidemiologic and laboratory studies relating pesticides to breast cancer risk is inconsistent. Women engaging in agricultural work or living in agricultural areas may experience appreciable exposures to a wide range of pesticides, including herbicides, fumigants, and fungicides. Methods: We examined exposure to herbicides, fumigants, and fungicides in relation to breast cancer risk among farmers’ wives with no prior history of breast cancer in the Agricultural Health Study. Women provided information on pesticide use, demographics, and reproductive history at enrollment (1993–1997) and at a 5-year follow-up interview. We used Cox proportional hazards regression to estimate associations (hazard ratios [HRs] and 95% confidence intervals [CIs]) between the women’s and their husbands’ self-reported use of individual pesticides and incident breast cancer risk. Results: Out of 30,594 women, 38% reported using herbicides, fumigants, or fungicides and 1,081 were diagnosed with breast cancer during a median 15.3 years of follow-up. We found elevated risk in relation to women’s ever use of the fungicide benomyl (HR = 1.6; 95% CI = 0.9, 2.7) and the herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) (HR = 1.6; 95% CI = 0.8, 3.1) and to their husbands’ use of the herbicide 2-(2,4,5-trichlorophenoxy) propionic acid (2,4,5-TP) (HR = 1.5; 95% CI = 0.9, 2.7). We observed few other chemical associations and little evidence of differential risk by tumor estrogen receptor status or linear exposure-response relationships. Conclusion: We did not observe clear excesses between use of specific pesticides and breast cancer risk across exposure metrics, although we did observe elevated risk associated with women’s use of benomyl and 2,4,5-T and husbands’ use of 2,4,5-TP.

Reactive oxygen species, potentially formed through environmental exposures, can overwhelm an organism's antioxidant capabilities resulting in oxidative stress. Long-term oxidative stress is linked with chronic diseases. Pesticide exposures have been shown to cause oxidative stress in vivo. We utilized a longitudinal study of corn farmers and non-farming controls in Iowa to examine the impact of exposure to the widely used herbicides atrazine and 2,4-dichlorophenoxyacetic acid (2,4-D) on markers of oxidative stress. 225 urine samples were collected during five agricultural time periods (pre-planting, planting, growing, harvest, off-season) for 30 farmers who applied pesticides occupationally and 10 controls who did not; all were non-smoking men ages 40-60. Atrazine mercapturate (atrazine metabolite), 2,4-D, and oxidative stress markers (malondialdehyde [MDA], 8-hydroxy-2'-deoxyguanosine [8-OHdG], and 8-isoprostaglandin-F2α [8-isoPGF]) were measured in urine. We calculated β estimates and 95% confidence intervals (95%CI) for each pesticide-oxidative stress marker combination using multivariate linear mixed-effect models for repeated measures. Farmers had higher urinary atrazine mercapturate and 2,4-D levels compared with controls. In regression models, after natural log transformation, 2,4-D was associated with elevated levels of 8-OHdG (β = 0.066, 95%CI = 0.008-0.124) and 8-isoPGF (β = 0.088, 95%CI = 0.004-0.172). 2,4-D may be associated with oxidative stress because of modest increases in 8-OHdG, a marker of oxidative DNA damage, and 8-isoPGF, a product of lipoprotein peroxidation, with recent 2,4-D exposure. Future studies should investigate the role of 2,4-D-induced oxidative stress in the pathogenesis of human diseases. Environ. Mol. Mutagen. 58:30-38, 2017. © 2016 Wiley Periodicals, Inc.

Reactive oxygen species, potentially formed through environmental exposures, can overwhelm an organism's antioxidant capabilities resulting in oxidative stress. Long-term oxidative stress is linked with chronic diseases. Pesticide exposures have been shown to cause oxidative stress in vivo. We utilized a longitudinal study of corn farmers and non-farming controls in Iowa to examine the impact of exposure to the widely used herbicides atrazine and 2,4-dichlorophenoxyacetic acid (2,4-D) on markers of oxidative stress. 225 urine samples were collected during five agricultural time periods (pre-planting, planting, growing, harvest, off-season) for 30 farmers who applied pesticides occupationally and 10 controls who did not; all were non-smoking men ages 40-60. Atrazine mercapturate (atrazine metabolite), 2,4-D, and oxidative stress markers (malondialdehyde [MDA], 8-hydroxy-2'-deoxyguanosine [8-OHdG], and 8-isoprostaglandin-F2α [8-isoPGF]) were measured in urine. We calculated β estimates and 95% confidence intervals (95%CI) for each pesticide-oxidative stress marker combination using multivariate linear mixed-effect models for repeated measures. Farmers had higher urinary atrazine mercapturate and 2,4-D levels compared with controls. In regression models, after natural log transformation, 2,4-D was associated with elevated levels of 8-OHdG (β = 0.066, 95%CI = 0.008-0.124) and 8-isoPGF (β = 0.088, 95%CI = 0.004-0.172). 2,4-D may be associated with oxidative stress because of modest increases in 8-OHdG, a marker of oxidative DNA damage, and 8-isoPGF, a product of lipoprotein peroxidation, with recent 2,4-D exposure. Future studies should investigate the role of 2,4-D-induced oxidative stress in the pathogenesis of human diseases. Environ. Mol. Mutagen. 58:30-38, 2017. © 2016 Wiley Periodicals, Inc.

Additional file 5: Table S5. Prostate specific antigen (PSA) frequencies by selected characteristicsa.

Additional file 5: Table S5. Prostate specific antigen (PSA) frequencies by selected characteristicsa.

Additional file 3: Table S3. Correlation analysis between take-home pesticides and organophosphates previously identified as associated with aggressive PCa in the AHS.

Additional file 2: Table S2. Association between pesticide (ever/never use) and overall PCa for those pesticides first reported at follow-up (Phase 2 and Phase 3 questionnaires) in the Agricultural Health Study (AHS).

Additional file 1: Table S1. Association between pesticide (ever/never use) and overall PCa for those pesticides first reported at the Phase 1 take-home (TH) questionnaire in the Agricultural Health Study (AHS).

Additional file 4: Table S4. Selected characteristics of participants in the Agricultural Health Study (AHS) cohort; aggressive prostate cancer (PCa) cases reported through 2014 in North Carolina and 2015 in Iowaa.

Additional file 1: Table S1. Association between pesticide (ever/never use) and overall PCa for those pesticides first reported at the Phase 1 take-home (TH) questionnaire in the Agricultural Health Study (AHS).

Additional file 2: Table S2. Association between pesticide (ever/never use) and overall PCa for those pesticides first reported at follow-up (Phase 2 and Phase 3 questionnaires) in the Agricultural Health Study (AHS).

Additional file 3: Table S3. Correlation analysis between take-home pesticides and organophosphates previously identified as associated with aggressive PCa in the AHS.

Additional file 4: Table S4. Selected characteristics of participants in the Agricultural Health Study (AHS) cohort; aggressive prostate cancer (PCa) cases reported through 2014 in North Carolina and 2015 in Iowaa.