Glyphosate is the most commonly used herbicide worldwide, with both residential and agricultural uses. In 2015, the International Agency for Research on Cancer classified glyphosate as “probably carcinogenic to humans,” noting strong mechanistic evidence and positive associations for non-Hodgkin lymphoma (NHL) in some epidemiologic studies. A previous evaluation in the Agricultural Health Study (AHS) with follow-up through 2001 found no statistically significant associations with glyphosate use and cancer at any site. The AHS is a prospective cohort of licensed pesticide applicators from North Carolina and Iowa. Here, we updated the previous evaluation of glyphosate with cancer incidence from registry linkages through 2012 (North Carolina)/2013 (Iowa). Lifetime days and intensity-weighted lifetime days of glyphosate use were based on self-reported information from enrollment (1993–1997) and follow-up questionnaires (1999–2005). We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) using Poisson regression, controlling for potential confounders, including use of other pesticides. All statistical tests were two-sided. Among 54 251 applicators, 44 932 (82.8%) used glyphosate, including 5779 incident cancer cases (79.3% of all cases). In unlagged analyses, glyphosate was not statistically significantly associated with cancer at any site. However, among applicators in the highest exposure quartile, there was an increased risk of acute myeloid leukemia (AML) compared with never users (RR = 2.44, 95% CI = 0.94 to 6.32, P_trend = .11), though this association was not statistically significant. Results for AML were similar with a five-year (RR_{Quartile 4} = 2.32, 95% CI = 0.98 to 5.51, P_trend = .07) and 20-year exposure lag (RR_{Tertile 3} = 2.04, 95% CI = 1.05 to 3.97, P_trend = .04). In this large, prospective cohort study, no association was apparent between glyphosate and any solid tumors or lymphoid malignancies overall, including NHL and its subtypes. There was some evidence of increased risk of AML among the highest exposed group that requires confirmation.

Excess mortality from lymphohematopoietic malignancies, in particular myeloid leukemia, and brain cancer has been found in surveys of anatomists, pathologists, and funeral industry workers, all of whom may have worked with formaldehyde. We investigated the relation of mortality to work practices and formaldehyde exposure levels among these professionals to address cancer risk in the funeral industry. Professionals employed in the funeral industry who died between January 1, 1960, and January 1, 1986, from lymphohematopoietic malignancies (n = 168) or brain tumors (n = 48) (ie, case subjects) were compared with deceased matched control subjects (n = 265) with regard to lifetime work practices and exposures in the funeral industry, which were obtained by interviews with next of kin and coworkers, and to estimated levels of formaldehyde exposure. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by use of logistic regression. All statistical tests were two-sided. Mortality from myeloid leukemia increased statistically significantly with increasing number of years of embalming (P for trend = .020) and with increasing peak formaldehyde exposure (P for trend = .036). Compared with subjects who performed fewer than 500 lifetime embalmings, mortality from myeloid leukemia was elevated among those who performed embalmings for more than 34 years (OR = 3.9, 95% CI = 1.2 to 12.5, P = .024), who performed more than 3068 embalmings (OR = 3.0, 95% CI = 1.0 to 9.2, P = .057), and those whose estimated cumulative formaldehyde exposure exceeded 9253 parts per million-hours (OR = 3.1; 95% CI = 1.0 to 9.6, P = .047). These exposures were not related to other lymphohematopoietic malignancies or to brain cancer. Duration of embalming practice and related formaldehyde exposures in the funeral industry were associated with statistically significantly increased risk for mortality from myeloid leukemia.

Formaldehyde exposure is associated with leukemia in some epidemiological studies. In the National Cancer Institute’s formaldehyde cohort, previously followed through December 31, 1979, and updated through December 31, 1994, formaldehyde exposure was associated with an increased risk for leukemia, particularly myeloid leukemia, that increased with peak and average intensity of exposure. We extended follow-up through December 31, 2004 (median follow-up = 42 years), for 25 619 workers employed at one of 10 formaldehyde-using or formaldehyde-producing plants before 1966. We used Poisson regression to calculate relative risk (RR) estimates and 95% confidence intervals (CIs) to examine associations between quantitative formaldehyde exposure estimates (peak exposure, average intensity and cumulative exposure) and death from lymphohematopoietic malignancies. All statistical tests were two-sided and considered to be significant at P = .05. When follow-up ended in 2004, there were statistically significant increased risks for the highest vs lowest peak formaldehyde exposure category (≥4 parts per million [ppm] vs >0 to .50), all leukemia (RR = 1.42; 95% CI = 0.92 to 2.18, P trend = .12), and myeloid leukemia (RR = 1.78; 95% CI = 0.87 to 3.64, P trend = .13). There was little evidence of association for any lymphohematopoietic malignancy with average intensity or cumulative exposure at the end of follow-up in 2004. However, disease associations varied over time. For peak exposure, the highest formaldehyde-related risks for myeloid leukemia occurred before 1980, but trend tests attained statistical significance in 1990 only. After the mid-1990s, the formaldehyde-related risk of myeloid leukemia declined. Evaluation of risks over time suggests a possible link between formaldehyde exposure and lymphohematopoietic malignancies, particularly myeloid leukemia but also perhaps Hodgkin lymphoma and multiple myeloma. Observed patterns could be due to chance but are also consistent with a causal association within the relatively short induction–incubation periods characteristic of leukemogenesis. Further epidemiological study and exploration of potential molecular mechanisms are warranted.

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Glyphosate is the most widely applied herbicide worldwide, and its use has been associated with increased risks of certain hematopoietic cancers in epidemiologic studies. Animal and in vitro experiments suggest that glyphosate may induce oxidative stress, a key characteristic of carcinogens; however, evidence in human populations remains scarce. We investigated associations between glyphosate exposure and urinary oxidative stress biomarkers in the Biomarkers of Exposure and Effect in Agriculture study, a molecular epidemiologic subcohort in the Agricultural Health Study. This analysis included 268 male farmers selected based on self-reported recent and lifetime occupational glyphosate use and 100 age- and geography-matched male nonfarmers. Concentrations of glyphosate and oxidative stress biomarkers (8-hydroxy-2′-deoxyguanosine [8-OHdG], 8-iso-prostaglandin-F2α, and malondialdehyde [MDA]) were quantified in first-morning-void urine. We performed multivariable linear regression to evaluate associations of urinary glyphosate and self-reported glyphosate use with each oxidative stress biomarker. Urinary glyphosate concentrations were positively associated with levels of 8-OHdG (highest vs lowest glyphosate quartile; geometric mean ratio = 1.15, 95% confidence interval = 1.03 to 1.28; P_trend = .02) and MDA (geometric mean ratio = 1.20, 95% confidence interval = 1.03 to 1.40; P_trend = .06) overall. Among farmers reporting recent glyphosate use (last 7 days), use in the previous day was also associated with statistically significantly increased 8-OHdG and MDA levels. Compared with nonfarmers, we observed elevated 8-iso-prostaglandin-F2α levels among farmers with recent, high past 12-month, or high lifetime glyphosate use. Our findings contribute to the weight of evidence supporting an association between glyphosate exposure and oxidative stress in humans and may inform evaluations of the carcinogenic potential of this herbicide.

Background: Prostate cancer (PCa) is one of the most commonly diagnosed cancers among men in developed countries; however, little is known about modifiable risk factors. Some studies have implicated organochlorine and organophosphate insecticides as risk factors (particularly the organodithioate class) and risk of clinically significant PCa subtypes. However, few studies have evaluated other pesticides. We used data from the Agricultural Health Study, a large prospective cohort of pesticide applicators in North Carolina and Iowa, to extend our previous work and evaluate 39 additional pesticides and aggressive PCa. Methods: We used Cox proportional hazards models, with age as the time scale, to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between ever use of individual pesticides and 883 cases of aggressive PCa (distant stage, poorly differentiated grade, Gleason score ≥ 7, or fatal prostate cancer) diagnosed between 1993 and 2015. All models adjusted for birth year, state, family history of PCa, race, and smoking status. We conducted exposure-response analyses for pesticides with reported lifetime years of use. Results: There was an increased aggressive PCa risk among ever users of the organodithioate insecticide dimethoate (n = 54 exposed cases, HR = 1.37, 95% CI = 1.04, 1.80) compared to never users. We observed an inverse association between aggressive PCa and the herbicide triclopyr (n = 35 exposed cases, HR = 0.68, 95% CI = 0.48, 0.95), with the strongest inverse association for those reporting durations of use above the median (≥ 4 years; n = 13 exposed cases, HR=0.44, 95% CI=0.26, 0.77). Conclusion: Few additional pesticides were associated with prostate cancer risk after evaluation of extended data from this large cohort of private pesticide applicators.