Agricultural Health Study Cohort Research Articles

An Updated Evaluation of Atrazine-Cancer Incidence Associations among Pesticide Applicators in the Agricultural Health Study Cohort.

Atrazine is a common agricultural herbicide in the United States. Few epidemiologic studies have evaluated cancer risks. Previous analyses within the Agricultural Health Study (AHS) have found some evidence of associations with cancer at some sites. We updated exposure information, incident cases, and follow-up time to assess the associations between atrazine use and cancer at specific sites in the AHS. Information about lifetime pesticide use was reported at enrollment (1993-1997) and follow-up (1999-2005). Among 53,562 pesticide applicators in North Carolina and Iowa, we identified 8,915 incident cases through cancer registry linkages through 2014 (North Carolina)/2017 (Iowa). We used Poisson regression to evaluate the association between ever/never and intensity-weighted lifetime days of atrazine use and incident cancer risk controlling for several confounders. We also evaluated lagged exposures and age-stratified risk. Approximately 71.2% of applicators reported ever using atrazine, which was associated with lung cancer [; 95% confidence interval (CI): 1.04, 1.46]. Aggressive prostate cancer risk was increased in the highest quartile (; 95% CI: 0.95, 1.52; ), particularly among those years old (; 95% CI: 1.61, 5.75; ; ). Among applicators years of age, ever-atrazine use was associated with non-Hodgkin lymphoma (NHL) (; 95% CI: 1.10, 5.38; ). For soft tissue sarcoma, there was an elevated risk in the highest tertile of exposure (: 2.54; 95% CI: 0.97, 6.62; ). In analyses with exposure lagged by 25 years, there was an elevated risk of pharyngeal (; 95% CI: 1.45, 6.36; ) and kidney (; 95% CI: 1.15, 2.29; ) cancers. We observed suggestive associations with some malignancies in overall, age-specific, and lagged analyses. Associations with aggressive prostate cancer and NHL were apparent among those diagnosed at younger ages and with cancers of the pharynx and kidney, and soft tissue sarcomas were observed in lagged analyses. Further work is needed to confirm these observed associations and elucidate potential underlying mechanisms. https://doi.org/10.1289/EHP13684.

Joint associations between established genetic susceptibility loci, pesticide exposures, and risk of prostate cancer

More than 200 genetic variants have been independently associated with prostate cancer risk. Studies among farmers have also observed increased prostate cancer risk associated with exposure to specific organophosphate (fonofos, terbufos, malathion, dimethoate) and organochlorine (aldrin, chlordane) insecticides. We examined the joint associations between these pesticides, established prostate cancer loci, and prostate cancer risk among 1,162 cases (588 aggressive) and 2,206 frequency-matched controls nested in the Agricultural Health Study cohort. History of lifetime pesticide use was combined with a polygenic risk score (PRS) generated using 256 established prostate cancer risk variants. Logistic regression models estimated the joint associations of the pesticides, the PRS, and the 256 individual genetic variants with risk of total and aggressive prostate cancer. Likelihood ratio tests assessed multiplicative interaction. We observed interaction between ever use of fonofos and the PRS in relation to total and aggressive prostate cancer risk. Compared to the reference group (never use, PRS < median), men with ever use of fonofos and PRS > median had elevated risks of total (OR 1.35 [1.06–1.73], p-interaction = 0.03) and aggressive (OR 1.49 [1.09–2.04], p-interaction = 0.19) prostate cancer. There was also suggestion of interaction between pesticides and individual genetic variants occurring in regions associated with DNA damage response (CDH3, EMSY genes) and with variants related to altered androgen receptor-driven transcriptional programs critical for prostate cancer. Our study provides evidence that men with greater genetic susceptibility to prostate cancer may be at higher risk if they are also exposed to pesticides and suggests potential mechanisms by which pesticides may increase prostate cancer risk.

CC16 polymorphisms in asthma, asthma subtypes, and asthma control in adults from the Agricultural Lung Health Study

BackgroundThe club cell secretory protein (CC16) has anti-inflammatory and antioxidant effects and is a potential early biomarker of lung damage. The CC16 single nucleotide polymorphism (SNP) rs3741240 risk allele (A) has been inconsistently linked to asthma; other tagging SNPs in the gene have not been explored. The aim was to determine whether CC16 tagging polymorphisms are associated with adult asthma, asthma subtypes or asthma control in the Agricultural Lung Health Study (ALHS).MethodsThe ALHS is an asthma case-control study nested in the Agricultural Health Study cohort. Asthma cases were individuals with current doctor diagnosed asthma, likely undiagnosed asthma, or asthma-COPD overlap defined by questionnaire. We also examined asthma subtypes and asthma control. Five CC16 tagging SNPs were imputed to 1000 Genomes Integrated phase 1 reference panel. Logistic regression was used to estimate associations between CC16 SNPs and asthma outcomes adjusted for covariates.ResultsThe sample included 1120 asthma cases and 1926 controls of European ancestry, with a mean age of 63 years. The frequency of the risk genotype (AA) for rs3741240 was 12.5% (n = 382). CC16 rs3741240 was not associated with adult asthma outcomes. A tagging SNP in the CC16 gene, rs12270961 was associated with uncontrolled asthma (n = 208, ORadj= 1.4, 95% CI 1.0, 1.9; p = 0.03).ConclusionThis study, the largest study to investigate associations between CC16 tagging SNPs and asthma phenotypes in adults, did not confirm an association of rs3741240 with adult asthma. A tagging SNP in CC16 suggests a potential relationship with asthma control.

Pesticide exposure, genetic susceptibility, and prostate cancer risk in the Agricultural Health Study

Background and aim: Specific pesticides have been associated with risk of prostate cancer, but interactions with genetic susceptibility loci have rarely been studied. We examined the joint associations of pesticides and genetic variants with prostate cancer risk. Methods: We studied 1,162 cases (588 aggressive) and 2,206 frequency-matched controls nested in the Agricultural Health Study cohort. History of pesticide use was self-reported at enrollment. Genotyping was conducted using the OncoArray-500K BeadChip (Illumina Inc). Logistic regression models estimated the joint associations of pesticides previously linked to prostate cancer (fonofos, terbufos, malathion, aldrin, linuron, and dimethoate) and 256 individual genetic variants and an aggregated polygenic risk score (PRS) with risk of total and aggressive prostate cancer. Likelihood ratio tests assessed multiplicative interaction. Results: We observed multiplicative interaction between fonofos and the PRS in relation to risk of total and aggressive prostate cancer. Compared to the reference group (non-exposed, PRS scores &amp;#x3c;median), those with fonofos exposure and PRS scores &amp;#x3e;median had elevated risks of total (OR 1.35, 95% CI 1.06-1.73, p-int=0.03) and aggressive (OR 1.49, 95% CI 1.09-2.04, p-int=0.19) prostate cancer. There was also evidence of interaction between the six pesticides and individual genetic variants occurring in genomic regions associated with 1) cancer signaling pathways, 2) hormonal perturbations relevant for prostate cancer, 3) DNA damage response and 4) neurological traits; many of the examined pesticides have known neurologic mechanisms. Conclusion: Joint exposure to the organophosphate insecticide fonofos and genetic susceptibility may further elevate the risk for total and aggressive prostate cancer, above the independent effects of each. These results, as well as those observed for individual genetic markers, suggest potential mechanisms by which these pesticides may increase prostate cancer risk. Keyword: Prostate Cancer, Pesticides, Occupational exposure, Genetic susceptibility

Atrazine use and cancer risk within the Agricultural Health Study (AHS) cohort: An update

In the United States, atrazine is a common agricultural herbicide. Few epidemiologic studies have evaluated cancer risks associated with this ubiquitous chemical. A previous analysis within the Agricultural Health Study (AHS) in 2011 found limited evidence of cancer risk based on 3,146 exposed cases. Here, we updated that analysis with additional follow-up time and exposure information. Information about lifetime pesticide use was reported on questionnaires at enrollment (1993-1997) and follow-up (1999-2005). Among 53,508 pesticide applicators in Iowa (IA) and North Carolina (NC), there were 6,401 incident exposed cancer cases identified through linkage to state cancer registries through 2017 (IA) and 2014 (NC). We evaluated cumulative intensity-weighted lifetime days of atrazine use. Atrazine exposures were categorized into quartiles among users and compared to a non-exposed referent group. Poisson regression was applied to estimate rate ratios (RR) and 95% confidence intervals (CI) adjusting for age, smoking status and pack-years, alcohol use, family cancer history, and correlated pesticides. We also stratified by age at cancer diagnosis. Approximately 71% of applicators reported ever using atrazine. Greater use of atrazine was associated with increased risk of cancers of the lung (RRQ4=1.21, CI=0.95-1.55, p-trend=0.19, n=551 cases), and prostate (RRQ4=1.12, CI=0.98-1.28, p-trend=0.10, n=2,521); the association was stronger for aggressive prostate cancer (RRQ4=1.37, CI=1.02-1.84, p-trend=0.07, n=553). The association with prostate cancer was most pronounced among those diagnosed &amp;#x3c;50 years of age (RRQ4=3.53, CI=1.34-9.29, p-interaction=0.012). Associations with lung cancer did not vary by age. Our findings with an average of 8.5 years of additional follow-up and twice as many cases compared to a previous analysis, suggest increased risk of prostate and lung cancers is associated with atrazine use. The associations with prostate cancer were most notable among those diagnosed at younger ages and those with aggressive disease. Further work is needed to investigate the reasons for these observations.

Abstract 708: A balanced ratio of omega-6 to omega-3 fatty acids intake and prostate cancer prevention, and the potential for effect modification from organophosphate pesticides

Abstract Purpose: Although the protective effect of omega-3 fatty acids on some cancers (e.g., breast cancer) has been found, dietary effect of a balanced ratio of omega-6 to omega-3 (N-6/N-3) on prostate cancer (PCa), remains unknown. Given the positive association of terbufos and fonofos with PCa in Agricultural Health Study (AHS), we evaluated the association between N-6/N-3 and PCa, and any potential effect modification by terbufos and fonofos exposure. Study Design: This case-control study was nested within AHS cohort of farmers with dietary data. Cases with all PCa were identified through the statewide cancer registries. Self-administrated questionnaires assessed diet in 1999-2003 and pesticide in 1993-1997. We summed percentages of energy intake from N-6 (Linoleic acid+arachidonic acid) and N-3 (Eicosapentaenoic acid+docosapentaenoic acid+docosahexaenoic acid+α-linolenic acid) and categorized the N-6/N-3 into quartiles. Multivariate logistic regression was used to calculate adjusted odds ratios (aORs), controlling for age at dietary assessment, race, physical activity, smoking, terbufos, fonofos, diabetes, lycopene, family history of PCa, and the interaction of N-6/N-3 with age, terbufos and fonofos. We also conducted a stratified regression analysis by ever-never exposure to terbufos and fonofos. Results: The multivariate analysis revealed that the lowest N-6/N-3 quartile was significantly associated with a decreased risk of PCa (aOR=0.61, 95% CI: 0.41-0.9) relative to the top quartile. Comparing two strata of terbufos and fonofos exposure (ever-never), the OR in each N-6/N-3 quartile was slightly smaller within “never” group versus the same quartile in ever-exposure with nonsignificant CI limits. Conclusion: A lower N-6/N-3 was associated with decreased risk of PCa. No significant interactions between organophosphate pesticides and N-6/N-3 were observed. Category OR 95% CI Pr&amp;gt;ChiSq Odds Ratio of PCa by Quartiles of N-6/N-3; Multivariate Logistic Regression Model (Cases: 681, Controls: 8,184) N-6/N-3 Ratio Q1 0.61 (0.41-0.9) 0.01 N-6/N-3 Ratio Q2 0.87 (0.63-1.21) 0.41 N-6/N-3 Ratio Q3 0.91 (0.69-1.21) 0.52 N-6/N-3 Ratio Q4 1 N-6/N-3 and Terbufos Interaction (1,193 PCa cases and 14,872 controls) Never Exposure to Terbufos N-6/N-3 Q1 0.69 (0.53-0.9) 0.007 N-6/N-3 Q2 0.87 (0.66-1.14) 0.31 N-6/N-3 Q3 0.84 (0.65-1.08) 0.16 N-6/N-3 Q4 1.02 (0.79-1.33) 0.86 Ever Exposure to Terbufos N-6/N-3 Q1 0.86 (0.67-1.10) 0.24 N-6/N-3 Q2 0.92 (0.7-1.21) 0.55 N-6/N-3 Q3 0.91 (0.72-1.16) 0.44 N-6/N-3 Q4 1 Never Exposure to Fonofos N-6/N-3 Q1 0.73 (0.54-0.98) 0.04 N-6/N-3 Q2 0.94 (0.66-1.33) 0.73 N-6/N-3 Q3 0.86 (0.64-1.15) 0.3 N-6/N-3 Q4 1.18 (0.85-1.64) 0.33 Ever Exposure to Fonofos N-6/N-3 Q1 0.85 (0.64-1.14) 0.27 N-6/N-3 Q2 1.14 (0.81-1.59) 0.47 N-6/N-3 Q3 0.96 (0.72-1.27) 0.75 N-6/N-3 Q4 1 1 Citation Format: Homa Sadeghi, Charles Lynch, Laura Beane-Freeman, William Field, Linda Snetselaar, Michael Jones, James Torner. A balanced ratio of omega-6 to omega-3 fatty acids intake and prostate cancer prevention, and the potential for effect modification from organophosphate pesticides [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 708.

Completeness of cohort-linked U.S. Medicare data: An example from the Agricultural Health Study (1999–2016)

Medicare Fee for Service (FFS) claims data, including inpatient (Part A) and outpatient (Part B) services, provide a valuable resource for research on older adults (≥65 year) in linked U.S. cohorts. Here we describe our experience linking the Agricultural Health Study cohort, including 47,501 licensed pesticide applicators and spouses from North Carolina (NC) and Iowa (IA) to Medicare claims data from 1999 to 2016. Given increased Part C (i.e., managed care/Medicare Advantage) enrollment during this period, and a resulting lack of available Part C claims data prior to 2015, we also explored potential for informative missingness. We compared those with partial or limited/no FFS to those with complete FFS coverage (i.e., ≥11 months per year parts AB, but not C, throughout Medicare enrollment) in relation to baseline farm size, general pesticide use, and mortality, in logistic regression models adjusted for age, sex, race, education, and smoking, and stratified by state. While 46,689 participants (98%) were linked to Medicare IDs, only 33,487 (70%) had complete FFS, 9353 (20%) had partial FFS (≥1 year FFS but not complete), and 3849 (8%) had limited/no FFS (Part A or Part C-only). Incomplete FFS was more common in NC, mostly due to Part C, and was associated with farm characteristics, pesticide use, and mortality. These findings indicate that, in addition to reduced sample size in analyses limited to complete FFS, missingness may not be random. The potential impact of incomplete FFS data and changes in coverage type need to be considered when planning linked analyses and interpreting results.

Residential proximity to animal feeding operations and risk of solid tumors in the Agricultural Health Study cohort

Background: Occupational exposure to animals has been associated with several types of cancers, but little is known about risk associated with living near intensive animal farming.Methods: We evaluated associations between residential proximity to animal feeding operations (AFOs) and cancer risk in the Agricultural Health Study, a prospective cohort of pesticide applicators (mostly male farmers) and their spouses. We linked enrollment (1993-1997) addresses for participants in Iowa (33,340 applicators and 20,186 spouses) to a database of permitted AFOs that included animal units (AUs), counts standardized by animal size and manure production. We computed an inverse distance-weighted AU metric that reflects exposure proximity and intensity within 5km of residences. We estimated risk of major solid tumor sites associated with AU metric quintiles using Cox regression (hazard ratio, HR; 95% confidence interval, 95%CI), adjusting for demographics, farming-related factors (occupational pesticide use, direct animal contact), and cancer site-specific potential confounders (e.g., reproductive history). Associations were also estimated separately by animal type (swine, poultry, cattle) and self-reported occupational animal contact.Results: There were 6,137 incident solid tumors diagnosed during follow-up 1993-2015. Among applicators, testicular cancer risk increased with AU quintiles within 5km of the home (HRQ5vsQ1=3.3, 95%CI=1.0-11.0; ptrend=0.03). Prostate cancer risk was significantly elevated in the highest AU quintile (HRQ5vsQ1=1.3; 95%CI=1.1-1.5; ptrend=0.0001). For lung cancer, there was an inverse, but non-significant trend with increasing AUs (HRQ5vsQ1=0.80; 95%CI=0.50-1.2; ptrend=0.09). Among spouses, uterine cancer risk was elevated (HRQ5vsQ1=1.9, 95%CI=1.2-2.9; ptrend=0.03). Risk of breast cancer increased with cattle AUs (ptrend=0.01), but not for other animal types. We observed no effect modification by animal-related work for any cancer site.Conclusions: Our results suggest that residential proximity to AFOs may influence risk of certain solid tumors, even after consideration of farming activities and other risk factors. These findings are novel, but further evaluation is needed to identify etiologic agents.

Pesticide use and incident Parkinson's disease in a cohort of farmers and their spouses

BackgroundExtensive literature suggests an association between general pesticide use and Parkinson's disease (PD). However, with few exceptions, little is known about associations between specific pesticides and PD. ObjectiveWe evaluated use of pesticides and incident PD in 38,274 pesticide applicators and 27,836 of their spouses in the Agricultural Health Study cohort followed over 20 years. MethodsWe used self-reported information on ever-use of 50 specific pesticides as of enrollment for both applicators and spouses, and considered intensity-weighted lifetime days (IWLD) reported at enrollment and through the first 5-year follow-up among applicators. We estimated covariate-adjusted hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression. We also examined heterogeneity in associations by history of head injury and chemical resistant glove use. ResultsA total of 373 applicators and 118 spouses self-reported incident doctor-diagnosed PD. Ever-use of the insecticide terbufos (HR:1.31, 95%CI:1.02–1.68) and the herbicides trifluralin (HR:1.29, 95%CI: 0.99–1.70) and 2,4,5-T (HR:1.57, 95%CI:1.21–2.04) was associated with elevated PD risk. On the other hand, diazinon (HR:0.73, 95%CI: 0.58–0.94) and 2,4,5-TP (HR:0.39, 95%CI:0.25–0.62) were associated with reduced risk. We observed heterogeneity in ever-use associations by head injury and chemical-resistant glove use for some pesticides, with higher risk among those who reported a history of head injury, or who did not use gloves. PD risk was also elevated for applicators in the highest category of IWLD for dichlorvos, permethrin (animal use), and benomyl. ConclusionsWe found evidence of increased PD risk for some pesticides. Our results also suggest higher susceptibility for pesticide-associated PD among individuals with head injury as well as protection with use of chemical resistant gloves, although further research is needed to understand the impact of head injury. Research on current and newer pesticides, including mechanisms relevant to PD, is important given widespread pesticide use.

Farming tasks and the development of rheumatoid arthritis in the agricultural health study

ObjectivesFarming has been associated with rheumatoid arthritis (RA). Some studies have evaluated the effects of pesticides, but other agricultural exposures may also affect immune response.MethodsWe investigated non-pesticide agricultural exposures in...

Modeling groundwater nitrate exposure in private wells of North Carolina for the Agricultural Health Study

Unregulated private wells in the United States are susceptible to many groundwater contaminants. Ingestion of nitrate, the most common anthropogenic private well contaminant in the United States, can lead to the endogenous formation of N-nitroso-compounds, which are known human carcinogens. In this study, we expand upon previous efforts to model private well groundwater nitrate concentration in North Carolina by developing multiple machine learning models and testing against out-of-sample prediction. Our purpose was to develop exposure estimates in unmonitored areas for use in the Agricultural Health Study (AHS) cohort. Using approximately 22,000 private well nitrate measurements in North Carolina, we trained and tested continuous models including a censored maximum likelihood-based linear model, random forest, gradient boosted machine, support vector machine, neural networks, and kriging. Continuous nitrate models had low predictive performance (R2 < 0.33), so multiple random forest classification models were also trained and tested. The final classification approach predicted <1 mg/L, 1–5 mg/L, and ≥5 mg/L using a random forest model with 58 variables and maximizing the Cohen's kappa statistic. The final model had an overall accuracy of 0.75 and high specificity for the higher two categories and high sensitivity for the lowest category. The results will be used for the categorical prediction of private well nitrate for AHS cohort participants that reside in North Carolina.

Residential Proximity to Animal Feeding Operations and Cancer Risk in the Agricultural Health Study

Background: Concentrated animal feeding operations (AFOs) are major sources of hazardous emissions into the surrounding environment, but few studies have investigated cancer risk associated with living near intensive animal agriculture.Methods: We evaluated the association between residential proximity to AFOs and cancer risk among licensed pesticide applicators (mostly male farmers) in the Agricultural Health Study cohort. We linked enrollment (1993-1997) addresses for 32,674 participants in Iowa to a statewide database of permitted AFOs that included animal counts standardized by animal size and manure production (animal units; AUs). We created metrics to reflect exposure proximity and intensity, enumerating AFOs and animal density (quartiles of AUs) within 2 and 5km of residences. Cox regression was used to estimate associations (hazard ratio, HR; 95% confidence interval, 95%CI) with incident cancer for major tumor sites, adjusting for demographic and farming-related factors (e.g., raising animals and occupational pesticide exposure).Results: There were 4,741 incident cancers from 1993-2015. We observed increased risk for non-Hodgkin lymphoma among those residing within 5km of at least one AFO (HR&amp;#61;1.9; 95%CI&amp;#61;1.3-3.0), but without a statistically significant trend across AU quartiles (ptrend&amp;#61;0.31). Prostate cancer risk was significantly elevated in the highest AU quartile (HR&amp;#61;1.4; 95%CI&amp;#61;1.1-1.6; ptrend&amp;#61;0.01). Lung cancer associations showed an inverse, monotonic trend with increasing AUs (HRQ4&amp;#61;0.74; 95%CI&amp;#61;0.5-1.1; ptrend&amp;#61;0.04). Adjustment for contact with animals and occupational use of pesticides previously associated with these cancers did not change the results, and patterns were similar for exposures within 2km. We found no associations for other cancers.Conclusions: Our findings suggest that residential proximity to AFOs may influence risk of cancer at certain sites, even after consideration of animal contact and occupational exposure to pesticides.

Sex Steroid Hormone Single-Nucleotide Polymorphisms, Pesticide Use, and the Risk of Prostate Cancer: A Nested Case-Control Study within the Agricultural Health Study.

Experimental and epidemiologic investigations suggest that certain pesticides may alter sex steroid hormone synthesis, metabolism or regulation, and the risk of hormone-related cancers. Here, we evaluated whether single-nucleotide polymorphisms (SNPs) involved in hormone homeostasis alter the effect of pesticide exposure on prostate cancer risk. We evaluated pesticide–SNP interactions between 39 pesticides and SNPs with respect to prostate cancer among 776 cases and 1,444 controls nested in the Agricultural Health Study cohort. In these interactions, we included candidate SNPs involved in hormone synthesis, metabolism or regulation (N = 1,100), as well as SNPs associated with circulating sex steroid concentrations, as identified by genome-wide association studies (N = 17). Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Multiplicative SNP–pesticide interactions were calculated using a likelihood ratio test. We translated p-values for interaction into q-values, which reflected the false discovery rate, to account for multiple comparisons. We observed a significant interaction, which was robust to multiple comparison testing, between the herbicide dicamba and rs8192166 in the testosterone metabolizing gene SRD5A1 (p-interaction = 4.0 × 10−5; q-value = 0.03), such that men with two copies of the wild-type genotype CC had a reduced risk of prostate cancer associated with low use of dicamba (OR = 0.62 95% CI: 0.41, 0.93) and high use of dicamba (OR = 0.44, 95% CI: 0.29, 0.68), compared to those who reported no use of dicamba; in contrast, there was no significant association between dicamba and prostate cancer among those carrying one or two copies of the variant T allele at rs8192166. In addition, interactions between two organophosphate insecticides and SNPs related to estradiol metabolism were observed to result in an increased risk of prostate cancer. While replication is needed, these data suggest both agonistic and antagonistic effects on circulating hormones, due to the combination of exposure to pesticides and genetic susceptibility, may impact prostate cancer risk.

Occupational pesticide exposure and subclinical hypothyroidism in the Agricultural Health Study

Introduction: Occupational use of specific pesticides affects thyroid function in humans but epidemiologic studies of thyroid disease are limited. Methods: We evaluated occupational pesticide exposure and subclinical hypothyroidism among 679 male pesticide applicators in the Agricultural Health Study cohort (Iowa, North Carolina, USA) who participated in the Biomarkers of Exposure and Effect in Agriculture study. Self-reported lifetime use of 50 pesticides was obtained at enrollment (1993-1997). Pesticide metrics incorporated total days of use adjusted for personal protection (intensity-weighted lifetime days: none, low ≤median, high &gt;median). Blood samples were collected in 2010-2013 and were measured for thyroid- stimulating hormone (TSH) using the Millipore human pituitary panel multiplexing kit. For 40 pesticides with &gt;5 exposed cases, we used multivariate logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for subclinical hypothyroidism (TSH&gt;4.5 mU/L) compared to normal TSH (0.4-&lt;4.5mU/L), adjusting for confounders. Results: Prevalence of subclinical hypothyroidism was 18% (vs. &lt;5% in men of similar age in a national sample). Applicators exposed to the herbicides cyanazine (ORHigh:2.4, CI 1.4‒4.1) and EPTC (ORHigh:2.0, CI 1.0‒3.9), and insecticides diazinon (ORHigh: 2.5, CI 1.1‒5.8) and aldrin (ORHigh:3.0, CI 1.3‒6.7) had increased prevalence of subclinical hypothyroidism with positive exposure-response trends (ptrend&lt;0.05). No other herbicides, insecticides, fungicides, or fumigants showed significant trends. Conclusions: In this comprehensive evaluation of occupational pesticide exposure, several pesticides were positively associated with subclinical hypothyroidism. Our results for diazinon are consistent with those for self-reported clinical hypothyroidism among pesticide applicators in the cohort, supporting a role for specific pesticide exposures in hypothyroidism.

Pesticide Exposures and Body Mass Index (BMI) of Pesticide Applicators From the Agricultural Health Study

Endocrine-disrupting chemicals, including pesticides, may be associated with weight gain. This is the first longitudinal study to examine a potential association between weight gain and pesticides using data on 8,365 male pesticide applicators from the Agricultural Health Study (AHS) cohort established in 1993. The relationship between total cumulative days of exposure to pesticide functional/chemical classes and to the four most frequently used individual pesticides was studied in relation to body mass index (BMI) at the time of 5-yr follow-up (beginning in 1998) with the length of the exposure period dating back to age 20 yr. Multiple regression, Spearman correlation, ordinal logistic regression, and logistic regression models all utilized a Bonferroni-adjusted p value, were adjusted for relevant covariates, and were stratified by state of residence (Iowa/North Carolina) and presence/absence of weight-related health conditions. Adjusted multiple regression yielded statistically significant positive parameter estimates for the study sample and Iowa subgroups with consistent findings for triazine herbicides and atrazine: Change in BMI per 100 cumulative pesticide exposure days ranged from 0.07 to 0.11 for triazine herbicides and from 0.10 to 0.19 for atrazine. Ordinal logistic regression compared normal weight with overweight and with obese using the zero exposure category as referent. Statistically significant adjusted odds ratios identified for the study sample and both state subgroups for the highest level of atrazine exposure ranged from 1.4 to 1.7. Further investigation is warranted to evaluate the associations identified here.

Use of Dieselized Farm Equipment and Incident Lung Cancer: Findings from the Agricultural Health Study Cohort.

Background:Diesel exhaust is a known lung carcinogen. Farmers use a variety of dieselized equipment and thus may be at increased risk of lung cancer, but farm exposures such as endotoxins may also be protective for lung cancer.Objectives:We evaluated the relative risk of incident lung cancer, including histological subtype, from enrollment (1993–1997) to 2010–2011 in relation to farm equipment use in the Agricultural Health Study (AHS), a prospective cohort study of pesticide applicators and spouses in Iowa and North Carolina, USA.Methods:Farm equipment use was reported by 21,273 farmers and 29,840 spouses. Rate ratios (RRs) were estimated separately for farmers and spouses with Poisson regression models adjusted for smoking and other confounders. We conducted stratified analyses by exposure to animals or stored grain, a surrogate for endotoxin exposure.Results:Daily diesel tractor use (vs. no use) was positively associated with lung cancer in farmers (RR = 1.48; 95% CI: 0.87, 2.50; 35 exposed, 32 unexposed cases), particularly adenocarcinoma (RR = 3.39; 95% CI: 1.23, 9.33; 12 exposed, 7 unexposed cases). The association of adenocarcinoma with daily (vs. low/no) use of diesel tractors was stronger for farmers with no animal or stored grain exposures (RR = 6.23; 95% CI: 2.25, 17.25; 5 exposed, 18 unexposed cases) than among farmers with these exposures (RR = 1.19; 95% CI: 0.51, 2.79; 7 exposed, 27 unexposed cases) (p-interaction = 0.05).Conclusions:This study provides preliminary evidence of an increased risk of lung adenocarcinoma among daily drivers of diesel tractors and suggests that exposure to endotoxins may modify the impact of diesel exposure on lung cancer risk. Confirmation of these findings with more exposed cases and more detailed exposure information is warranted.Citation:Tual S, Silverman DT, Koutros S, Blair A, Sandler DP, Lebailly P, Andreotti G, Hoppin JA, Beane Freeman LE. 2016. Use of dieselized farm equipment and incident lung cancer: findings from the Agricultural Health Study Cohort. Environ Health Perspect 124:611–618; http://dx.doi.org/10.1289/ehp.1409238

Modeling groundwater nitrate concentrations in private wells in Iowa

Contamination of drinking water by nitrate is a growing problem in many agricultural areas of the country. Ingested nitrate can lead to the endogenous formation of N-nitroso compounds, potent carcinogens. We developed a predictive model for nitrate concentrations in private wells in Iowa. Using 34,084 measurements of nitrate in private wells, we trained and tested random forest models to predict log nitrate levels by systematically assessing the predictive performance of 179 variables in 36 thematic groups (well depth, distance to sinkholes, location, land use, soil characteristics, nitrogen inputs, meteorology, and other factors). The final model contained 66 variables in 17 groups. Some of the most important variables were well depth, slope length within 1km of the well, year of sample, and distance to nearest animal feeding operation. The correlation between observed and estimated nitrate concentrations was excellent in the training set (r-square=0.77) and was acceptable in the testing set (r-square=0.38). The random forest model had substantially better predictive performance than a traditional linear regression model or a regression tree. Our model will be used to investigate the association between nitrate levels in drinking water and cancer risk in the Iowa participants of the Agricultural Health Study cohort.

Incidence of solid tumours among pesticide applicators exposed to the organophosphate insecticide diazinon in the Agricultural Health Study: an updated analysis

ObjectiveDiazinon, a common organophosphate insecticide with genotoxic properties, was previously associated with lung cancer in the Agricultural Health Study (AHS) cohort, but few other epidemiological studies have examined diazinon-associated cancer...

Predicting Nitrate Levels in Private Wells in Iowa for the Agricultural Health Study

Background: Contamination of drinking water by nitrate is a growing problem in many agricultural areas of the country. Ingested nitrate can lead to the endogenous formation of N-nitroso compounds (NOC), which are potent animal carcinogens. Objective: The goal was to develop a predictive model for nitrate levels in private wells in Iowa for the Agricultural Health Study. Methods: We obtained 34,084 measurements of nitrate in private wells, along with well depth and location. We created a training set of approximately 30% of the observations (n = 11,940) with sampling stratified on decade of sample (1980, 1990, 2000) and bedrock status (in or above). We built random forest models to predict log nitrate levels in the training set by systematically assessing the predictive performance of 179 variables in 36 thematic groups (well depth, land use, soil characteristics, nitrogen inputs, meteorology, and other factors). Results: The final model contained 17 variable groups and 66 variables. The most important variable was well depth. Other important variables included slope length within 1 km of the well, year of sample, distance to nearest animal feeding operation, and fertilizer applications with 1 km of the well in 1978. The mean squared error in the validation samples in the training set was 2.56 and the pseudo R-square of the estimated log nitrate in the training set was 0.81. We predicted nitrate levels in the testing set (n = 22,153) with good agreement (r = 0.62) between reported nitrate levels and model predictions. The random forest model had substantially better predictive performance than a traditional linear regression model or a classification tree. Conclusion: Our results demonstrate that a random forest is useful for predicting nitrate levels in private wells. The random forest model predictions of log nitrate will be used to investigate the association between nitrate levels in drinking water and cancer risk in the Agricultural Health Study cohort.

0301 Use of acetochlor and cancer incidence in the Agricultural Health Study Cohort

ObjectivesSince its registration in 1994, acetochlor, an herbicide licensed for use on corn, has been one of the most commonly used pesticides in the US. We evaluated use of acetochlor...