Pesticide use and inflammatory bowel disease in licensed pesticide applicators and spouses in the Agricultural Health Study.

BACKGROUND: Pesticide exposure has been linked to some autoimmune diseases and colorectal cancer, possibly via alteration of gut microbiota or other mechanisms. While pesticides have been linked to gut dysbiosis and inflammation in animal models, few epidemiologic studies have examined pesticides in relation to inflammatory bowel disease (IBD). OBJECTIVES: We evaluated use of pesticides and incident IBD in 68,480 eligible pesticide applicators and spouses enrolled in the Agricultural Health Study. METHODS: Self-reported IBD cases were identified from follow-up questionnaires between enrollment (1993-1997) and 2022. We evaluated IBD incidence in relation to self-reported ever use of 50 pesticides among applicators and spouses. We also explored associations with intensity-weighted lifetime days (IWLD) of pesticide use among male applicators. Covariate-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression. RESULTS: We identified 454 IBD cases, including 227 among male applicators. In analyses with applicators and spouses combined, associations were positive (HR > 1.2) for ever vs. never use of five organochlorine insecticides, three organophosphate insecticides, one fungicide, and five herbicides. HRs were highest for dieldrin (HR = 1.59, 95%CI: 1.03, 2.44), toxaphene (HR = 1.61, 95%CI: 1.17, 2.21), parathion (HR = 1.42, 95%CI: 1.03, 1.95), and terbufos (HR = 1.53, 95%CI: 1.19, 1.96). We had limited power in many IWLD of pesticide use analyses and did not find clear evidence of exposure-response trends; however, we observed elevated HRs in all tertiles of IWLD use of terbufos compared to never use (T1 vs. never use HR = 1.52, 95%CI: 1.03, 2.24; T2 vs. never use HR = 1.53, 95%CI: 1.04, 2.26; T3 vs. never use HR = 1.51, 95%CI: 1.03, 2.23). CONCLUSIONS: Exposure to specific pesticides was associated with elevated hazards of IBD. These findings may have public health importance given the widespread use of pesticides and the limited number of known modifiable environmental risk factors for IBD.

Occupational farm work activities influence workers' indoor home microbiome.

BACKGROUND: Farm work entails a heterogeneous mixture of exposures that vary considerably across farms and farmers. Farm work is associated with various health outcomes, both adverse and beneficial. One mechanism by which farming exposures can impact health is through the microbiome, including the indoor home environment microbiome. It is unknown how individual occupational exposures shape the microbial composition in workers' homes. OBJECTIVES: We investigated associations between farm work activities, including specific tasks and pesticide use, and the indoor microbiome in the homes of 468 male farmers. METHODS: Participants were licensed pesticide applicators, mostly farmers, enrolled in the Agricultural Lung Health Study from 2008 to 2011. Vacuumed dust from participants' bedrooms underwent whole-genome shotgun sequencing for indoor microbiome assessment. Using questionnaire data, we evaluated 6 farm work tasks (processing of either hay, silage, animal feed, fertilizer, or soy/grains, and cleaning grain bins) and 19 pesticide ingredients currently used in the past year, plus 7 banned persistent pesticide ingredients ever used. RESULTS: All 6 work tasks were associated with increased microbial diversity levels, with a positive dose-response for the total number of tasks performed (P = 0.001). All tasks were associated with altered microbial compositions (weighted UniFrac P = 0.001) and with higher abundance of specific microbes, including soil-based commensal microbes such as Haloterrigena. Among the 19 pesticides, current use of glyphosate and past use of lindane were associated with increased microbial diversity (P = 0.02-0.04). Ten currently used pesticides and all 7 banned pesticides were associated with altered microbial composition (P = 0.001-0.04). Six pesticides were associated with differential abundance of certain microbes. DISCUSSION: Different farm activities and exposures can uniquely impact the dust microbiome inside homes. Our work suggests that changes to the home microbiome could serve as one pathway for how occupational exposures impact the health of workers and their cohabitating family members, offering possible future intervention targets.

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.

The role of environmental exposures and gene-environment interactions in the etiology of systemic lupus erythematous.

Systemic lupus erythematosus (SLE) is a complex, chronic autoimmune disease, whose etiology includes both genetic and environmental factors. Individual genetic risk factors likely only account for about one-third of observed heritability among individuals with a family history of SLE. A large portion of the remaining risk may be attributable to environmental exposures and gene-environment interactions. This review focuses on SLE risk associated with environmental factors, ranging from chemical and physical environmental exposures to lifestyle behaviors, with the weight of evidence supporting positive associations between SLE and occupational exposure to crystalline silica, current smoking, and exogenous estrogens (e.g., oral contraceptives and postmenopausal hormones). Other risk factors may include lifestyle behaviors (e.g., dietary intake and sleep) and other exposures (e.g., ultraviolet [UV] radiation, air pollution, solvents, pesticides, vaccines and medications, and infections). Alcohol use may be associated with decreased SLE risk. We also describe the more limited body of knowledge on gene-environment interactions and SLE risk, including IL-10, ESR1, IL-33, ITGAM, and NAT2 and observed interactions with smoking, UV exposure, and alcohol. Understanding genetic and environmental risk factors for SLE, and how they may interact, can help to elucidate SLE pathogenesis and its clinical heterogeneity. Ultimately, this knowledge may facilitate the development of preventive interventions that address modifiable risk factors in susceptible individuals and vulnerable populations.

Baseline factors associated with self-reported disease flares following COVID-19 vaccination among adults with systemic rheumatic disease: results from the COVID-19 global rheumatology alliance vaccine survey.

OBJECTIVE: To examine the frequency of, and risk factors for, disease flare following COVID-19 vaccination in patients with systemic rheumatic disease (SRD). METHODS: An international study was conducted from 2 April to 16 August 2021, using an online survey of 5619 adults with SRD for adverse events following COVID-19 vaccination, including flares of disease requiring a change in treatment. We examined risk factors identified a priori based on published associations with SRD activity and SARS-CoV-2 severity, including demographics, SRD type, comorbidities, vaccine type, cessation of immunosuppressive medications around vaccination and history of reactions to non-COVID-19 vaccines, using multivariable logistic regression. RESULTS: Flares requiring a change in treatment following COVID-19 vaccination were reported by 4.9% of patients. Compared with rheumatoid arthritis, certain SRD, including systemic lupus erythematosus (OR 1.51, 95% CI 1.03, 2.20), psoriatic arthritis (OR 1.95, 95% CI 1.20, 3.18) and polymyalgia rheumatica (OR 1.94, 95% CI 1.08, 2.48) were associated with higher odds of flare, while idiopathic inflammatory myopathies were associated with lower odds for flare (OR 0.54, 95% CI 0.31-0.96). The Oxford-AstraZeneca vaccine was associated with higher odds of flare relative to the Pfizer-BioNTech vaccine (OR 1.44, 95% CI 1.07, 1.95), as were a prior reaction to a non-COVID-19 vaccine (OR 2.50, 95% CI 1.76, 3.54) and female sex (OR 2.71, 95% CI 1.55, 4.72). CONCLUSION: SRD flares requiring changes in treatment following COVID-19 vaccination were uncommon in this large international study. Several potential risk factors, as well as differences by disease type, warrant further examination in prospective cohorts.

High Pesticide Exposure Events and Dream-Enacting Behaviors Among US Farmers.

BACKGROUND: Dream-enacting behavior is a characteristic feature of rapid eye movement sleep behavior disorder, the most specific prodromal marker of synucleinopathies. Pesticide exposure may be associated with dream-enacting behaviors, but epidemiological evidence is limited. OBJECTIVES: To examine high pesticide exposure events in relation to dream-enacting behaviors among farmers in the Agricultural Health Study. METHODS: We conducted multivariable logistic regression analyses to examine high pesticide exposure events reported from 1993 to 1997 in relation to dream-enacting behaviors assessed from 2013 to 2015 among 11,248 farmers (age 47 ± 11 years). RESULTS: A history of dream-enacting behaviors was reported by 939 (8.3%) farmers. Compared with farmers who did not report any high pesticide exposure event, those who reported were more likely to endorse dream-enacting behaviors 2 decades later (odds ratio = 1.75; 95% confidence interval [CI], 1.49-2.05). The association appeared stronger when there was a long delay in washing with soap and water after the event (2.63 [95% CI, 1.62-4.27] for waiting >6 hours vs. 1.71 [95% CI, 1.36-2.15] for washing within 30 minutes) and when the exposure involved the respiratory or digestive tract (2.04 [95% CI, 1.62-2.57] vs. 1.58 [95% CI, 1.29-1.93] for dermal contact only). In the analyses of specific pesticides involved, we found positive associations with two organochlorine insecticides (dichlorodiphenyltrichloroethane and lindane), four organophosphate insecticides (phorate, ethoprop, terbufos, and parathion), two herbicides (alachlor and paraquat), and fungicides as a group. CONCLUSIONS: This study provides the first epidemiological evidence that high pesticide exposures may be associated with a higher risk of dream-enacting behaviors. © 2022 International Parkinson and Movement Disorder Society.

Use of permethrin and other pyrethroids and mortality in the Agricultural Health Study.

OBJECTIVES: Pyrethroid insecticides have been linked with multiple health outcomes. One study reported an association with increased all-cause and cardiovascular mortality. Given the widespread use of pyrethroids, these findings warrant confirmation. We explored associations of permethrin/pyrethroid use with overall and cause-specific mortality among 50 665 licensed pesticide applicators in the Agricultural Health Study. METHODS: At enrolment (1993-1997), participants self-reported information on permethrin/pyrethroid use. Information on causes of death came from linkage with death registries through 2016. We used Cox proportional hazards models to estimate HRs and 95% CIs with adjustment for potential confounders. RESULTS: Over an average 21 years of follow-up, 19.6% (9,955) of the cohort died. We found no clear evidence that ever-use of permethrin/pyrethroid was associated with elevated overall mortality or with mortality from most causes examined. There was suggestive evidence, based on a small number of deaths among those exposed, for elevated pyrethroid-associated mortality from some neurological, respiratory and genitourinary diseases in the overall sample and from lung cancer among never-smokers. CONCLUSION: Although based on mortality, which is also affected by survival, rather than incidence, these findings are biologically plausible, and future investigations in other populations may be warranted.

House dust microbiota in relation to adult asthma and atopy in a US farming population.

BACKGROUND: Bacterial exposure from house dust has been associated with asthma and atopy in children but whether these relationships are present in adults remains unclear. OBJECTIVE: We sought to examine associations of house dust microbiota with adult asthma, atopy, and hay fever. METHODS: Vacuumed bedroom dust samples from the homes of 879 participants (average age, 62 years) in the Agricultural Lung Health Study, a case-control study of asthma nested within a farming cohort, were subjected to 16S rRNA amplicon sequencing to characterize bacterial communities. We defined current asthma and hay fever using questionnaires and current atopy by blood specific IgE level > 0.70 IU/mL to 1 or more of 10 common allergens. We used linear regression to examine whether overall within-sample bacterial diversity differed by outcome, microbiome regression-based kernel association test to evaluate whether between-sample bacterial community compositions differed by outcome, and analysis of composition of microbiomes to identify differentially abundant bacterial taxa. RESULTS: Overall diversity of bacterial communities in house dust was similar by asthma status but was lower (P < .05) with atopy or hay fever. Many individual bacterial taxa were differentially abundant (false-discovery rate, <0.05) by asthma, atopy, or hay fever. Several taxa from Cyanobacteria, Bacteroidetes, and Fusobacteria were more abundant with asthma, atopy, or hay fever. In contrast, several taxa from Firmicutes were more abundant in homes of individuals with adequately controlled asthma (vs inadequately controlled asthma), individuals without atopy, or individuals without hay fever. CONCLUSIONS: Microbial composition of house dust may influence allergic outcomes in adults.

Pesticide use and kidney function among farmers in the Biomarkers of Exposure and Effect in Agriculture study.

BACKGROUND: Pesticides have been reported to be associated with malignant and non-malignant kidney disease. Few studies have examined the relationship between individual pesticides and kidney dysfunction. OBJECTIVE: We evaluated the associations of pesticide use with measured kidney function among male pesticide applicators in the Biomarkers of Exposure and Effect in Agriculture (BEEA) study, a subcohort in the Agricultural Health Study. METHODS: Serum creatinine was measured in 1545 BEEA participants and estimated glomerular filtration rate (eGFR) was calculated with the chronic kidney disease epidemiology collaboration (CKD-EPI) equation. Using reported information on lifetime use of 41 pesticides, multivariable linear and logistic regression was used to examine associations with eGFR modeled continuously and with CKD (eGFR <60 mL/min/1.73 m2), respectively. Models were adjusted for possible confounding factors related to kidney function and correlated pesticides. RESULTS: Lower eGFR was observed among pesticide applicators who ever used the herbicides pendimethalin (-3.7%, 95% confidence interval (CI): 5.8%, -1.5%), atrazine (-3.7%, 95% CI: 6.9%, -0.4%), and dicamba (-2.8%, 95% CI: 5.3%, -0.2%) compared with never users of each pesticide. Ever use of pendimethalin (odds ratio (OR)=1.6, 95% CI: 1.1, 2.2) and atrazine (OR=1.8, 95% CI: 1.0, 3.0) was also associated with elevated odds of CKD, with an exposure-response association between intensity-weighted lifetime days of pendimethalin use and CKD among active farmers (N=1302; ptrend=0.04). Atrazine use within the last year was associated with lower eGFR and elevated odds of CKD when compared with never users, and we observed exposure-response associations with intensity-weighted lifetime days among recent users. Use of several other pesticides was associated with higher eGFR. DISCUSSION: These results suggest that two widely used herbicides, pendimethalin and atrazine, may be associated with altered kidney function among pesticide applicators. Our findings for these herbicides are consistent with observed associations with end-stage renal disease in the Agricultural Health Study.

Racial/Ethnic Disparities in the Relationship Between Traumatic Childhood Experiences and Suboptimal Sleep Dimensions Among Adult Women: Findings from the Sister Study.

BACKGROUND: Traumatic childhood experiences (TCEs) are associated with poor adulthood sleep, but racial/ethnic disparities have not been well-studied. We investigated the TCE-adulthood sleep relationship among non-Hispanic (NH)-White, NH-Black, and Hispanic/Latina women. METHOD: Women enrolled in the Sister Study from 2003 to 2009 reported the following TCEs in a follow-up interview (2008-2012): natural disasters; major accidents; household dysfunction; and sexual, physical, and psychological/emotional abuse. Sleep characteristics included short sleep duration (< 7 h vs. 7-9 h), long sleep onset latency (SOL) (> 30 vs. ≤ 30 min), frequent night awakenings (≥ 3 times/night ≥ 3 times/week [yes vs. no]), and frequent napping (≥ 3 vs. < 3 times/week). Using log-binomial regression to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs) for sleep characteristics among women with vs. without TCEs, we investigated racial/ethnic-specific associations and race/ethnicity as a moderator. RESULTS: Among 40,082 participants (mean age = 55 ± 8.8 years), 55% reported ≥ 1 TCE (NH-White, 54%; NH-Black, 62%; Hispanic/Latina, 57%). NH-White, NH-Black, and Hispanic/Latina women reporting any TCE had a higher prevalence of short sleep compared with their within-race/ethnicity counterparts without TCEs. Associations were strongest among NH-Whites. Compared to NH-Whites with no TCEs, racial/ethnic minorities who reported any TCEs had a higher prevalence of short sleep (PRBlacks = 2.13 [95% CI 2.02-2.24], PRHispanics/Latinas = 1.47 [1.35-1.60]) and long SOL. When comparing racial/ethnic minorities with TCEs to NH-Whites with TCEs, PRs for short sleep (PRBlacks = 1.98 [1.88-2.08] and PRHispanics/Latinas = 1.36 [1.25-1.48]) and long SOL were weaker. CONCLUSION: TCEs were positively associated with poor sleep characteristics among women, and TCEs appear to contribute to short sleep duration and long SOL disparities.

Epigenome-wide association study of DNA methylation and adult asthma in the Agricultural Lung Health Study.

Epigenome-wide studies of methylation in children support a role for epigenetic mechanisms in asthma; however, studies in adults are rare and few have examined non-atopic asthma. We conducted the largest epigenome-wide association study (EWAS) of blood DNA methylation in adults in relation to non-atopic and atopic asthma.We measured DNA methylation in blood using the Illumina MethylationEPIC array among 2286 participants in a case-control study of current adult asthma nested within a United States agricultural cohort. Atopy was defined by serum specific immunoglobulin E (IgE). Participants were categorised as atopy without asthma (n=185), non-atopic asthma (n=673), atopic asthma (n=271), or a reference group of neither atopy nor asthma (n=1157). Analyses were conducted using logistic regression.No associations were observed with atopy without asthma. Numerous cytosine-phosphate-guanine (CpG) sites were differentially methylated in non-atopic asthma (eight at family-wise error rate (FWER) p<9×10-8, 524 at false discovery rate (FDR) less than 0.05) and implicated 382 novel genes. More CpG sites were identified in atopic asthma (181 at FWER, 1086 at FDR) and implicated 569 novel genes. 104 FDR CpG sites overlapped. 35% of CpG sites in non-atopic asthma and 91% in atopic asthma replicated in studies of whole blood, eosinophils, airway epithelium, or nasal epithelium. Implicated genes were enriched in pathways related to the nervous system or inflammation.We identified numerous, distinct differentially methylated CpG sites in non-atopic and atopic asthma. Many CpG sites from blood replicated in asthma-relevant tissues. These circulating biomarkers reflect risk and sequelae of disease, as well as implicate novel genes associated with non-atopic and atopic asthma.

Residential Proximity to Intensive Animal Agriculture and Risk of Lymphohematopoietic Cancers in the Agricultural Health Study.

BACKGROUND: Although occupational exposure to animals has been associated with lymphohematopoietic malignancies, to our knowledge no studies have evaluated adult cancer risks associated with living near intensive animal agriculture. METHODS: We linked participants in the prospective Agricultural Health Study to permitted animal feeding operations in Iowa. We created metrics reflecting the intensity of animal exposures within 2 and 5 km of participants' residences, enumerating both total and inverse distance-weighted animal units (AUs), standardized by animal size and manure production. We estimated risk of lymphohematopoietic malignancies and subtypes [hazard ratio (HR), 95% confidence interval (95% CI)], adjusting for demographic and farming-related factors, including occupational pesticide exposure. We stratified associations by animal type and animal-related work activities. RESULTS: We observed 519 cases (1993-2015) among 32,635 pesticide applicators and 211 cases among 19,743 spouses. Among applicators, no associations were evident within 2 km, but risk of any lymphohematopoietic cancer was elevated across quintiles of weighted AUs within 5 km. Risk of non-Hodgkin lymphoma (NHL) was elevated for the second (HR = 1.5; 95% CI, 1.1, 2.1), third (HR = 1.6; 95% CI, 1.1, 2.2), and fourth (HR = 1.7; 95% CI, 1.3, 2.4) highest quintiles of weighted AUs within 5 km (Ptrend = 0.52) and increased with dairy cattle AUs (Ptrend = 0.04). We found positive trends for leukemia and some NHL subtypes with increasing numbers of both beef and dairy cattle. Risks did not vary by animal-related work (Pinteraction = 0.61). Associations were similar using the total exposure metric and inconsistent among spouses. CONCLUSION: Residential proximity to intensive animal agriculture was positively associated with risk of NHL and leukemia, even after consideration of occupational animal and pesticide exposures.

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

BACKGROUND: Extensive 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. OBJECTIVE: We 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. METHODS: We 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. RESULTS: A 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. CONCLUSIONS: We 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.

Pesticide exposure and risk of aggressive prostate cancer among private pesticide applicators.

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.

Cancer incidence in the Agricultural Health Study after 20 years of follow-up.

PURPOSE: To evaluate cancer incidence in the Agricultural Health Study (AHS), a cohort of private pesticide applicators, their spouses, and commercial applicators, based on 12,420 cancers, adding 5,989 cancers, and 9 years of follow-up since last evaluation. METHODS: We calculated age, year, sex, and race-adjusted standardized incidence ratios (SIR) and 95% confidence intervals (CI) for cancer sites in the AHS relative to the general population. RESULTS: Overall AHS cancer incidence was lower than the general population (SIRprivate = 0.91, CI 0.89-0.93; SIRspouse = 0.89, CI 0.86-0.92; SIRcommercial = 0.83, CI 0.76-0.92), with notable deficits across applicators and spouses for oral cavity, pancreas, and lung cancers. Cancer excesses included prostate cancer, lip cancer, certain B-cell lymphomas (e.g., multiple myeloma), acute myeloid leukemia (AML), thyroid cancer, testicular cancer, and peritoneal cancer. The lung cancer deficit was strongest among applicators reporting potential exposure to endotoxin at study enrollment (tasks such as raising animals and handling stored grain). CONCLUSIONS: Although an overall deficit in cancer was observed, there were notable exceptions, including newly observed excesses for AML, thyroid, testicular, and peritoneal cancers. Furthermore, endotoxin exposure may, in part, account for observed lung cancer incidence deficits. Cancer incidence patterns in the AHS suggest farm exposures' relevance to cancer etiology.

Cellular aging over 13 years associated with incident antinuclear antibody positivity in the Baltimore Longitudinal Study of Aging.

Age-associated increases in antinuclear antibodies (ANA) in the general population are commonly noted but the mechanisms underlying this observation are unclear. This study aims to evaluate whether shorter peripheral blood mononuclear cell (PBMC) telomere length, a marker of more advanced biological age, is associated with ANA positivity prevalence and incidence in middle and older aged autoimmune disease-free individuals from the Baltimore Longitudinal Study of Aging (BLSA). Telomere length was measured by Southern Blot and categorized into tertiles. ANA was measured in a 1:80 and a 1:160 dilution of sera by immunofluorescence using HEp-2 cells (seropositive = 3 or 4). Multiple logistic regression was used to estimate the odds ratios and 95% confidence intervals of ANA positivity comparing the shorter tertiles of telomere length to the longest tertile for two cross-sectional points in time and then longitudinally to assess the association between shorter telomere length and incident ANA positivity. Cross-sectional analyses were adjusted for sex, race and BMI (N = 368 baseline, N = 370 follow-up) and longitudinal analyses were adjusted for sex, race, BMI and time between baseline and follow-up (N = 246). No statistically significant cross-sectional associations were observed at baseline or follow-up. Among those where ANA negative at baseline, individuals with shorter telomeres were more likely to be ANA positive at follow-up, an average 13 years later. Individuals with short telomeres at both time periods were more likely to be ANA positive. Findings suggest that ANA positivity in the general population may be indicative of immune dysfunction resulting from advanced cellular aging processes.

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

OBJECTIVES: Farming has been associated with rheumatoid arthritis (RA). Some studies have evaluated the effects of pesticides, but other agricultural exposures may also affect immune response. METHODS: We investigated non-pesticide agricultural exposures in relation to RA in licensed pesticide applicators (n=27 175, mostly male farmers) and their spouses (n=22 231) in the Agricultural Health Study (AHS) cohort (1993-1997) who completed at least one follow-up survey through 2015. Incident RA cases (n=229 applicators and 249 spouses) were identified based on self-report confirmed by use of disease-modifying antirheumatic drugs or medical records. Hazard Ratios (HRs) and 95% Confidence Intervals (CIs) were estimated by Cox proportional hazard models adjusting for applicator status, state, smoking, education and specific pesticide use, allowing estimates to vary by median age when hazards assumptions were not met. RESULTS: Overall, RA was associated with regularly applying chemical fertilisers (HR=1.50; 95% CI 1.11 to 2.02), using non-gasoline solvents (HR=1.40; 95% CI 1.09 to 1.80), and painting (HR=1.26; 95% CI 1.00 to 1.59). In older applicators (>62 years), RA was associated with driving combines (HR=2.46; 95% CI 1.05 to 5.78) and milking cows (HR=2.56; 95% CI 1.01 to 6.53). In younger participants (≤62 years), RA was inversely associated with raising animals as well as crops (HR=0.68; 95% CI 0.51 to 0.89 vs crops only). Associations with specific crops varied by age: some (eg, hay) were inversely associated with RA in younger participants, while others (eg, alfalfa) were associated with RA in older participants. CONCLUSION: These findings suggest several agricultural tasks and exposures may contribute to development of RA.

Overall and cause-specific mortality in a cohort of farmers and their spouses.

OBJECTIVES: Lower mortality rates compared with the general population have been reported for Agricultural Health Study (AHS) participants (enrolled 1993-1997) followed through 2007. We extended analysis of mortality among AHS participants (51 502 private pesticide applicators, their 31 867 spouses and 4677 commercial pesticide applicators from North Carolina and Iowa) through 2015 and compared results using several analytical approaches. METHODS: We calculated standardised mortality ratios (SMRs), causal mortality ratios (CMR) and relative SMRs (rSMR) using state-specific mortality rates of the general populations as the referent. RESULTS: Over the average 16 years of follow-up (1999-2015), 9305 private applicators, 3384 spouses and 415 commercial applicators died. SMRs and CMRs, with expected deaths calculated using the person-time among the cohort and the general population, respectively, indicated lower overall mortality in all study subgroups (SMRs from 0.61 to 0.69 and CMRs from 0.74 to 0.89), although CMRs indicated elevated mortality in private applicators from North Carolina and in ever-smokers. In SMR analyses, there were fewer than expected deaths from many causes, but deaths from some external causes including transportation-related injuries and mechanical forces were elevated in private applicators. CMRs indicated higher than expected deaths from prostate cancer, lymphohaematopoietic cancers, Parkinson's and Alzheimer's disease, and chronic glomerulonephritis in private applicators, and non-Hodgkin's lymphoma in spouses (from 1.19 to 1.53). rSMR results were generally elevated, similar to CMR findings. CONCLUSIONS: AHS participants experienced lower overall mortality than the general population.Mortality from a few specific causes was increased in private applicators, specifically when CMR and rSMR approaches were used.

Pesticide use and incident hyperthyroidism in farmers in the Agricultural Health Study.

BACKGROUND: Few studies have evaluated associations between pesticides and hyperthyroidism. OBJECTIVE: We evaluated associations between specific pesticides and incident hyperthyroidism in private pesticide applicators in the Agricultural Health Study. METHODS: We used Cox proportional hazards models to estimate HRs and 95% CIs for associations between pesticide use at enrolment and hyperthyroidism (n=271) in 35 150 applicators (mostly men), adjusting for potential confounders. RESULTS: Ever use of several pesticides (organophosphate insecticide malathion, fungicide maneb/mancozeb, herbicides dicamba, metolachlor, and atrazine in overall sample and chlorimuron ethyl among those ≤62 years) was associated with reduced hyperthyroidism risk, with HRs ranging from 0.50 (95% CI 0.30 to 0.83) for maneb/mancozeb to 0.77 (95% CI 0.59 to 1.00) for atrazine. Hyperthyroidism risk was lowest among those with higher intensity-weighted lifetime days of using carbofuran and chlorpyrifos (ptrend ≤0.05). CONCLUSIONS: Observed associations between pesticides and decreased risk of hyperthyroidism warrant further investigation.

Childhood Residential and Agricultural Pesticide Exposures in Relation to Adult-Onset Rheumatoid Arthritis in Women.

Farming and pesticide exposure may influence risk of rheumatoid arthritis (RA); the role of early-life pesticide exposure is unknown. The Sister Study includes a US national cohort of women aged 35-74 years (enrolled 2004-2009); we examined childhood pesticide exposure in women in this cohort with adult-onset RA. Cases (n = 424) were compared with 48,919 noncases. Data included pesticide use at the longest childhood residence through age 14 years, farm residence of at least 12 months with agricultural pesticide exposure through age 18 years, and maternal farm experience. Odds ratios and 95% confidence intervals were adjusted for age, race or ethnicity, education, smoking, and childhood socioeconomic factors. Cases with RA reported more frequent and direct (personal) residential pesticide use in childhood (for infrequent/indirect pesticide use, odds ratio (OR) = 1.1; for frequent/direct use, OR = 1.8; P for trend = 0.013). Compared with women without residential farm history, odds of having RA increased for those reporting a childhood-only farm residence with personal exposure to pesticides used on crops (OR = 1.8, 95% confidence interval: 1.1, 2.9) or livestock (OR = 2.0, 95% confidence interval: 1.2, 3.3). Our findings suggest adult-onset RA may be related to childhood exposure to residential and agricultural pesticides, and support further investigations of lifetime pesticide use in RA.