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.

High Pesticide Exposure Events and Olfactory Impairment among U.S. Farmers.

BACKGROUND: Olfactory impairment (OI) is common among older adults and independently predicts all-cause mortality and the risk of several major neurodegenerative diseases. Pesticide exposure may impair olfaction, but empirical evidence is lacking. OBJECTIVE: We aimed to examine high pesticide exposure events (HPEEs) in relation to self-reported OI in participants in the Agricultural Health Study (AHS). METHODS: We conducted multivariable logistic regression to examine the associations between HPEEs reported at enrollment (1993­1997) and self-reported OI at the latest AHS follow-up (2013­2015) among 11,232 farmers, using farmers without HPEEs as the reference or unexposed group. RESULTS: A total of 1,186 (10.6%) farmers reported OI. A history of HPEEs reported at enrollment was associated with a higher likelihood of reporting OI two decades later {odds ratio [Formula: see text] [95% confidence interval (CI): 1.28, 1.73]}. In the analyses on the HPEE involving the highest exposure, the association appears to be stronger when there was a [Formula: see text] delay between HPEE and washing with soap and water [e.g., [Formula: see text] (95% CI: 1.48, 2.89) for 4-6 h vs. [Formula: see text] (95% CI: 1.11, 1.75) for [Formula: see text]]. Further, significant associations were observed both for HPEEs involving the respiratory or digestive tract [[Formula: see text] (95% CI: 1.22, 1.92)] and dermal contact [[Formula: see text] (95% CI: 1.22, 1.78)]. Finally, we found significant associations with several specific pesticides involved in the highest exposed HPEEs, including two organochlorine insecticides (DDT and lindane) and four herbicides (alachlor, metolachlor, 2,4-D, and pendimethalin). HPEEs that occurred after enrollment were also associated with OI development. CONCLUSIONS: HPEEs may cause long-lasting olfactory deficit. Future studies should confirm these findings with objectively assessed OI and also investigate potential mechanisms. https://doi.org/10.1289/EHP3713.

Pesticide Use and Incident Hypothyroidism in Pesticide Applicators in the Agricultural Health Study.

BACKGROUND: Though evidence suggests that some pesticides may have thyroid-disrupting properties, prospective studies of associations between specific pesticides and incident thyroid disease are limited. OBJECTIVE: We evaluated associations between use of specific pesticides and incident hypothyroidism in private pesticide applicators in the Agricultural Health Study (AHS). METHODS: Self-reported incident hypothyroidism ([Formula: see text] cases) was studied in relation to ever-use and intensity-weighted cumulative days of pesticide use at study enrollment. We estimated adjusted hazard ratios (HRs) and 95% confidence intervals (CI) using Cox proportional hazards models applied to 35,150 male and female applicators followed over 20 y. All models were stratified by state and education to meet proportional hazards assumptions ([Formula: see text] for age x covariate interactions). Models of pesticides that did not meet proportional hazards assumptions were stratified by median attained age (62 y). RESULTS: Hypothyroidism risk was significantly increased with ever- vs. never-use of four organochlorine insecticides (aldrin, heptachlor, and lindane among participants with attained age [Formula: see text]; chlordane in all participants), four organophosphate insecticides (coumaphos in those [Formula: see text]; diazinon, dichlorvos, and malathion in all participants) and three herbicides (dicamba, glyphosate, and 2,4-D in all participants). HRs ranged from 1.21; 95% CI: 1.04, 1.41 (chlordane) to 1.54; 95% CI: 1.23, 19.4 (lindane in those [Formula: see text]). Hypothyroidism risk was greatest among those with higher intensity-weighted lifetime days of using chlordane, lindane, coumaphos (over age 62), diazinon, permethrin, and 2,4-D. CONCLUSIONS: Our findings support associations between exposure to several pesticides and increased hypothyroidism risk. These findings are generally consistent with prior analyses of prevalent hypothyroidism in the AHS. https://doi.org/10.1289/EHP3194.

Factors associated with dream enacting behaviors among US farmers.

INTRODUCTION: Dream enacting behavior (DEB) during REM sleep is a characteristic feature of REM sleep behavior disorder (RBD), the most specific prodromal symptom for Parkinson's disease (PD) and related synucleinopathies. METHODS: We screened for DEB among 20,591 male farmers in 2013-2015 using a validated question, and examined its association with pesticide uses and other potential risk factors reported about twenty years ago in 1993-1997. We reported odds ratios (OR) and 95% confidence intervals (CI) from multivariable logistic regression models. RESULTS: A total of 1623 (7.9%) farmers reported having had DEB. Farmers with DEB were more likely to report other nonmotor and motor symptoms of PD with age-adjusted ORs ranging from 1.9 to 3.0. DEB prevalence varied little by age, but was significantly associated with current smoking (adjusted OR: 1.4, 95%CI: 1.2, 1.6), daily alcohol drinking (OR: 1.4, 95%CI: 1.1, 1.6), a history of head injury (OR: 1.3, 95%CI: 1.2, 1.5), and being married (OR: 1.4, 95%CI: 1.1, 1.7). We identified significant associations for several pesticides, especially cyclodiene organochlorines and pyrethroids, with adjusted ORs ranging from 1.2 to 1.5. The results were similar after excluding PD cases or when farmers with at least three DEB episodes in life were considered as DEB cases. CONCLUSIONS: This study suggests that DEB are not rare among male farmers. Findings on potential risk factors for DEB are intriguing, and given the close link between RBD and PD, these associations should be further investigated.

Incident thyroid disease in female spouses of private pesticide applicators.

BACKGROUND: Little is known about modifiable risk factors for thyroid disease. Several pesticides have been implicated in thyroid disruption, but clinical implications are not clear. OBJECTIVE: We assessed associations between pesticide use and other farm exposures and incident hypothyroidism and hyperthyroidism in female spouses of farmers in the Agricultural Health Study (AHS). METHODS: We used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals for risk of thyroid disease in 24,092 spouses who completed at least one follow-up questionnaire. RESULTS: We identified 1627 hypothyroid and 531 hyperthyroid cases over 20 years of follow-up. The fungicides benomyl, maneb/mancozeb, and metalaxyl, the herbicide pendimethalin, and among those over 60 years of age the insecticides parathion and permethrin (applied to crops) were associated with elevated hypothyroidism risk, with HR ranging from 1.56-2.44. Conversely, the insecticide phorate, and the herbicides imazethapyr and metolachlor were associated with decreased risk (HR ranging 0.63-0.73), as were long-term farm residence and other farm-related activities (HR ranging 0.69-0.84). For hyperthyroidism, the insecticide diazinon, the fungicides maneb/mancozeb, and the herbicide metolachlor were associated with increased risk (HR ranging 1.35-2.01) and the herbicide trifluralin with decreased risk (HR: 0.57). CONCLUSIONS: Several individual pesticides were associated with increased risk of hypothyroidism and hyperthyroidism, although some pesticides were associated with decreased risk. Some of the findings, specifically associations with fungicides, are consistent with results from an earlier analysis of prevalent diseases in AHS spouses.

Blood Lead, Bone Turnover, and Survival in Amyotrophic Lateral Sclerosis.

Blood lead and bone turnover may be associated with the risk of amyotrophic lateral sclerosis (ALS). We aimed to assess whether these factors were also associated with time from ALS diagnosis to death through a survival analysis of 145 ALS patients enrolled during 2007 in the National Registry of Veterans with ALS. Associations of survival time with blood lead and plasma biomarkers of bone resorption (C-terminal telopeptides of type I collagen (CTX)) and bone formation (procollagen type I amino-terminal peptide (PINP)) were estimated using Cox models adjusted for age at diagnosis, diagnostic certainty, diagnostic delay, site of onset, and score on the Revised ALS Functional Rating Scale. Hazard ratios were calculated for each doubling of biomarker concentration. Blood lead, plasma CTX, and plasma PINP were mutually adjusted for one another. Increased lead (hazard ratio (HR) = 1.38; 95% confidence interval (CI): 1.03, 1.84) and CTX (HR = 2.03; 95% CI: 1.42, 2.89) were both associated with shorter survival, whereas higher PINP was associated with longer survival (HR = 0.59; 95% CI: 0.42, 0.83), after ALS diagnosis. No interactions were observed between lead or bone turnover and other prognostic indicators. Lead toxicity and bone metabolism may be involved in ALS pathophysiology.

Military service, deployments, and exposures in relation to amyotrophic lateral sclerosis survival.

BACKGROUND: Military veterans may have higher rates of amyotrophic lateral sclerosis (ALS) mortality than non-veterans. Few studies, with sparse exposure information and mixed results, have studied relationships between military-related factors and ALS survival. We evaluated associations between military-related factors and ALS survival among U.S. military veteran cases. METHODS: We followed 616 medical record-confirmed cases from enrollment (2005-2010) in the Genes and Environmental Exposures in Veterans with Amyotrophic Lateral Sclerosis study until death or July 25, 2013, whichever came first. We ascertained vital status information from several sources within the Department of Veterans Affairs. We obtained information regarding military service, deployments, and 39 related exposures via standardized telephone interviews. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals. We adjusted for potential confounding and missing covariate data biases via inverse probability weights. We also used inverse probability weights to adjust for potential selection bias among a case group that included a disproportionate number of long-term survivors at enrollment. RESULTS: We observed 446 deaths during 24,267 person-months of follow-up (median follow-up: 28 months). Survival was shorter for cases who served before 1950, were deployed to World War II, or mixed and applied burning agents, with HRs between 1.58 and 2.57. Longer survival was associated with exposure to: paint, solvents, or petrochemical substances; local food not provided by the Armed Forces; or burning agents or Agent Orange in the field with HRs between 0.56 and 0.73. CONCLUSIONS: Although most military-related factors were not associated with survival, associations we observed with shorter survival are potentially important because of the large number of military veterans.

Nonmotor symptoms and Parkinson disease in United States farmers and spouses.

OBJECTIVES: Few studies have evaluated the presence of multiple nonmotor symptoms (NMS) in relation to Parkinson disease (PD). Therefore, we examined cross-sectional associations between individual and multiple NMS and PD in the Agricultural Health Study. METHODS: 20,473 male farmers and 16,259 female spouses provided information on six NMS (reduced sense of smell, dream-enacting behavior, daytime sleepiness, infrequent bowel movement, depression, and anxiety) in the cohort's 2013-2015 follow-up survey. 191 men and 68 women reported physician-diagnosed PD. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression models separately by sex. RESULTS: NMS were each associated with PD, with the strongest association for reduced sense of smell in men and dream-enacting behavior in women. The number of NMS showed a strong dose-response relationship with PD, particularly in men. ORs were 5.5 (95% CI 3.4-8.8) for one, 17 (95% CI 10.4-28.0) for two, and 53.4 (95% CI 33.2-86.1) for three or more NMS in men; the corresponding ORs were 4.6 (95% CI 2.3-9.5), 6.7 (95% CI 2.9-15.6), and 23.6 (95% CI 10.7-52.4) in women (PNMS-interaction-with-sex = 0.07). CONCLUSIONS: The number of NMS was associated with PD in a dose-response manner and the association appeared stronger in men than in women. These findings should be further investigated in population-based prospective studies.

Pesticide Use and Age-Related Macular Degeneration in the Agricultural Health Study.

BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of blindness in developed countries. Few studies have investigated its relationship to environmental neurotoxicants. In previous cross-sectional studies, we found an association between pesticide use and self-reported retinal degeneration. OBJECTIVE: We evaluated the association of pesticide use with physician-confirmed incident AMD. METHODS: The Agricultural Health Study (AHS) is a prospective cohort of pesticide applicators and their spouses enrolled from 1993-1997 in Iowa and North Carolina. Cohort members reported lifetime use of 50 specific pesticides at enrollment. Self-reports of incident AMD during follow-up through 2007 were confirmed by reports from participants' physicians and by independent evaluation of retinal photographs provided by the physicians. Confirmed cases (n=161) were compared with AHS cohort members without AMD (n=39,108). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) by logistic regression with adjustment for age, gender, and smoking. RESULTS: AMD was associated with ever use of organochlorine [OR=2.7 (95% CI: 1.8, 4.0)] and organophosphate [OR=2.0 (95% CI: 1.3, 3.0)] insecticides and phenoxyacetate herbicides [OR=1.9 (95% CI: 1.2, 2.8)]. Specific pesticides consistently associated with AMD included chlordane, dichlorodiphenyltrichloroethane (DDT), malathion, and captan; others with notable but slightly less consistent associations were heptachlor, diazinon, phorate, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), and 2,4-dichlorophenoxyacetic acid (2,4-D). Results were similar for men and women. Some specific pesticides were associated with both early- and late-stage AMD, but others were associated with only one stage. CONCLUSIONS: Exposures to specific pesticides may be modifiable risk factors for AMD. https://doi.org/10.1289/EHP793.

Organic solvent exposure and depressive symptoms among licensed pesticide applicators in the Agricultural Health Study.

PURPOSE: Although organic solvents are often used in agricultural operations, neurotoxic effects of solvent exposure have not been extensively studied among farmers. The current analysis examined associations between questionnaire-based metrics of organic solvent exposure and depressive symptoms among farmers. METHODS: Results from 692 male Agricultural Health Study participants were analyzed. Solvent type and exposure duration were assessed by questionnaire. An "ever-use" variable and years of use categories were constructed for exposure to gasoline, paint/lacquer thinner, petroleum distillates, and any solvent. Depressive symptoms were ascertained with the Center for Epidemiologic Studies Depression Scale (CES-D); scores were analyzed separately as continuous (0-60) and dichotomous (<16 versus ≥16) variables. Multivariate linear and logistic regression models were used to estimate crude and adjusted associations between measures of solvent exposure and CES-D score. RESULTS: Forty-one percent of the sample reported some solvent exposure. The mean CES-D score was 6.5 (SD 6.4; median 5; range 0-44); 92% of the sample had a score below 16. After adjusting for covariates, statistically significant associations were observed between ever-use of any solvent, long duration of any solvent exposure, ever-use of gasoline, ever-use of petroleum distillates, and short duration of petroleum distillate exposure and continuous CES-D score (p < 0.05). Although nearly all associations were positive, fewer statistically significant associations were observed between metrics of solvent exposure and the dichotomized CES-D variable. CONCLUSIONS: Solvent exposures were associated with depressive symptoms among farmers. Efforts to limit exposure to organic solvents may reduce the risk of depressive symptoms among farmers.

Assessing the Potential for Bias From Nonresponse to a Study Follow-up Interview: An Example From the Agricultural Health Study.

Prospective cohort studies are important tools for identifying causes of disease. However, these studies are susceptible to attrition. When information collected after enrollment is through interview or exam, attrition leads to missing information for nonrespondents. The Agricultural Health Study enrolled 52,394 farmers in 1993-1997 and collected additional information during subsequent interviews. Forty-six percent of enrolled farmers responded to the 2005-2010 interview; 7% of farmers died prior to the interview. We examined whether response was related to attributes measured at enrollment. To characterize potential bias from attrition, we evaluated differences in associations between smoking and incidence of 3 cancer types between the enrolled cohort and the subcohort of 2005-2010 respondents, using cancer registry information. In the subcohort we evaluated the ability of inverse probability weighting (IPW) to reduce bias. Response was related to age, state, race/ethnicity, education, marital status, smoking, and alcohol consumption. When exposure and outcome were associated and case response was differential by exposure, some bias was observed; IPW conditional on exposure and covariates failed to correct estimates. When response was nondifferential, subcohort and full-cohort estimates were similar, making IPW unnecessary. This example provides a demonstration of investigating the influence of attrition in cohort studies using information that has been self-reported after enrollment.

Association of fractures with the incidence of amyotrophic lateral sclerosis.

OBJECTIVE: Elevated bone turnover observed in ALS patients suggests poor bone health and increased fracture risk. We therefore evaluated the relationship of fracture to subsequent ALS risk. METHODS: We followed 4,529,460 Swedes from 1987 to 2010 and identified ALS and fractures from the Swedish National Patient Register. We examined associations of ALS risk with all fractures, osteoporotic and non-osteoporotic fractures, and traumatic and non-traumatic fractures among individuals aged 30-80 years. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). We analysed the association of ALS with time since fracture using a Poisson regression model. RESULTS: All fractures (HR: 1.51, 95% CI 1.39-1.65) as well as osteoporotic (HR: 1.59, 95% CI 1.41-1.79), non-osteoporotic (HR: 1.46, 95% CI 1.31-1.63), traumatic (HR: 1.50, 95% CI 1.37-1.63), and non-traumatic (HR: 1.80, 95% CI 1.35-2.40) fractures were associated with a higher incidence of ALS. Increased ALS incidence was associated with fractures occurring from one (HR: 2.33, 95% CI 2.04-2.66) to 18 (HR: 1.19, 95% CI 1.01-1.43) years before ALS diagnosis. CONCLUSIONS: Poor bone health may be related to ALS. These findings may offer insight into ALS pathophysiology.

Retrospective Assessment of Occupational Exposures for the GENEVA Study of ALS among Military Veterans.

OBJECTIVE: This paper describes the retrospective exposure assessment conducted to assess occupational exposures for the Genes and Environmental Exposures in Veterans (GENEVA) study, a case-control study investigating the joint contribution of genetics and environmental exposures to the risk of amyotrophic lateral sclerosis (ALS) among military veterans. METHODS: Occupational histories for 1597 study participants collected as part of the GENEVA study were the basis for this retrospective exposure assessment. The data set included 15528 jobs held from 1924 to 2010, representing 4539 unique industry and occupation (I&O) combinations. Three industrial hygiene experts were recruited to independently rate occupational exposures to specific agents previously associated with an increased risk of ALS. Utilizing information on industry, job title, tasks performed, and materials used for each job held, raters assigned exposures associated with each I&O for the 'current time' defined as the period after 1995 (post-1995). The exposure assessment targeted agents identified as potential occupational risk factors for ALS. Experts rated semi-quantitatively exposure intensity in five exposure categories (0-4) for Group A agents (lead, formaldehyde, hydrocarbon solvents, and chlorinated solvents) and qualitatively as yes/no (1/0) exposed for Group B agents (mercury, selenium, arsenic, polychlorinated biphenyls, electromagnetic field, pesticides, and viral agents). Confidence scores (0-3) were reported for every I&O rated based on raters' experience with that industry and/or job. Each I&O was assigned an average exposure score of the raters and an alternative exposure rating was developed for each I&O by excluding low confidence (<2) scores before averaging. Exposure reconstruction for jobs held pre-1995 was done by comparing exposure data extracted from the OSHA Chemical Exposure and Health Database (CEHD) during pre-1995 and post-1995. For agents with limited exposure data in the CEHD, pre-1995 exposures were determined based on raters' judgment. RESULTS: The proportion of I&O combinations determined to be 'exposed' ranged from 0.1 to 26% across different agents, with the highest values corresponding to hydrocarbon solvents and the lowest to selenium. Industries with the highest proportion of exposed records include manufacturing, utilities, healthcare, and military with non-combat jobs. Analyses for raters' reliability showed the best agreement between the raters when rating exposure to viral agents (kappa = 0.67), hydrocarbon solvents (kappa = 0.53), and lead (kappa = 0.50). The proportion of 'exposed' I&O combinations increased for hydrocarbon solvents, chlorinated solvents, and pesticides when exposure ratings were adjusted by raters' confidence. Compared to post-1995, exposures in the earlier period (pre-1995) were deemed higher or the same for most of the agents and lower for formaldehyde and electromagnetic field exposures. CONCLUSIONS: Our results indicate that using raters' confidence assessment in determining exposure scores increases both the proportion of I&O combinations regarded as exposed and the intensity scores, suggesting raters tend to be conservative in their assessment when they lack detailed knowledge of an industry or job.

Body Mass Index and Amyotrophic Lateral Sclerosis: A Study of US Military Veterans.

Amyotrophic lateral sclerosis (ALS) may be associated with low body mass index (BMI) at the time of diagnosis. However, the role of premorbid BMI in the development of ALS and survival after diagnosis remains unclear. In 2005-2010, we interviewed 467 patients with ALS from the US National Registry of Veterans with ALS and 975 frequency-matched veteran controls. In this sample, we evaluated the association of BMI and BMI change at different ages with ALS risk using unconditional logistic models and with survival after ALS diagnosis using Cox proportional hazards models. After adjustment for confounders, compared with a moderate increase in BMI between ages 25 and 40 years, stable or decreasing BMI was positively associated with ALS risk (odds ratio (OR) = 1.61, 95% confidence interval (CI): 1.20, 2.16). A 1-unit increase in BMI at age 40 years (OR = 0.95, 95% CI: 0.91, 0.98) but not at age 25 years (OR = 0.99, 95% CI: 0.95, 1.03) was inversely associated with ALS. These associations were similar for bulbar and spinal ALS but stronger for those with a delay of less than 1 year between symptom onset and diagnosis. We found no association between prediagnosis BMI and survival. A decreasing BMI from early to middle age and a low BMI in middle age may be positively associated with ALS risk.

Occupational exposures and the risk of amyotrophic lateral sclerosis.

OBJECTIVES: To examine the associations of specific occupations and occupational exposures with the risk of amyotrophic lateral sclerosis (ALS) in the Swedish population. METHODS: A nested case-control study was conducted in Sweden. Patients with ALS diagnosed during 1991-2010 (n=5020) were identified from the National Patient Register and 5 controls per case (n=25 100) were randomly selected from the general Swedish population, individually matched to cases by birth year and sex. Occupational history was obtained from the Swedish censuses in 1970, 1980 and 1990. The Nordic Occupational Cancer Study Job Exposure Matrix was used to identify exposures related to individual occupations. Conditional logistic regression was used to estimate ORs and their 95% CIs. RESULTS: Higher risk of ALS was associated with precision-tool manufacturing (OR 1.68, 95% CI 1.11 to 2.52) and glass, pottery and tile work (OR 1.76, 95% CI 1.03 to 3.00), whereas lower risk was associated with textile work (OR 0.44, 95% CI 0.21 to 0.91). None of the examined occupational exposures were associated with ALS risk overall. However, among individuals younger than 65 years of age, an association with a higher risk of ALS was found for formaldehyde (OR 1.29, 95% CI 1.00 to 1.65), and an association with a lower risk of ALS was found for methylene chloride (OR 0.49, 95% CI 0.26 to 0.93). CONCLUSIONS: We identified several occupations and occupational exposures that may be associated with the risk of ALS in Sweden. Occupational history obtained from censuses every 10 years remains a limitation of the study.

Pesticide use and LINE-1 methylation among male private pesticide applicators in the Agricultural Health Study.

Cancer risk may be associated with DNA methylation (DNAm) levels in Long Interspersed Nucleotide Element 1 (LINE-1), a surrogate for global DNAm. Exposure to certain pesticides may increase risk of particular cancers, perhaps mediated in part through global DNAm alterations. To date, human data on pesticide exposure and global DNAm alterations are limited. The goal of this study was to evaluate alterations of LINE-1 DNAm by pesticides in a variety of classes. Data from 596 cancer-free male participants enrolled in the Agricultural Health Study (AHS) were used to examine associations between use of 57 pesticides and LINE-1 DNAm measured via Pyrosequencing in peripheral blood leucocytes. Participants provided information on pesticide use at three contacts between 1993 and 2010. Associations of ever/never pesticide use and lifetime days of application (years of use × days per year) and LINE-1 DNAm level were assessed using linear regression, adjusting for potential confounders (race, age at blood draw, and frequency of drinking alcohol) and other moderately correlated pesticides. After adjustment, ever application of 10 pesticides was positively associated and ever application of eight pesticides was negatively associated with LINE-1 DNAm. In dose-response analyses, increases in five pesticides (imazethapyr, fenthion, EPTC, butylate, and heptachlor) were associated with increasing LINE-1 DNAm (ptrend < 0.05) and increases in three pesticides (carbaryl, chlordane, and paraquat) were associated with decreasing LINE-1 DNAm (ptrend < 0.05). This study provides some mechanistic insight into the pesticide-cancer relationship, which may be mediated in part by epigenetics.

High pesticide exposure events and DNA methylation among pesticide applicators in the agricultural health study.

Pesticide exposure has been associated with acute and chronic adverse health effects. DNA methylation (DNAm) may mediate these effects. We evaluated the association between experiencing unusually high pesticide exposure events (HPEEs) and DNAm among pesticide applicators in the Agricultural Health Study (AHS), a prospective study of applicators from Iowa and North Carolina. DNA was extracted from whole blood from male AHS pesticide applicators (n = 695). Questionnaire data were used to ascertain the occurrence of HPEEs over the participant's lifetime. Pyrosequencing was used to quantify DNAm in CDH1, GSTp1, and MGMT promoters, and in the repetitive element, LINE-1. Linear and robust regression analyses evaluated adjusted associations between HPEE and DNAm. Ever having an HPEE (n = 142; 24%) was associated with elevated DNAm in the GSTp1 promoter at CpG7 (chr11:67,351,134; P < 0.01) and for the mean across the CpGs measured in the GSTp1 promoter (P < 0.01). In stratified analyses, elevated GSTP1 promoter DNAm associated with HPEE was more pronounced among applicators >59 years and those with plasma folate levels ≤16.56 ng/mL (p-interaction <0.01); HPEE was associated with reduced MGMT promoter DNAm at CpG2 (chr10:131,265,803; P = 0.03), CpG3 (chr10:131,265,810; P = 0.05), and the mean across CpGs measured in the MGMT promoter (P = 0.03) among applicators >59 years and reduced LINE-1 DNAm (P = 0.05) among applicators with ≤16.56 ng/mL plasma folate. Non-specific HPEEs may contribute to increased DNAm in GSTp1, and in some groups, reduced DNAm in MGMT and LINE-1. The impacts of these alterations on disease development are unclear, but elevated GSTp1 promoter DNAm and subsequent gene inactivation has been consistently associated with prostate cancer. Environ. Mol. Mutagen. 58:19-29, 2017. © 2016 Wiley Periodicals, Inc.

Mortality from neurodegenerative diseases in a cohort of US flight attendants.

BACKGROUND: Concern exists about the potential chronic neurological effects among aircrew of exposure to chemical contaminants from engine oil in aircraft cabin air. We evaluated mortality from neurodegenerative diseases among 11,311 former US flight attendants. METHODS: Vital status was ascertained through 2007, and life table analyses were conducted to obtain standardized mortality ratios (SMRs). RESULTS: Amyotrophic lateral sclerosis (ALS) mortality was over twice as high in the cohort as in the US general population, based on nine observed ALS deaths. There was no clear pattern in risk when SMRs for ALS were stratified by exposure duration. Mortality from other neurodegenerative diseases was not elevated. CONCLUSIONS: Our findings are limited due to small numbers of observed deaths and reliance on mortality data, but suggest that flight attendants may have an increased risk of ALS. Additional research is needed. Am. J. Ind. Med. 59:532-537, 2016. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Blood levels of trace metals and amyotrophic lateral sclerosis.

Some trace metals may increase risk of amyotrophic lateral sclerosis (ALS), whereas others may be beneficial. Our goal was to examine associations of ALS with blood levels of selenium (Se), zinc (Zn), copper (Cu), and manganese (Mn). We conducted a case-control study of 163 neurologist confirmed patients from the National Registry of Veterans with ALS and 229 frequency-matched veteran controls. We measured metal levels in blood using inductively coupled plasma mass spectrometry and estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between ALS and a doubling of metal levels using unconditional logistic regression, adjusting for age, gender, and race/ethnicity. ALS was inversely associated with both Se (OR=0.4, 95% CI: 0.2-0.8) and Zn (OR=0.4, 95% CI: 0.2-0.8). Inverse associations with Se were stronger in patients with bulbar compared to spinal onset, worse function, longer diagnostic delay, and longer collection delay; inverse associations with Zn were stronger for those with worse function and longer collection delay. In contrast, ALS was positively associated with Cu (OR=3.4, 95% CI: 1.5-7.9). For Mn, no linear trend was evident (OR=0.9, 95% CI: 0.6-1.3, Ptrend=0.51). Associations of Se, Zn, Cu, and Mn with ALS were independent of one another. Adjustment for lead levels attenuated the positive association of ALS with Cu but did not change associations with Se, Zn, or Mn. In conclusion, Se and Zn were inversely associated with ALS, particularly among those with worse function, suggesting that supplementation with these metals may benefit such patients, while Cu was positively associated with ALS. Deficiencies of Se and Zn and excess Cu may have a role in ALS etiology.

Military service, deployments, and exposures in relation to amyotrophic lateral sclerosis etiology.

BACKGROUND: Factors underlying a possible excess of amyotrophic lateral sclerosis (ALS) among military veterans remain unidentified. Limitations of previous studies on this topic include reliance on ALS mortality as a surrogate for ALS incidence, low statistical power, and sparse information on military-related factors. OBJECTIVES: We evaluated associations between military-related factors and ALS using data from a case-control study of U.S. military veterans. METHODS: From 2005 to 2010, we identified medical record-confirmed ALS cases via the National Registry of Veterans with ALS and controls via the Veterans Benefits Administration's Beneficiary Identification and Records Locator System database. In total, we enrolled 621 cases and 958 frequency-matched controls in the Genes and Environmental Exposures in Veterans with Amyotrophic Lateral Sclerosis study. We collected information on military service and deployments and 39 related exposures. We used unconditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). We used inverse probability weighting to adjust for potential bias from confounding, missing covariate data, and selection arising from a case group that disproportionately included long-term survivors and a control group that may or may not differ from U.S. military veterans at large. RESULTS: The odds of ALS did not differ for veterans of the Air Force, Army, Marines, and Navy. We found higher odds of ALS for veterans whose longest deployment was World War II or the Korean War and a positive trend with total years of all deployments (OR=1.27; 95% CI: 1.06, 1.52). ALS was positively associated with exposure to herbicides for military purposes, nasopharyngeal radium, personal pesticides, exhaust from heaters or generators, high-intensity radar waves, contaminated food, explosions within one mile, herbicides in the field, mixing and application of burning agents, burning agents in the field, and Agent Orange in the field, with ORs between 1.50 and 7.75. CONCLUSIONS: Although our results need confirmation, they are potentially important given the large number of U.S. military veterans, and they provide clues to potential factors underlying the apparent increase of ALS in veteran populations.