Background

Occupation has been suggested to play a role in amyotrophic lateral sclerosis (ALS) etiology, but detailed information on the importance of specific workplace exposures is lacking.

Objectives

Our aim was to assess the relationship between workplace exposures and the risk of ALS and to evaluate potential interactions between these exposures and smoking.

Methods

We conducted a case–control study in New England between 1993 and 1996, comprising 109 cases and 253 controls who completed a structured interview covering occupations and workplace exposures. Unconditional logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for ALS. Analyses were conducted among the entire study population and after stratification by smoking.

Results

We observed a higher risk of ALS for construction workers excluding supervisors (OR = 2.9; 95% CI, 1.2–7.2) and precision metal workers (OR = 3.5; 95% CI, 1.2–10.5). Self-reported exposures to paint strippers; cutting, cooling, or lubricating oils; antifreeze or coolants; mineral or white spirits; and dry cleaning agents each appeared to be associated with a 60–90% higher risk. Specific chemicals related to a > 50% increase in risk of ALS included aliphatic chlorinated hydrocarbons, glycols, glycol ethers, and hexane. Relative risks associated with these workplace exposures and chemicals were greater among nonsmokers and persisted in mutually adjusted models.

Conclusions

Our data suggest that certain occupations and workplace exposures may be associated with increased risk of ALS. These results need to be confirmed in independent populations.

Background

Mitochondrial dysfunction and oxidative stress are pathophysiologic mechanisms implicated in experimental models and genetic forms of Parkinson’s disease (PD). Certain pesticides may affect these mechanisms, but no pesticide has been definitively associated with PD in humans.

Objectives

Our goal was to determine whether pesticides that cause mitochondrial dysfunction or oxidative stress are associated with PD or clinical features of parkinsonism in humans.

Methods

We assessed lifetime use of pesticides selected by mechanism in a case–control study nested in the Agricultural Health Study (AHS). PD was diagnosed by movement disorders specialists. Controls were a stratified random sample of all AHS participants frequency-matched to cases by age, sex, and state at approximately three controls: one case.

Results

In 110 PD cases and 358 controls, PD was associated with use of a group of pesticides that inhibit mitochondrial complex I [odds ratio (OR) = 1.7; 95% confidence interval (CI), 1.0–2.8] including rotenone (OR = 2.5; 95% CI, 1.3–4.7) and with use of a group of pesticides that cause oxidative stress (OR = 2.0; 95% CI, 1.2–3.6), including paraquat (OR = 2.5; 95% CI, 1.4–4.7).

Conclusions

PD was positively associated with two groups of pesticides defined by mechanisms implicated experimentally—those that impair mitochondrial function and those that increase oxidative stress—supporting a role for these mechanisms in PD pathophysiology.

Background

Soy formula containing estrogenic isoflavones is widely used in the United States. Infants consuming soy formula exclusively have high isoflavone exposures. We wanted to study whether soy formula prolonged the physiologic estrogenization of newborns, but available quantitative descriptions of the natural history of breast and genital development are inadequate for study design.

Objective

We piloted techniques for assessing infants’ responses to the withdrawal from maternal estrogen and gathered data on breast and genital development in infants at different ages.

Methods

We studied 37 boys and 35 girls, from term pregnancies with normal birth weights, who were < 48 hr to 6 months of age, and residents of Philadelphia, Pennsylvania, during 2004–2005. One-third of the children of each sex and age interval were exclusively fed breast milk, soy formula, or cow-milk formula. Our cross-sectional study measured breast adipose tissue, breast buds, and testicular volume; observed breast and genital development; and collected vaginal wall cells and information on vaginal discharge. We assessed reliability of the measures.

Results

Breast tissue was maximal at birth and disappeared in older children, consistent with waning maternal estrogen. Genital development did not change by age. Breast-milk secretion and withdrawal bleeding were unusual. Vaginal wall cells showed maximal estrogen effect at birth and then reverted; girls on soy appeared to show reestrogenization at 6 months.

Conclusions

Examination of infants for plausible effects of estrogens is valid and repeatable. Measurement of breast tissue and characterization of vaginal wall cells could be used to evaluate exposures with estrogen-like effects.

Background: An association may exist between pesticide exposure and suicide.

Objective: We sought to evaluate the existence of an association between pesticide use and suicide using data from the Agricultural Health Study (AHS), a prospective cohort study of licensed pesticide applicators and their spouses in Iowa and North Carolina.

Methods: Via linkage to state mortality files and the National Death Index, we identified 110 suicides occurring between enrollment in the AHS (from 1993 to 1997) and 31 May 2009, among 81,998 cohort members contributing 1,092,943 person-years of follow-up. The average length of follow-up was 13.3 years. AHS participants provided data on pesticide use and potential confounders via self-administered questionnaires at enrollment. We evaluated several measures of pesticide use: use of any pesticide, ever use of 50 specific pesticides, cumulative lifetime days of use and intensity-adjusted cumulative lifetime days of use of 22 specific pesticides, and ever use of 10 functional and chemical classes of pesticides. We used Cox proportional hazards regression models to estimate adjusted hazard ratios and 95% confidence intervals.

Results: After adjusting for age at enrollment, sex, number of children in family, frequency of alcohol consumption during the past 12 months, and smoking status, we found no association between prior pesticide use and suicide in applicators and their spouses. Results were the same for applicators and spouses together or for applicators alone and were consistent across several measures of pesticide use.

Conclusions: Our findings do not support an association between moderate pesticide use and suicide.

Background

Reasons for the variability in survival among ALS cases are unknown but may include exposure to environmental neurotoxicants.

Objectives

We aimed to determine whether lead exposure, assessed by measuring blood and bone lead levels, is associated with survival in amyotrophic lateral sclerosis (ALS).

Methods

We evaluated the relationship of lead exposure to ALS survival in 110 cases from a case–control study conducted in New England in 1993–1996 that included measurements of blood and bone lead. We retrieved information on date and cause of death through 31 December 2003 from the National Death Index Plus and the Social Security Administration Death Index. We evaluated the relationship of survival to lead exposure using Cox proportional hazard analysis, with adjustment for age, sex, and smoking.

Results

We found mortality data for 100 of 110 cases; 93 of 100 death certificates mentioned ALS. Median survival from diagnosis to death was 28 months. Shorter survival was associated with older age at diagnosis, female sex, bulbar onset, shorter interval between symptom onset and diagnosis, and reduced lung function. Shorter survival from diagnosis to death had a weak inverse association with blood lead (hazard ratio = 0.9; 95% confidence interval, 0.8–1.0) and a stronger inverse association with patella lead (0.5; 0.2–1.0) and tibia lead (0.3; 0.1–0.7); similar results were found for survival from symptom onset to death.

Conclusions

These results suggest that lead exposure is associated with longer survival in ALS cases and, if confirmed, may shed light on mechanisms involved in disease progression.

Background: Pesticide exposure may be positively associated with depression. Few previous studies have considered the episodic nature of depression or examined individual pesticides.

Objective: We evaluated associations between pesticide exposure and depression among male private pesticide applicators in the Agricultural Health Study.

Methods: We analyzed data for 10 pesticide classes and 50 specific pesticides used by 21,208 applicators enrolled in 1993–1997 who completed a follow-up telephone interview in 2005–2010. We divided applicators who reported a physician diagnosis of depression (n = 1,702; 8%) into those who reported a previous diagnosis of depression at enrollment but not follow-up (n = 474; 28%), at both enrollment and follow-up (n = 540; 32%), and at follow-up but not enrollment (n = 688; 40%) and used polytomous logistic regression to estimate odds ratios (ORs) and 95% CIs. We used inverse probability weighting to adjust for potential confounders and to account for the exclusion of 3,315 applicators with missing covariate data and 24,619 who did not complete the follow-up interview.

Results: After weighting for potential confounders, missing covariate data, and dropout, ever-use of two pesticide classes, fumigants and organochlorine insecticides, and seven individual pesticides—the fumigants aluminum phosphide and ethylene dibromide; the phenoxy herbicide (2,4,5-trichlorophenoxy)acetic acid (2,4,5-T); the organochlorine insecticide dieldrin; and the organophosphate insecticides diazinon, malathion, and parathion—were all positively associated with depression in each case group, with ORs between 1.1 and 1.9.

Conclusions: Our study supports a positive association between pesticide exposure and depression, including associations with several specific pesticides.

Citation: Beard JD, Umbach DM, Hoppin JA, Richards M, Alavanja MCR, Blair A, Sandler DP, Kamel F. 2014. Pesticide exposure and depression among male private pesticide applicators in the Agricultural Health Study. Environ Health Perspect 122:984–991; http://dx.doi.org/10.1289/ehp.1307450

Previous studies have suggested that lead exposure may be associated with increased risk of amyotrophic lateral sclerosis (ALS). Polymorphisms in the genes for delta-aminolevulinic acid dehydratase (ALAD) and the vitamin D receptor (VDR) may affect susceptibility to lead exposure. We used data from a case-control study conducted in New England from 1993 to 1996 to evaluate the relationship of ALS to polymorphisms in ALAD and VDR and the effect of these polymorphisms on the association of ALS with lead exposure. The ALAD 2 allele (177G to C; K59N) was associated with decreased lead levels in both patella and tibia, although not in blood, and with an imprecise increase in ALS risk [odds ratio (OR) = 1.9; 95% confidence interval (95% CI), 0.60-6.3]. We found a previously unreported polymorphism in ALAD at an Msp1 site in intron 2 (IVS2+299G>A) that was associated with decreased bone lead levels and with an imprecise decrease in ALS risk (OR = 0.35; 95% CI, 0.10-1.2). The VDR B allele was not associated with lead levels or ALS risk. Our ability to observe effects of genotype on associations of ALS with occupational exposure to lead or with blood or bone lead levels was limited. These findings suggest that genetic susceptibility conferred by polymorphisms in ALAD may affect ALS risk, possibly through a mechanism related to internal lead exposure.

Background:

Environmental factors can influence the house dust microbiota, which may impact health outcomes. Little is known about how farming exposures impact the indoor microbiota.

Objective:

We aimed to identify exposures related to bacterial communities in house dust in a U.S. farming population.

Methods:

We used 16S rRNA amplicon sequencing to characterize bacterial communities in vacuumed dust samples from the bedrooms of a subset of 879 households of farmers and farmers’ spouses enrolled in the Agricultural Lung Health Study (ALHS), a case–control study of asthma nested within the Agricultural Health Study (AHS) in North Carolina and Iowa. Information on current farming (past 12 mo), including both crop and animal farming, and other potential microbial sources was obtained via questionnaires. We used linear regression to evaluate associations between exposures and bacterial diversity within each sample, analysis of similarity (ANOSIM), and permutational multivariate analysis of variance (PERMANOVA) to identify exposures related to diversity between samples, and analysis of composition of microbiome to examine whether exposures related to diversity were also related to differential abundance of specific operational taxonomic units (OTUs).

Results:

Current farming was positively associated with bacterial diversity in house dust, with or without adjustment for nonfarm exposures related to diversity, including presence of indoor pets, home condition, and season of dust collection. Many taxa exhibited differential abundance related to farming. Some taxa in the phyla Chloroflexi and Verrucomicrobia were associated [false discovery rate (FDR)<0.05] with farming but not with other nonfarm factors. Many taxa correlated with the concentration of house dust of endotoxin, commonly studied as a general marker of exposure to the farming environment.

Conclusions:

In this farming population, house dust microbiota differed by current farming status. Understanding the determinants of the indoor microbiota is the first step toward understanding potential relationships with health outcomes. https://doi.org/10.1289/EHP3145

Background:

Growing evidence suggests that pesticide use may contribute to respiratory symptoms.

Objective:

We evaluated the association of currently used pesticides with allergic and non-allergic wheeze among male farmers.

Methods:

Using the 2005–2010 interview data of the Agricultural Health Study, a prospective study of farmers in North Carolina and Iowa, we evaluated the association between allergic and non-allergic wheeze and self-reported use of 78 specific pesticides, reported by ≥ 1% of the 22,134 men interviewed. We used polytomous regression models adjusted for age, BMI, state, smoking, and current asthma, as well as for days applying pesticides and days driving diesel tractors. We defined allergic wheeze as reporting both wheeze and doctor-diagnosed hay fever (n = 1,310, 6%) and non-allergic wheeze as reporting wheeze but not hay fever (n = 3,939, 18%); men without wheeze were the referent.

Results:

In models evaluating current use of specific pesticides, 19 pesticides were significantly associated (p < 0.05) with allergic wheeze (18 positive, 1 negative) and 21 pesticides with non-allergic wheeze (19 positive, 2 negative); 11 pesticides were associated with both. Seven pesticides (herbicides: 2,4-D and simazine; insecticides: carbaryl, dimethoate, disulfoton, and zeta-cypermethrin; and fungicide pyraclostrobin) had significantly different associations for allergic and non-allergic wheeze. In exposure–response models with up to five exposure categories, we saw evidence of an exposure–response relationship for several pesticides including the commonly used herbicides 2,4-D and glyphosate, the insecticides permethrin and carbaryl, and the rodenticide warfarin.

Conclusions:

These results for farmers implicate several pesticides that are commonly used in agricultural and residential settings with adverse respiratory effects.

Citation:

Hoppin JA, Umbach DM, Long S, London SJ, Henneberger PK, Blair A, Alavanja M, Beane Freeman LE, Sandler DP. 2017. Pesticides are associated with allergic and non-allergic wheeze among male farmers. Environ Health Perspect 125:535–543; http://dx.doi.org/10.1289/EHP315

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 (n=829 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 (p≤0.10 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 >62y; chlordane in all participants), four organophosphate insecticides (coumaphos in those >62y; 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 >62y). 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

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 (1993–1997) and self-reported OI at the latest AHS follow-up (2013–2015) 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 (OR)=1.49 [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 >4-h delay between HPEE and washing with soap and water [e.g., OR=2.07 (95% CI: 1.48, 2.89) for 4–6 h vs. OR=1.39 (95% CI: 1.11, 1.75) for <30 min]. Further, significant associations were observed both for HPEEs involving the respiratory or digestive tract [OR=1.53 (95% CI: 1.22, 1.92)] and dermal contact [OR=1.47 (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

Background:

Early-life exposure to estrogenic compounds affects the development of the reproductive system in rodent models and humans. Soy products, which contain phytoestrogens such as genistein, are one source of exposure in infants fed soy formula, and they result in high serum concentrations.

Objectives:

Our goal was to determine whether soy exposure is associated with differential DNA methylation in vaginal cells from soy-fed infant girls.

Methods:

Using the Illumina HumanMethylation450 BeadChip, we evaluated epigenome-wide DNA methylation in vaginal cells from four soy formula–fed and six cow formula–fed girls from the Infant Feeding and Early Development (IFED) study. Using pyrosequencing we followed up the two most differentially methylated sites in 214 vaginal cell samples serially collected between birth and 9 months of age from 50 girls (28 soy formula–fed and 22 cow formula–fed). With a mouse model, we examined the effect of neonatal exposure to genistein on gene specific mRNA levels in vaginal tissue.

Results:

The epigenome-wide scan suggested differences in methylation between soy formula–fed and cow formula–fed infants at three CpGs in the gene proline rich 5 like (PRR5L) (p < 10). Pyrosequencing of the two feeding groups found that methylation levels progressively diverged with age, with pointwise differences becoming statistically significant after 126 days. Genistein-exposed mice showed a 50% decrease in vaginal Prr5l mRNA levels compared to controls.

Conclusions:

Girls fed soy formula have altered DNA methylation in vaginal cell DNA which may be associated with decreased expression of an estrogen-responsive gene.

Citation:

Harlid S, Adgent M, Jefferson WN, Panduri V, Umbach DM, Xu Z, Stallings VA, Williams CJ, Rogan WJ, Taylor JA. 2017. Soy formula and epigenetic modifications: analysis of vaginal epithelial cells from infant girls in the IFED study. Environ Health Perspect 125:447–452; http://dx.doi.org/10.1289/EHP428

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