Lifetime Days Of Use Research Articles

Abstract 4220: Occupational pesticide use and relative leukocyte telomere length in the biomarkers of exposure and effect in agriculture study

Abstract Background: Previous epidemiologic studies have reported increased risks of certain cancers in relation to specific pesticide exposures, although the mechanisms underlying many of these associations remain poorly understood. Within the Biomarkers of Exposure and Effect in Agriculture (BEEA) study, a molecular epidemiologic investigation of pesticide applicators in Iowa and North Carolina, we examined whether occupational use of pesticides is associated with alterations in leukocyte telomere length. Telomeres are essential in maintaining chromosomal stability and altered telomere length has been linked to various malignancies. Methods: Relative telomere length (RTL) was measured using quantitative PCR in leukocytes from 1,539 male pesticide applicators ≥50 years of age. Using self-reported information on pesticide use, we characterized lifetime use of specific pesticides in terms of ever use and intensity-weighted lifetime days (IWLDs), a metric integrating total lifetime days of use and other factors influencing exposure. Multivariable linear regression models were used to estimate differences in geometric mean RTL (and corresponding 95% confidence intervals) by ever vs. never use of 48 pesticides and in exposure-response analyses for IWLDs of use of 46 pesticides, adjusting for age, state of residence, race/ethnicity, body mass index, and cigarette smoking status and pack-years. Results: Among ever users of the insecticides lindane and aldicarb, mean RTL was significantly longer compared to never users (p=0.01 and 0.03, respectively); in exposure-response analyses, we also observed a suggestive but non-statistically significant trend between increasing IWLDs of lindane use and longer RTL (p-trend=0.07). Higher IWLDs of use of the insecticide diazinon was also associated with longer RTL (p-trend=0.03) while increasing IWLDs of the insecticide heptachlor and the herbicide 2,4,5-TP were associated with shorter RTL (p-trends=0.04 and 0.03, respectively). Conclusions: This is, to our knowledge, the largest investigation of occupational pesticide use and RTL to date. Our findings provide novel evidence suggesting that use of certain pesticides could be associated with altered leukocyte telomere length. Notably, diazinon and lindane have previously been associated with increased risks of lung and lymphoid malignancies, respectively, and longer leukocyte telomere length has been implicated in the development of these cancers. Citation Format: Patricia A. Erickson, Vicky C. Chang, Casey L. Dagnall, Kedest Teshome, Mitchell J. Machiela, Kathryn H. Barry, Shahinaz M. Gadalla, Laura E. Beane Freeman, Gabriella Andreotti, Jonathan N. Hofmann. Occupational pesticide use and relative leukocyte telomere length in the biomarkers of exposure and effect in agriculture study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4220.

Epigenome-Wide DNA Methylation and Pesticide Use in the Agricultural Lung Health Study.

Background:Pesticide exposure is associated with many long-term health outcomes; the potential underlying mechanisms are not well established for most associations. Epigenetic modifications, such as DNA methylation, may contribute. Individual pesticides may be associated with specific DNA methylation patterns but no epigenome-wide association study (EWAS) has evaluated methylation in relation to individual pesticides.Objectives:We conducted an EWAS of DNA methylation in relation to several pesticide active ingredients.Methods:The Agricultural Lung Health Study is a case–control study of asthma, nested within the Agricultural Health Study. We analyzed blood DNA methylation measured using Illumina’s EPIC array in 1,170 male farmers of European ancestry. For pesticides still on the market at blood collection (2009–2013), we evaluated nine active ingredients for which at least 30 participants reported past and current (within the last 12 months) use, as well as seven banned organochlorines with at least 30 participants reporting past use. We used robust linear regression to compare methylation at individual C-phosphate-G sites (CpGs) among users of a specific pesticide to never users.Results:Using family-wise error rate () or false-discovery rate (), we identified 162 differentially methylated CpGs across 8 of 9 currently marketed active ingredients (acetochlor, atrazine, dicamba, glyphosate, malathion, metolachlor, mesotrione, and picloram) and one banned organochlorine (heptachlor). Differentially methylated CpGs were unique to each active ingredient, and a dose–response relationship with lifetime days of use was observed for most. Significant CpGs were enriched for transcription motifs and 28% of CpGs were associated with whole blood cis-gene expression, supporting functional effects of findings. We corroborated a previously reported association between dichlorodiphenyltrichloroethane (banned in the United States in 1972) and epigenetic age acceleration.Discussion:We identified differential methylation for several active ingredients in male farmers of European ancestry. These may serve as biomarkers of chronic exposure and could inform mechanisms of long-term health outcomes from pesticide exposure. https://doi.org/10.1289/EHP8928

Lifetime Pesticide Use and Monoclonal Gammopathy of Undetermined Significance in a Prospective Cohort of Male Farmers.

Background:Farmers have a higher incidence of multiple myeloma, and there is suggestive evidence of an elevated prevalence of its precursor, monoclonal gammopathy of undetermined significance (MGUS), relative to the general population. Pesticide exposures are suspected to play a role; however, the biologic plausibility for associations with multiple myeloma remains unclear.Objectives:Our objectives were to examine the prevalence of MGUS and evaluate associations with a wide range of pesticides in a large sample of farmers.Methods:We obtained sera and assessed MGUS among 1,638 male farmers of age in the Agricultural Health Study (AHS), a prospective cohort in Iowa and North Carolina. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed to estimate associations with MGUS for recent use (within the 12 months before phlebotomy) and cumulative intensity-weighted lifetime days of use of specific pesticides.Results:The age-standardized MGUS prevalence was significantly elevated among AHS farmers (7.7%) compared with demographically similar men in the National Health and Nutrition Examination Survey (2.8%) or Olmsted County, Minnesota (3.8%; ). Recent use of permethrin was associated with MGUS [recent use vs. no recent use, (95% CI: 1.06, 3.13)], especially among those who had also used it in the past [recent and past use vs. never use, (95% CI: 1.32, 4.69)]. High intensity-weighted lifetime use of the organochlorine insecticides aldrin and dieldrin was associated with MGUS relative to those who never used either of these pesticides [ (95% CI: 1.29, 4.54); ]. We also observed a positive association with high lifetime use of petroleum oil/distillates as an herbicide, as well as an inverse association with fonofos use.Discussion:This is the largest investigation of MGUS in farmers and the first to identify an association with MGUS for permethrin, a pyrethroid insecticide previously associated with multiple myeloma. Given the continued widespread use of permethrin in various residential and commercial settings, our findings may have important implications for exposed individuals in the general population. https://doi.org/10.1289/EHP6960

Occupational pesticide use and self-reported olfactory impairment in United States farmers

Background: Pesticide exposure may impair human olfaction through direct damage to peripheral olfactory structures, or through neurotoxic effects on the central nervous system, but empirical evidence is largely lacking. Objective: We examined associations between occupational use of specific pesticides and olfactory impairment among 20,409 pesticide applicators (mostly farmers) in the Agricultural Health Study, an ongoing prospective study in Iowa and North Carolina. Methods: Participants provided information on ever-use and lifetime days of use of 50 specific pesticides at enrollment (1993-1997) and on self-reported olfactory impairment two decades later (2013-2016). We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations, adjusting for age, sex, state of residence, education, smoking, whether involved in other activities (repairing engines, working in swine confinement areas, handling stored grain, welding, and painting), and correlated pesticides. Results: About 10% of participants reported olfactory impairment. The overall cumulative days of any pesticide use at enrollment was associated with a higher odds of reporting poor sense of smell twenty years later [OR (highest vs. lowest quartile): 1.17 (95% CI:1.02-1.34), p-trend=0.003]. In the analyses of 50 specific pesticides, ever-use of 20 pesticides showed modest associations with olfactory impairment, with ORs ranging from 1.11 to 1.33. Of these, higher lifetime days of use of 12 pesticides were associated with higher odds of olfactory impairment as compared to never use (p-trend ≤ 0.05), including five insecticides DDT, lindane (organochlorines), diazinon, malathion (organophosphates), permethrin (pyrethroid), one fungicide captan, and six herbicides (glyphosate, paraquat, petroleum distillates, 2,4-D, 2,4,5-T, and metribuzin). Conclusion: Occupational use of certain pesticides may be associated with olfactory impairment. Our findings of associations with multiple pesticides across several chemical classes may indicate that pesticides could affect olfaction through multiple pathways. Future epidemiological studies with objective measurement of olfaction are required to confirm these findings.

Use of specific pesticides is associated with increased risk of developing shingles in the Agricultural Health Study

BACKGROUND: Some pesticides are immunotoxic and may increase risk of immune-mediated diseases. Risk of shingles, the clinical reactivation of varicella zoster virus (VZV), increases with aging and immunosuppression; little is known about associations with pesticides. OBJECTIVE: We evaluated pesticide use in relation to incident shingles among licensed pesticide applicators in the Agricultural Health Study, a prospective cohort in Iowa and North Carolina. METHODS: We identified 590 incident shingles cases among 12,820 applicators (97% male farmers) enrolled in 1993-7 and followed for a median of 12 years (IQR 11,13). We evaluated associations with ever-use of 48 pesticides reported at enrollment and examined exposure-response trends for cumulative intensity-weighted lifetime days of use. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazard models, adjusting for state and correlated pesticides, and allowing estimates to vary by median age of cases (60 years). RESULTS: Shingles risk was associated with ever-use of 14 pesticides (5 insecticides, 2 fumigants, 2 fungicides, and 5 herbicides (HRs 1.22 to 1.94). Increasing exposure-response trends (p<0.01) were seen for four insecticides (coumaphos, carbaryl, diazinon, permethrin on crops), two fumigants (methyl bromide, carbon tetrachloride), and two herbicides (trifluralin, and 2,4-D). In older participants, shingles was associated with self-reported history of a high pesticide exposure event (HR 1.89; 95%CI 1.45, 2.45). Findings were similar after excluding those with a history of leukemia/lymphoma or autoimmune diseases. CONCLUSIONS: Specific pesticides were related to shingles risk in farmers, with several demonstrating exposure-response trends. These novel findings support further investigation of pesticides in relation to shingles risk and VZV immunity. Some pesticides may compromise cell-mediated immune responses to VZV, as seen with aging and immunosuppressant medications, which may have broader implications for vaccine efficacy and susceptibility to other infections.

Epigenome-wide Association Study of DNA Methylation and Specific Pesticide Use Among U.S. Farmers

Background: Pesticide exposure is associated with certain cancers and neurologic diseases, but the underlying mechanisms are not fully understood. DNA methylation, an epigenetic modification, may play a role. DNA methylation patterns likely differ by specific pesticide, but no epigenome-wide association studies have evaluated methylation patterns across different pesticides. We conducted epigenome-wide analyses of DNA methylation in relation to several pesticides used among U.S. farmers.Methods: The Agricultural Lung Health Study (ALHS) is a case-control study of asthma, nested within the Agricultural Health Study (AHS). For 1,170 ALHS male farmers, blood DNA methylation was measured with Illumina’s MethylationEPIC array. Participants self-reported pesticide use in the AHS (past use) and ALHS (current use, defined as past 12 months). Pesticides were grouped by chemical class and active ingredients. Using robust linear regression, we analyzed 13 chemical classes and 16 active ingredients with 30+ exposed men. Analyses were adjusted for age, smoking status, packyears, state, asthma status, and estimated cell type proportions.Results: Participants who reported past and current use of pesticide class or active ingredient were compared to those who never reported use. Using family-wise error rate (p<9×10-8) or false discovery rate (p<0.05), we identified differentially methylated C-phosphate-G (CpG) sites for 10 chemical classes and 9 active ingredients. Most differentially methylated CpG sites were unique to each active ingredient. For 5 of the 9 active ingredients, lifetime days of use was available and there was evidence of a dose-response at most differentially methylated CpG sites. Significant CpG sites were enriched for transcription factor motifs. We plan to correlate significant CpG sites with gene expression in external data.Conclusions: We observed differential methylation associated with several chemical classes and active ingredients. These differential methylation patterns could be biomarkers of long-term exposure and may provide additional biological insight into health effects of pesticide exposure.

Occupational pesticide use and self-reported olfactory impairment in US farmers

ObjectivesPesticide exposure may impair human olfaction, but empirical evidence is limited. We examined associations between occupational use of 50 specific pesticides and olfactory impairment, both self-reported, among 20 409 participants...

Pesticide exposure and risk of rheumatoid arthritis among licensed male pesticide applicators in the Agricultural Health Study

Background: Studies suggest an association between farming and risk of rheumatoid arthritis (RA). However, the role of pesticides remains unclear. Objectives: We investigated associations of RA with specific pesticides among male pesticide applicators in the Agricultural Health Study. Methods: Of 30,316 participants enrolled in 1993-97 who completed at least one follow-up questionnaire through 2014, 358 (220 incident) cases of RA were confirmed by physician or reported use of disease modifying anti-rheumatic drugs. We evaluated associations between ever and lifetime days of use for 47 specific pesticides and RA, comparing cases and non-cases (n=27,744) who did not self-report RA. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression, adjusting for age at enrollment, state, smoking pack-years, and education. Results: Incident RA was associated with chlorimuron ethyl (OR: 1.45; 95%CI: 1.01-2.07), fonofos (OR: 1.70; 95%CI: 1.22-2.37), and carbaryl (OR: 1.51; 95%CI: 1.03-2.23), while total RA was also associated with terbufos (OR: 1.27; 95%CI: 1.01-1.60), DDT (OR: 1.38; 95%CI: 1.01-1.89), any organophosphates (OR: 1.51; 95%CI: 1.02-2.23) or organothiophosphates (OR: 1.33; 95%CI: 1.00-1.75). Significant exposure-response trends were observed for incident RA across quartiles of lifetime days used atrazine, fonofos, carbaryl, and toxaphene. For RA cases overall, exposure-response relationships were also confirmed for terbufos, alachlor, glyphosate and DDT. Conclusions: Our results provide evidence of association between exposure to specific pesticides and increased risk of RA among men.

Occupational Exposure to Pesticides and the Incidence of Lung Cancer in the Agricultural Health Study.

Background:Occupational pesticide use is associated with lung cancer in some, but not all, epidemiologic studies. In the Agricultural Health Study (AHS), we previously reported positive associations between several pesticides and lung cancer incidence.Objective:We evaluated use of 43 pesticides and 654 lung cancer cases after 10 years of additional follow-up in the AHS, a prospective cohort study comprising 57,310 pesticide applicators from Iowa and North Carolina.Methods:Information about lifetime pesticide use and other factors was ascertained at enrollment (1993–1997) and updated with a follow-up questionnaire (1999–2005). Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for smoking (smoking status and pack-years), sex, and lifetime days of use of any pesticides.Results:Hazard ratios were elevated in the highest exposure category of lifetime days of use for pendimethalin (1.50; 95% CI: 0.98, 2.31), dieldrin (1.93; 95% CI: 0.70, 5.30), and chlorimuron ethyl (1.74; 95% CI: 1.02, 2.96), although monotonic exposure–response gradients were not evident. The HRs for intensity-weighted lifetime days of use of these pesticides were similar. For parathion, the trend was statistically significant for intensity-weighted lifetime days (p = 0.049) and borderline for lifetime days (p = 0.073). None of the remaining pesticides evaluated was associated with lung cancer incidence.Conclusions:These analyses provide additional evidence for an association between pendimethalin, dieldrin, and parathion use and lung cancer risk. We found an association between chlorimuron ethyl, a herbicide introduced in 1986, and lung cancer that has not been previously reported. Continued follow-up is warranted.Citation:Bonner MR, Beane Freeman LE, Hoppin JA, Koutros S, Sandler DP, Lynch CF, Hines CJ, Thomas K, Blair A, Alavanja MCR. 2017. Occupational exposure to pesticides and the incidence of lung cancer in the Agricultural Health Study. Environ Health Perspect 125:544–551; http://dx.doi.org/10.1289/EHP456

An Evaluation Of Glyphosate Use And The Risks Of Non-Hodgkin Lymphoma Major Histological Sub-Types In The North American Pooled Project (Napp)

Objectives: Glyphosate is a commonly used herbicide worldwide. Some epidemiological studies have linked exposure with the development of non-Hodgkin lymphoma (NHL), a group of cancers with distinct risk factors and etiologies. This study aimed to evaluate possible associations between glyphosate exposure and NHL risk. Methods: The NAPP, composed of pooled case-control studies from the US and Canada, includes NHL cases (N=1690) and controls (N=5131) who provided information on pesticide use. Cases (follicular lymphoma [FL], diffuse large B-cell lymphoma [DLBCL], small lymphocytic lymphoma [SLL], other) from cancer registries and hospitals were frequency-matched to population-based controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) by ever/never, duration, frequency, and lifetime days of glyphosate use. Models were adjusted for age, sex, location, proxy respondent, family history of lymphatohematopoietic cancer, and personal protective equipment. Results: Cases who ever used glyphosate had elevated NHL risk overall (OR=1.51, 95% CI: 1.18, 1.95). The highest risks were found for “other” sub-types (OR=1.91, 95% CI: 1.20, 3.04). Subjects who used glyphosate for =5 years had increased SLL risk (OR=2.58, 95% CI: 1.03, 6.48). Compared to non-handlers, those who handled glyphosate for =2 days/year had significantly elevated odds of NHL overall (OR=2.66, 95% CI: 1.61, 4.40) and FL (OR=2.36, 95% CI: 1.06, 5.29), DLBCL (OR=3.11, 95% CI: 1.61, 6.00), and other (OR=2.99, 95% CI: 1.10, 8.09) sub-types. There were suggestive increases in NHL risk overall with more lifetime days of use but this trend was not statistically significant (p=0.065). Conclusion: This study provides some evidence that glyphosate use may be associated with increased NHL risk. Effects may differ by histological sub-type. The large sample size of the NAPP enabled a detailed investigation despite some inconsistent results across different exposure metrics.

394 2,4-D Use and Cancer Incidence in Pesticide Applicators in the Agricultural Health Study

Objectives2,4-dichlorophenoxyacetic acid (2,4-D) is one of the most widely used herbicides in the world. It has been associated with increased risk of non-Hodgkin lymphoma (NHL) in multiple epidemiologic studies, with...

Genetic variation in nucleotide excision repair pathway genes, pesticide exposure and prostate cancer risk

Previous research demonstrates increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, human biomonitoring studies indicate increased genetic damage (e.g. chromosomal aberrations) with pesticide exposure. Given that the nucleotide excision repair (NER) pathway repairs a broad range of DNA damage, we evaluated interactions between pesticide exposure and 324 single-nucleotide polymorphisms (SNPs) tagging 27 NER genes among 776 prostate cancer cases and 1444 male controls in a nested case-control study of white Agricultural Health Study pesticide applicators. We determined interaction P values using likelihood ratio tests from logistic regression models and three-level pesticide variables (none/low/high) based on lifetime days of use weighted to an intensity score. We adjusted for multiple comparisons using the false discovery rate (FDR) method. Of the 17 interactions that met FDR <0.2, 3 displayed a monotonic increase in prostate cancer risk with increasing exposure in one genotype group and no significant association in the other group. Men carrying the variant A allele at ERCC1 rs2298881 exhibited increased prostate cancer risk with high versus no fonofos use [odds ratio (OR) 2.98; 95% confidence interval (CI) 1.65-5.39; P(interact) = 3.6 × 10(-4); FDR-adjusted P = 0.11]. Men carrying the homozygous wild-type TT genotype at two correlated CDK7 SNPs, rs11744596 and rs2932778 (r(2) = 1.0), exhibited increased risk with high versus no carbofuran use (OR 2.01; 95% CI 1.31-3.10 for rs11744596; P(interact) = 7.2 × 10(-4); FDR-adjusted P = 0.09). In contrast, we did not observe associations among men with other genotypes at these loci. While requiring replication, our findings suggest a role for NER genetic variation in pesticide-associated prostate cancer risk.

Abstract B51: Genetic variation in nucleotide excision repair pathway genes, pesticide exposure, and prostate cancer risk

Abstract Introduction: Previous research has demonstrated increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, human biomonitoring studies indicate increased genetic damage with pesticide exposure. Given that the nucleotide excision repair (NER) pathway repairs a broad range of DNA damage, we evaluated interactions between pesticide use and 324 single nucleotide polymorphisms (SNPs) tagging 27 NER genes among 776 prostate cancer cases and 1,444 male controls in a nested case-control study of white pesticide applicators in the Agricultural Health Study, a prospective cohort of pesticide applicators in Iowa and North Carolina. Methods: We used likelihood ratio tests from logistic regression models to determine P-values for interactions between three-level pesticide variables (none/low/high) based on lifetime days of use weighted to an intensity score and SNPs (assuming a dominant model). We employed the False Discovery Rate (FDR) method to adjust for multiple comparisons. Results: Of the seventeen interactions that met FDR&amp;lt;0.2, three also displayed a monotonic increase in prostate cancer risk with increasing pesticide use in one genotype group and no significant association in the other group. Men carrying the variant A allele at ERCC1 rs2298881 exhibited increased prostate cancer risk with high versus no fonofos use (Odds Ratio (OR): 2.98; 95% Confidence Interval (CI): 1.65–5.39; Pinteract=3.6×10–4; FDR-adjusted P=0.11). Men carrying the homozygous wild-type TT genotype at two correlated CDK7 SNPs, rs11744596 and rs2932778 (r2=1.0), exhibited increased prostate cancer risk with high versus no carbofuran use (OR: 2.01; 95% CI: 1.31–3.10 for rs11744596; Pinteract=7.2×10–4; FDR-adjusted P=0.09). In contrast, we did not observe associations with prostate cancer among men with other genotypes at these loci. Conclusions: While requiring replication, our findings suggest a role for NER genetic variation in pesticide-associated prostate cancer risk. Citation Information: Cancer Prev Res 2011;4(10 Suppl):B51.

Atrazine and cancer incidence among pesticide applicators in the Agricultural Health Study (1994–2007)

ObjectivesAtrazine is a triazine herbicide with endocrine-disrupting properties and is used widely in the United States. Atrazine causes mammary tumours in rats, but the mechanism does not appear to operate...

Neurobehavioral function and organophosphate insecticide use among pesticide applicators in the Agricultural Health Study

Although persistent decrements in cognitive function have been observed among persons who have recovered from clinically overt organophosphate (OP) pesticide poisoning, little is known about the cognitive effects of chronic OP exposures that do not result in acute poisoning. To examine associations between long-term pesticide use and neurobehavioral (NB) function, NB tests were administered to licensed pesticide applicators enrolled in the Agricultural Health Study (AHS) in Iowa and North Carolina. Between 2006 and 2008, 701 male participants completed nine NB tests to assess memory, motor speed and coordination, sustained attention, verbal learning and visual scanning and processing. Data on ever-use and lifetime days of use of 16 OP pesticides were obtained from AHS interviews conducted before testing between 1993 and 2007 and during the NB visit. The mean age of participants was 61years (SD=12). Associations between pesticide use and NB test performance were estimated with linear regression controlling for age and outcome-specific covariates. NB test performance was associated with lifetime days of use of some pesticides. Ethoprop was significantly associated with reduced performance on a test of motor speed and visual scanning. Malathion was significantly associated with poor performance on a test of visual scanning and processing. Conversely, we observed significantly better test performance for five OP pesticides. Specifically, chlorpyrifos, coumaphos, parathion, phorate, and tetrachlorvinphos were associated with better verbal learning and memory; coumaphos was associated with better performance on a test of motor speed and visual scanning; and parathion was associated with better performance on a test of sustained attention. Several associations varied by state. Overall, we found no consistent evidence of an association between OP pesticide use and adverse NB test performance among this older sample of pesticide applicators. Potential reasons for these mostly null results include a true absence of effect as well as possible selective participation by healthier applicators.

Suicide and Pesticide Use among Pesticide Applicators and Their Spouses in the Agricultural Health Study

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.

Hearing loss among licensed pesticide applicators in the agricultural health study.

We evaluated self-reported hearing loss and pesticide exposure in licensed private pesticide applicators enrolled in the Agricultural Health Study in 1993 to 1997 in Iowa and North Carolina. Among 14,229 white male applicators in 1999 to 2003, 4926 reported hearing loss (35%). Logistic regression was performed with adjustment for state, age, and noise, solvents, and metals. We classified pesticides by lifetime days of use. Compared with no exposure, the odds ratio (95% confidence interval) for the highest quartile of exposure was 1.19 (1.04 to 1.35) for insecticides and 1.17 (1.03 to 1.31) for organophosphate insecticides. Odds of hearing loss were elevated for high pesticide exposure events (1.38, 1.25 to 1.54), pesticide-related doctor visits (1.38, 1.17 to 1.62) or hospitalization (1.81, 1.25 to 2.62), and diagnosed pesticide poisoning (1.75, 1.36 to 2.26). Although control for exposure to noise or other neurotoxicants was limited, this study extends previous reports suggesting that organophosphate exposure increases risk of hearing loss.

Incident Diabetes and Pesticide Exposure among Licensed Pesticide Applicators: Agricultural Health Study, 1993-2003

Exposure to certain environmental toxicants may be associated with increased risk of developing diabetes. The authors' aim was to investigate the relation between lifetime exposure to specific agricultural pesticides and diabetes incidence among pesticide applicators. The study included 33,457 licensed applicators, predominantly non-Hispanic White males, enrolled in the Agricultural Health Study. Incident diabetes was self-reported in a 5-year follow-up interview (1999-2003), giving 1,176 diabetics and 30,611 nondiabetics for analysis. Lifetime exposure to pesticides and covariate information were reported by participants at enrollment (1993-1997). Using logistic regression, the authors considered two primary measures of pesticide exposure: ever use and cumulative lifetime days of use. They found seven specific pesticides (aldrin, chlordane, heptachlor, dichlorvos, trichlorfon, alachlor, and cyanazine) for which the odds of diabetes incidence increased with both ever use and cumulative days of use. Applicators who had used the organochlorine insecticides aldrin, chlordane, and heptachlor more than 100 lifetime days had 51%, 63%, and 94% increased odds of diabetes, respectively. The observed association of organochlorine and organophosphate insecticides with diabetes is consistent with results from previous human and animal studies. Long-term exposure from handling certain pesticides, in particular, organochlorine and organophosphate insecticides, may be associated with increased risk of diabetes.

More Concerns for Farmers: Neurologic Effects of Chronic Pesticide Exposure

Although there is considerable evidence that pesticides are neurotoxic, most research has focused on the short- and long-term consequences of acute high-level exposure such as that seen during industrial accidents or food contamination. To date, little has been known about the effects of chronic moderate exposure such as that experienced by farmers and other workers who regularly use agricultural pesticides. Now, a recent analysis of data collected in the Agricultural Health Study (AHS) links chronic moderate pesticide exposure to neurologic symptoms affecting both the central and peripheral nervous systems [EHP 113:877–882]. According to the research team, increases in such symptoms may be an early indicator of impaired neurological function. The AHS, an ongoing study sponsored by the NIEHS, the National Cancer Institute, and the U.S. Environmental Protection Agency, furnished a rich data source for the researchers to investigate possible links. Between 1993 and 1997, approximately 20,000 private pesticide applicators (primarily farmers) in Iowa and North Carolina enrolled in the AHS and completed two questionnaires on demographic characteristics, lifestyle, medical history (including neurologic symptoms), and pesticide use. The current analysis focused on 18,782 of these individuals, white men aged 18–75 years who provided complete symptom information. The 23 symptoms in the analysis included headache, dizziness, depression, limb weakness, poor balance, difficulty concentrating, and vision difficulties. In addition to the symptom information, participants detailed how long and how frequently they used any of 50 pesticides, including insecticides, herbicides, fungicides, and fumigants. They also indicated whether they had ever experienced pesticide poisoning or high-exposure incidents such as accidental skin contact with a large amount of pesticide. To define cumulative exposure, the researchers calculated lifetime days of use from the number of years and the number of days per year that the applicators had used each pesticide. The team considered two measures of symptoms: the absolute number and the presence of 10 or more. To control for confounding by pesticide poisoning or high-exposure incidents, the researchers conducted analyses with and without those data from affected individuals. They also considered potential effects from pesticide use within the past year. For pesticides overall, applicators with the most (more than 500) cumulative lifetime days of pesticide use reported more symptoms than those with the fewest lifetime days of use. The relationship between cumulative exposure and symptoms was strongest with insecticides; applicants with the most lifetime days of use were 2.5 times more likely to have 10 or more symptoms as applicators who had never used insecticides. Within the insecticide category, relationships with symptoms were strongest for organophosphates and organochlorines. Neither recent use nor a history of poisoning or high-exposure incident affected the results. The results of this study extend previous research demonstrating a link between chronic moderate pesticide exposure and a range of cognitive, sensory, and motor symptoms. The AHS is unusually robust due to its large size and its wealth of detailed exposure information. The results of this analysis provide substantial evidence that neurologic symptoms may be increased by even moderate insecticide exposure, and that cumulative exposure may be as important as recent exposure, although more work is needed to understand the pathology underlying the reported symptoms.

Cancer incidence among glyphosate-exposed pesticide applicators in the Agricultural Health Study.

Glyphosate is a broad-spectrum herbicide that is one of the most frequently applied pesticides in the world. Although there has been little consistent evidence of genotoxicity or carcinogenicity from in vitro and animal studies, a few epidemiologic reports have indicated potential health effects of glyphosate. We evaluated associations between glyphosate exposure and cancer incidence in the Agricultural Health Study (AHS), a prospective cohort study of 57,311 licensed pesticide applicators in Iowa and North Carolina. Detailed information on pesticide use and other factors was obtained from a self-administered questionnaire completed at time of enrollment (1993–1997). Among private and commercial applicators, 75.5% reported having ever used glyphosate, of which > 97% were men. In this analysis, glyphosate exposure was defined as a) ever personally mixed or applied products containing glyphosate; b) cumulative lifetime days of use, or “cumulative exposure days” (years of use × days/year); and c) intensity-weighted cumulative exposure days (years of use × days/year × estimated intensity level). Poisson regression was used to estimate exposure–response relations between glyphosate and incidence of all cancers combined and 12 relatively common cancer subtypes. Glyphosate exposure was not associated with cancer incidence overall or with most of the cancer subtypes we studied. There was a suggested association with multiple myeloma incidence that should be followed up as more cases occur in the AHS. Given the widespread use of glyphosate, future analyses of the AHS will allow further examination of long-term health effects, including less common cancers.